Volume I
Neurology in Clinical Practice Principles of Diagnosis and Management Fourth EditionEdited by
Walter G. Bradley, D . M . , F.R.C.P Professor and Chairman, Department of Neurology, University of Miami School of Medicine; Chief Neurology Service, University of Miami-Jackson Memorial Medical Center, Miami, Florida Robert B. Daroff, M . D , Chief of Staff and Senior Vice President for Academic Affairs, University Hospitals of Cleveland; Professor of Neurology and Associate Dean, Case Western University School of Medicine, Cleveland, Ohio Gerald M. Fenichel, M . D . Professor of Neurology and Pediatrics, Vanderbilt University School of Medicine; Director, Division of Pediatric Neurology; Neurologist-in-Chief, Vanderbilt Children's Hospital, Nashville, Tennessee Joseph Jankovic, M . D . Professor of Neurology; Director, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas
With 120 contributing authors
s l U T T E R W O R T H E I N E M A N N An
Imprint of Elsevier
U T T E R W O R T H E [ N E M A M N
An Imprint of Elsevier 625 Walnut Street Philadelphia, PA 19106 NEUROLOGY IN CLINICAL PRACTICE
9997625889
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Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1
Neurology in Clinical Practice
Neurology in Clinical Practice
Contents Contributing Authors
xi
Preface to the Fourth Edition
xxiii
Volume I Principles of Diagnosis and Management Part I. Approach to Common Neurological Problems 1
I
Diagnosis of Neurological Disease Walter G. Bradley, Robert B. Daroff, Gerald M. Fenichel, and Joseph Jankovic
2
Episodic Impairment of Consciousness
3
Falls and Drop Attacks
4
Delirium
5
Clinical Approach to Stupor and Coma
6
Approaches to Intellectual and Memory Impairments
7
Global Developmental Delay and Developmental Regression
8
Behavior and Personality Disturbances
9
Depression and Psychosis in Neurological Practice
10
Joseph Bruni
3 11
Bernd F. Remler and Robert B. Daroff
23
Mario F. Mendez and David N. Gershfield
29
Joseph R. Berger
43
Howard S. Kirshner
65
David J. Michelson and Stephen Ashwal
Jane S. Paulsen and Carissa Neb!
75 85
John A. Bertelson and Bruce H, Price
103
Intentional Motor Disorders and the Apraxias Kenneth M. tieilman, Edward Valenstem, Leslie J. Gonzalez Rothi, and Robert T. Watson
11
The Agnosias
12
Language and Speech Disorders A. Aphasia Howard S. Kirshner B,
Todd E. Feinberg and Martha J. Farah
117 131
141
Dysarthria and Apraxia of Speech
Howard S. Kirshner
161
13
Neurogenic Dysphagia
Ronald F. Pfeiffer
165
14
Vision Loss
15
Abnormalities of the Optic Nerve and Retina
16
Eye Movement Disorders: Diplopia, Nystagmus, and Other Ocular Oscillations
17
Pupillary and Eyelid Abnormalities
18
Dizziness and Vertigo
19
Hearing Loss and Tinnitus without Dizziness or Vertigo
20
Disturbances of Taste and Smell
21
Cranial and Facial Pain
Robert L. Tomsak
177 Roy W, Beck and Laura J. Balcer
I85 Patrick J. M. Lavin
Terry A. Cox and Robert B. Daroff
B. Todd Troost
195 223 233
B. Todd Troost and Lisa C. Arguelio
Pasquale F. Finelti and Robert G. Mair
/. D. Bartleson, David F. Black, and Jerry W. Swanson
247 257 265
vi
CONTENTS
22
Brainstem Syndromes
Michael Wall
273
23
Ataxic Disorders
24
Movement Disorders: Diagnosis and Assessment
25
Gait Disorders
26
Hemiplegia and Monoplegia
27
Paraplegia and Spinal Cord Syndromes
28
Proximal, Distal, and Generalized Weakness
S. hi. Subramony
287 Joseph jankofic and Anthony E. Lang
Philip D. Thompson
323
Karl E. Misulis
337
Thomas N. Byrne and Stephen G. Waxman
David C. Preston, Barbara E. Shapiro, and Michael H. Brooke 29
Muscle Pain and Cramps
30
The Floppy Infant
31
Sensory Abnormalities of the Limbs, Trunk, and Face
32
Neurological Causes of Bladder, Bowel, and Sexual Dysfunction
33
Arm and Neck Pain
34
Lower Back and Lower Limb Pain
Waqar Waheed and Alan Pestronk
36
Thomas O. Crawford
367
393 Karl E. Misulis Clare J. Fowler
Michael Ronthal
407 419 433
Karl E. Misulis
445
Laboratory Investigations in Diagnosis and Management of Neurological Disease Walter G. Bradley, Robert B, Daroff, Gerald M. Fenichel, and Joseph Jankovic
457
459
Clinical Neurophysiology A. B.
37
351
387
Part H. Neurological Investigations and Related Clinical Neurosciences 35
293
Electroencephalography and Evoked Potentials Clinical Electromyography Bashar Katirji
Ronald G. Emerson and Timothy A. Pedley
465 491
Neuroimaging A.
Structural Neuroimaging Evelyn M. L. Sklar, Armando Ruiz, Robert M. Quencer, and Steven F. Falcone B. Computed Tomographic and Magnetic Resonance Vascular Imaging Brian C. Bowen, Gaurav Saigal, and Armando Ruiz C. Neuroangiographic Anatomy and Common Cerebrovascular Diseases johnny S. Sandbu and Ajay K. Wakbloo D. Ultrasound Imaging of the Cerebral Vasculature Viken L. Babikian and Charles H. Tegeler E. Functional Neuroimaging Darin D. Dougherty, Alan J. Fischman, and Scott L. Rauch Jane S. Paulsen and Karin Ferneybougb Moth
521 599 625 645 667
38
Neuropsychology
675
39
Neuro-Ophthalmology: Ocular Motor System
Patrick J. M. Lavin and Sean P. Donahue
701
40
Neuro-Ophthalmology: Afferent Visual System
Robert L. Tomsak
727
41
Neuro-Otology
42
Nenrourology
B. Todd Troost and Lisa C. Arguello
739
Clare J, Fowler and Ranan DasGupta
749
CONTENTS 43
Neiiroepidemiology
Mitchell T. Wallin and John F. Kurtzke
44
Clinical Neurogenetics
45
Neuroimmunology
46
Neuro
47
Neuroendocrinology
48
Management of Neurological Disease
763
Thomas D. Bird and Stephen J, Tapscott
781
Tanuja Chitnis and Samia J. Khoury
virology
John
R.
vii
809
Corboy
and
Kenneth
L.
Tyler
Paul E. Cooper
831 849
Walter G. Bradley, Robert B. Daroff, Gerald M. Fenichel, and Joseph Jankovic
869
49
Principles of Neuropharmacology and Therapeutics
50
Principles of Pain Management
51
Principles
52
Principles of Neurosurgery Roberto C. Heros, Deborah O, Heros, and James M. Schumacher
963
Principles of Endovascular Surgery Ajay K. Wakhloo and Johnny S. Sandhu
993
53
54
of
Neuro
in
Michael J. McLean
877
Paul L. Moots and Padmaja Kandula
tensive
Care
Eliahu
S.
Feen,
Osama
921 O.
Zaidat,
and
Jose
I.
Suarez
Principles and Practices of Neurological Rehabilitation Bruce H. Dobkin
941
1027
Volume II The Neurological Disorders Part lil. Neurological Diseases 55
Neurological Complications of Systemic Disease A. B.
56
In Adults Michael J. Aminoff In Children Bruce O. Berg
1073 1101
Trauma of the Nervous System A. B. C. D.
57
1071
Basic Nenroscience of Neurotrauma W. Dalton Dietrich and Helen M. Bramlett Craniocerebral Trauma Donald W. Marion, Michael C. Sharts, and Elizabeth C. Tyler-Kabara Spinal Cord Trauma Paul Santiago and Richard G. Fessler Peripheral Nerve Trauma Brian Murray
1115 1127 1149 1179
Vascular Diseases of the Nervous System A. B. C.
Ischemic Cerebrovascular Disease Jose Biller and Betsy B. Love Intracerebral Hemorrhage Carlos S. Kase Intracranial Aneurysms and Subarachnoid Hemorrhage Warren R. Selman, Jeffrey L. Sunshine, Robert W. Tarr, and Robert A. Ratcheson D. Arteriovenous Malformations Warren R. Selman, Robert W. Tarr, Jeffrey L. Sunshine, and Robert A. Ratcheson E. Stroke in Children Meredith R. Golomb and Jose Biller F. Spinal Cord Vascular Disease Da fid S. Geldmacber and G. Central Nervous System Vasculitis James W. Schmidtey
58
Cancer and the Nervous System A.
Tracy T. Batchelor
Epidemiology of Primary Brain Tumors Tracy T, Batchelor, Molly V. Dorfman, and Davtd J. Hunter
1197 1251 1269
Brian
C.
Bowen
1285 1299 1313 1323 1327 1329
viii
CONTENTS
B.
Pathology and Molecular Genetics of Nervous System Tumors Ark Perry, Reid R. Heffner, Jr., and David N. Louis C. Clinical Features and Complications Pierre Giglio and Mark R. Gilbert D. Ncuroimaging John W. Hettson and R. Gilberto Gonzalez E. Management of Primary Nervous System Tumors in Adults Joachim M, Baehring and Fred H. Hochberg F. Management of Primary Nervous System Tumors in Infants and Children Alfredo D. Voloschm, Tracy T. Batcbelor, and Jeffrey C. Alien G. Nervous System Metastases David Schiff and Patrick Wen H. Paraneoplastic Disorders of the Nervous System Myrna R. Rosenfeld and Josep Dalmau 59
Infections of the Nervous System A. B. C. D. E. F. G.
60
61
62
63
64
Asbok Verma
I 34 | 1363 1371 1401 142.5 1441 146) 1473
Bacterial Infections Asbok Verma and Marylou V. Solbrig Viral Infections Roberta L. DeBiasi, Marylou V. Solbrig, and Kenneth L. Tyler Fungal Infections Madburi Bebari, Manjari Tripatbi, and Asbok Verma Parasitic Infections Madburi Bebari, Sumit Singh, and Asbok Verma Neurological Manifestations of Human Immunodeficiency Virus Infection in Adults Ashok Verma Neurological Manifestations of Human Immunodeficiency Virus Infection in Children Asbok Verma and Anita L. Belman Prion Diseases Marcin Sadowski, Asbok Verma, and Thomas Wisniewski
1475 1515 1545 1555 1581 1603 1613
Multiple Sclerosis and Other Inflammatory Demyelinating Diseases of the Central Nervous System Michael J, Olek and David M. Dawson
1631
Hypoxic/Anoxic and Ischemic Encephalopathies Bruce D. Snyder and Robert B. Daroff
1 (,65
Toxic and Metabolic Encephalopathies Alan H. hockwood
1673
Deficiency Diseases of the Nervous System Yuen T. So and Roger P. Simon
1693
Effects of Toxins and Physical Agents on the Nervous System A. Effects of Occupational Toxins on the Nervous System Micbael J. Aminoff B. Effects of Drug Abuse on the Nervous System Yuen T. So C. Neurotoxins of Animals and Plants Neil E. Schwartz and Yuen T. So D. Marine Toxins Neil E. Schwartz and Yuen T. So E. Effect of Physical Agents on the Nervous System Michael J. Aminoff
1709 17I9 1727 1735 1741
65
Brain Edema and Disorders of Cerebrospinal Fluid Circulation
1745
66
Developmental Disorders of the Nervous System
67
Developmental Disabilities
68
Inborn Errors of Metabolism of the Nervous System
69
Mitochondrial Disorders
70
Channelopathics: Episodic and Electrical Disorders of the Nervous System Robert A. Lenz and Louis J. Ptacek
1847
Neurocutaneous Syndromes
1867
71
Gary A. Rosenberg
Harvey B. Sarnat and Laura Vlores-Sarnat
Ruth Nass
1763 1791
Gregory M. Pastores and Edwin H. Kolodny
Ashok Verma and Carlos T. Moraes
Cesar C. Santos, Van S. Miller, and E. Steve Roach
1811 1833
CONTENTS
ix
72
The Dementias
Steven T. DeKosky, Daniel I. Kaufer, and Oscar L. Lopez
1901
73
The Epilepsies
William H. Trescker and Ronald P. Lesser
1953
74
Sleep and Its Disorders
75
Headache and Other Craniofacial Pain Christopher J, Boes, David j. Capobianco, F. Michael Cutrer, David W. Dodick, Eric J. Eross,
Sudhansu Chokroverty
1993
and jerry W. Swanson
2055
76
Cranial Neuropathies
Patrick j. Sweeney and Maurice R. Hanson
2107
77
Movement Disorders
Kathleen M. Shannon
2125
78
Disorders of the Cerebellum, Including the Degenerative Ataxias
79
Disorders of Bones, Joints, Ligaments, and Meninges
80
Disorders of Upper and Lower Motor Neurons
S. H. Suhramony
Richard B. Rosenhaum and David P. Ciaverelia
Brian Murray and Hiroshi Mitsumoto 81
Disorders of Nerve Roots and Plexuses
82
Disorders of Peripheral Nerves
83
Disorders of the Autonomic Nervous System
84
Disorders of Neuromuscular Transmission
85
Disorders of Skeletal Muscle
86
Neurological Problems of the Newborn
87
Neurological Problems of Pregnancy Index
1 1 f>L> 2 I 89
2223
David A. Chad
E. Peter Bosch and Benn E. Smith Christopher j. Mathias Donald B. Sanders and James F. Howard, Jr.
Anthony A. Amato and Michael H. Brooke Alan Hill
D, Malcolm Shaner
2267 2299 2403 2441 2463 2511 2531 i
Contributing Authors Jeffrey C. Allen, M.D. Chief, Division of Pediatric Neurology, Hyman-Newman Institute for Neurology and Neurosurgery, Beth Israel Medical Center, New York; Professor of Neurology, Albert Einstein College of Medicine, Bronx, New York 58F. Cancer and the Nervous System: Management of Primary Nervous System Tumors in Infants and Children Anthony A. Amato, M.D. Associate Professor of Neurology, Harvard Medical School, Boston, Massachusetts; Vice Chairman, Department of Neurology, and Chief, Neuromuscular Division, Brigham and Women's Hospital, Boston, Massachusetts 85. Disorders of Skeletal Muscle Michael J. Aminoff, M.D., D.Sc, F.R.C.P. Professor of Neurology, University of California, School of Medicine, San Francisco, California; Attending Physician, Department of Neurology, Medical Center at the University of California, San Francisco 55A. Neurological Complications of Systemic Disease: In Adults; 64A. Effects of Toxins and Physical Agents on the Nervous System: Effects of Occupational Toxins on the Nervous System; 64E. Effects of Toxins and Physical Agents on the Nervous System: Effects of Physical Agents on the Nervous System Lisa C. Argueilo, M.Ed., C.C.C.-A. Clinical Audiologist, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 19, Hearing Loss and Tinnitus without Dizziness or Vertigo; 41, Neuro-Otology Stephen Ashwal, M.D. Professor of Pediatric Neurology, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California 7. Global Developmental Delay and Developmental Regression
Laura J. Baker, M.D., M.S.C.E. Associate Professor, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 15. Abnormalities of the Optic Nerve and Retina J. D. Bartleson, M.D. Associate Professor of Neurology, Mayo Graduate School of Medicine, Rochester, Minnesota; Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota 21. Cranial and Facial Pain Tracy T. Batchelor, M.D., M.P.H. Assistant Professor of Neurology, Harvard Medical School, Boston, Massachusetts; Executive Director, Brain Tumor Center, and Director of Neuromedical Oncology, Massachusetts General Hospital, Boston 58. Cancer and the Nervous System; 58A, Cancer and the Nervous System: Epidemiology of Primary Brain Tumors; 58F. Cancer and the Nervous System: Management of Primary Nervous System Tumors in Infants and Children Roy W. Beck, M.D., Ph.D. Executive Director, Jaeb Center for Health Research, Tampa, Honda 15. Abnormalities of the Optic Nerve and Retina Madhuri Behari, M.D., D.M. Professor and Head, All India Institute of Medical Sciences, New Delhi 59C Infections of the Nervous System: Fungal Infections; 59D. Infections of the Nervous System: Parasitic Infections Anita L. Bclman, M.D. Professor of Neurology and Pediatrics, State University of New York Health Sciences Center at Stony Brook School of Medicine, New York; Attending Neurologist, University Hospital, Stony Brook, New York 59F. Infections of the Nervous System: Neurological Manifestations of Human Immunodeficiency Virus Infection in Children
Vikcn L. Babikian, M.D. Professor of Neurology, Boston University School of Medicine; Director and Co-Director, Stroke Service, Boston Medical Center, Boston, Massachusetts 37D. Neuroimaging: Ultrasound Imaging of the Cerebral Vasculature
Bruce O. Berg, M.D. Professor of Neurology and Pediatrics Emeritus, University of California Medical Center, San Francisco 55B. Neurological Complications of Systemic Disease: In Children
Joachim M. Baehring, M.D. Assistant Professor of Neurology and Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 58E. Cancer and the Nervous System: Management of Primary Nervous System Tumors in Adults
Joseph R. Berger, M.D. Chairman, Department of Neurology, University of Kentucky, Professor or Internal Medicine, Lmversitv of Kentucky Medical School, Lexington 5. Clinical Approach to Stupor and (loma
xii
CONTRIBUTING AUTHORS
John A. Bcrtetson, M.D. Instructor, Department of Psychiatry, Harvard Medical School, Boston; Ronald F, Coles Fellow, Behavioral Neurology and Neuropsychiatry, McLean Hospital, Belmont, Massachusetts 9. Depression and Psychosis in Neurological Practice Jose Biller, M.D, Professor and Chairman, Department of Neurology, Indiana University School of Medicine; Chief, Neurology Services, Department of Neurology, Indiana University Medical Center, Indianapolis 57 A. Vascular Diseases of the Nervous System: Ischemic Cerebrovascular Disease; 57E. Vascular Diseases of the Nervous System: Stroke in Children Thomas D. Bird, M.D. Professor of Neurology and Medicine, and Head, Division of Neurogenetics, University of Washington School of Medicine; Research Neurologist, Geriatrics Research Education and Clinical Center, Veterans Administration Medical Center, Seattle, Washington 44. Clinical Neurogenetics David F. Black, M.D. Instructor of Neurology, Mayo Medical School; Senior Associate Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota 21. Cranial and Facial Pain Christopher J. Boes, M.D. Assistant Ptofessor of Neurology, Mayo Medical School; Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota 75. Headache and Other Craniofacial Pain E. Peter Bosch, M.D. Professor of Neurology, Mayo Medical School, Rochester, Minnesota; Consultant in Neurology, Mayo Clinic, Scottsdale, Arizona 82. Disorders of the Peripheral Nerves Brian C. Bowen, M.D., Ph.D. Professor of Radiology, Neurology, and Neurological Surgery, and Director, Clinical MR Research, Department of Radiology, University of Miami School of Medicine, Florida .J7B. Neuroimaging: Computed Tomographic and Magnetic Resonance Vascular Imaging; 57F. Vascular Diseases of the Nervous System: Spinal Cord Vascular Disease Helen M. Bramlett, Ph.D. Assistant Professor, Department of Neurological Surgery, University of Miami School of Medicine, Miami, Florida 56A. Trauma of the Nervous System: Basic Neuroscience of Neurotrauma
Michael H. Brooke, M.B., B.Ch., F.R.C.P.C. Professor Emeritus, University of Alberta; Clinical Professor, University of Calgary, Edmonton, Canada 28. Proximal, Distal, and Generalized Weakness; 85. Disorders of Skeletal Muscle Joseph Bruni, M.D., F.R.C.P.C Associate Professor of Medicine, University of Toronto Faculty of Medicine; Consultant Neurologist, St. Michael's Hospital, Toronto, Canada 2. Episodic Impairment of Consciousness Thomas N. Byrne, M.D, Clinical Professor of Neurology, Neurosurgery, and Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 27. Paraplegia and Spinal Cord Syndromes David J. Capobianco, M.D. Assistant Professor of Neurology, Mayo Medical School, Rochester, Minnesota; Consultant, Department of Neurology, Mayo Clinic, Jacksonville, Florida 75. Headache and Other Craniofacial Pain David A. Chad, M.D. Professor of Neurology and Pathology, University of Massachusetts Medical School, Worcester; Attending Neurologist, and Director, MDA Clinic, University of Massachusetts Memorial Health Care, Worcester 81. Disorders of Nerve Roots and Plexuses Tanuja Chitnis, M.D, Instructor in Neurology, Center for Neurologic Diseases, Harvard Medical School; Associate Neurologist, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 45. Neuroimmunology Sudhansu Chokroverty, M.D. Professor of Neurology, New York Medical College, Valhalla; Associate Chairman of Neurology, Chairman, Division of Neurophysiology, and Director, Center for Sleep Medicine, Saint Vincent's Hospital and Medical Center, New York 74. Sleep and Its Disorders David P. Ciavcrella, D.O. Radiology Division, The Oregon Clinic, Portland 79. Disorders of Bones, Joints, Ligaments, and Meninges Paul E. Cooper, M.D., F.R.C.P.C. Associate Professor of Neurology, University of Western Ontario Faculty of Medicine; Chief of Clinical Neurological Sciences, St. Joseph's Health Centre, London, Ontario, Canada 47. Neuroendocrinology
CONTRIBUTING AUTHORS John R. Corboy, M.D. Assistant Professor of Neurology, University of Colorado School of Medicine; Staff Neurologist, University of Colorado Health Sciences Center, and Denver V.A. Medical Center, Denver, Colorado 46. Neurovirology Terry A. Cox, M.D., Ph.D. Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland 17. Pupillary and Eyelid Abnormalities Thomas O. Crawford, M.D. Associate Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Child Neurologist, Johns Hopkins Hospital, Baltimore, Maryland 30. The Floppy Infant F, Michael Cutrer, M.D. Assistant Professor of Neurology, Mayo Medical School; Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota 75. Headache and Other Craniofacial Pain Josep Dalmau, M.D., Ph.D. Associate Professor, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 58H. Cancer and the Nervous System: Paraneoplastic Disorders of the Nervous System Ranan DasGupta, M.R.C.S. Specialist Registrar in Urology, Department of UroNeurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom 42. Neurourology David M. Dawson, M.D. Professor of Neurology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 60. Multiple Sclerosis and Other Inflammatory Demyelinating Diseases of the Central Nervous System Roberta L. DcBiasi, M.D. Assistant Professor of Pediatrics and Neurology, University of Colorado Health Sciences Center/The Children's Hospital, Denver 59B. Infections of the Nervous System: Viral Infections Steven T. DcKosky, M.D. Professor and Chair, Department of Neurology; Directot, Alzheimer's Disease Research Center, University of Pittsburgh, Pennsylvania 72. The Dementias
xiii
W. Dalton Dietrich, M.D. Kinetic Concepts Distinguished Chair in Neurosurgery and Professor of Neurological Surgery, Neurology, and Cell Biology and Anatomy, University of Miami School of Medicine; Scientific Director, The Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, Florida S6A. Trauma of the Nervous System: Basic Neuroscience of Neurotrauma Bruce H. Dobkin, M.D. Professor of Neurology, Neurologic Rehabilitation and Research Program, University of California, Los Angeles School of Medicine, Los Angeles 54. Principles and Practices of Neurological Rehabilitation David W. Dodick, M.D. Associate Professor of Neurology, Mayo Medical School, Rochester, Minnesota; Consultant, Department of Neurology, Mayo Clinic, Scottsdale, Arizona 75. Headache and Other Craniofacial Pain Sean P. Donahue, M.D., Ph.D. Associate Professor of Ophthalmology, Neurology, and Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 39. Neuro-Opbtbalmology: Ocular Motor System Molly V. Dorfman, B.A. Clinical Research Associate, Brain Tumor Center, Massachusetts General Hospital, Boston 58A. Cancer and the Nervous System: Epidemiology of Primary Brain Tumors Darin D. Dougherty, M.D, Assistant Professor of Psychiatry, Harvard Medical School; Assistant Director, Psychiatric Neuroimaging Research, Massachusetts General Hospital, Boston 37E. Neuroimaging: Functional Neuroimaging Ronald G. Emerson, M.D. Professor of Clinical Neurology, Columbia University College of Physicians and Surgeons, New York 36A. Clinical Neurophysiology: Electroencephalography and Evoked Potentials Eric J. Eross, D.O. Instructor of Neurology, and Associate Consultant, Department of Neurology, Mayo Clinic, Scottsdale, Arizona 75. Headache and Other Craniofacial Pain Steven F. Falcone, M.D. Assistant Professor of Radiology and Neurological Surgery, University of Miami School of Medicine/Jackson Memorial Medical Center, Miami, Florida 37A. Neuroimaging: Structural Neuroimaging
xiv
CONTRIBUTING AUTHORS
Martha J. Farah, Ph.D. Professor of Psychology, Philadelphia 11. The Agnosias
University
of Pennsylvania,
Eliahn S. Fcen, M.D. Neurology Resident, University Hospitals of Cleveland, Cleveland, Ohio 51. Principles ofNeurointenstve Care Todd E. Fcinberg, M.D. Neurobehavior Center, New York 11. The Agnosias
Beth
Israel
Medical
Center,
Karin Ferneyhough Hoth, M.A. Graduate Research Assistant, University of Iowa, Iowa City 38. Neuropsychology Richard G. Fessler, M.D. Professor of Surgery, Section of Neurological Surgery, University of Chicago, Chicago, Illinois 56C. Trauma of the Nervous System: Spinal Cord Trauma Pasquale F. Finelli, M.D. Professor of Neurology, University of Connecticut School of Medicine, Farmington; Associate Director of Neurology, Hartford Hospital, Hartford, Connecticut 20. Disturbances of Taste and Smell Alan J. Fischman, M.D., Ph.D. Professor, Harvard Medical School; Director of Nuclear Medicine, Massachusetts General Hospital, Boston 37E. Neuroimaging: Functional Neuroimaging Laura Flore s-S a mat, M.D. Postdoctoral Research Fellow in Neuropathology, CedarsSinai Medical Center, Los Angeles, California 66. Developmental Disorders of the Nervous System Clare J. Fowler, F.R.C.P. Professor of Uro-Neurology, Institute of Neurology, Institute of Urology, University College London; Consultant in Uro-Neurology, The National Hospital for Neurology and Neurosurgery, London, United Kingdom 32. Neurological Causes of Bladder, Bowel, and Sexual Dysfunction; 42. Neurourology David S. Geldtnacher, M.D. Associate Professor, Department of Neurology, University of Virginia, Charlottesville S7F. Vascular Diseases of the Nervous System: Spinal Cord Vascular Disease David N. Gershfield, M.D. Fellow in Neuromuscular Disorders and Clinical Neurophysiology, Department of Neurology and Neurological
Sciences, Stanford Stanford, California 4. Delirium
University
School
of
Medicine,
Pierre Giglio, M.D. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston 58C. Cancer and the Nervous System: Clinical Features and Complications Mark R. Gilbert, M.D. Associate Professor, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston 5&C. Cancer and the Nervous System: Clinical Features and Complications Meredith R. Golomb, M.D., M.Sc. Department of Neurology, Indiana University Medical Center, Indianapolis 57E. Vascular Diseases of the Nervous System: Stroke in Children R. Gilberto Gonzalez, M.D., Ph.D. Associate Professor of Radiology, Harvard Medical School; Director of Neuroradiology, Massachusetts General Hospital, Boston 58D. Cancer and the Nervous System: Neuroimaging Maurice R. Hanson, M.D. Physician, Clinical Neurology and Neurophysiology, Cleveland Clinic Florida, Fort Lauderdale 76. Cranial Neuropathies Kenneth M. Heilman, M.D. James D. Rooks, Jr. Distinguished Professor, Department of Neurology, University of Florida College of Medicine; Program Director and Chief of Neurology, Veterans Administration Medical Center, Gainesville, Florida 10. Intentional Motor Disorders and the Apraxias Reid R. Heffner, Jr., M.D. Professor and Chair, Department of Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, New York S8R. Cancer and the Nervous System: Pathology and Molecular Genetics of Nervous System Tumors John W. Henson, M.D. Associate Professor of Neurology, Harvard Medical School; Associate Neurologist, Massachusetts General Hospital, Boston 58D. Cancer and the Nervous System: Neuroimaging Deborah O. Heros, M.D. Director of Neuro-Oncology, Mt. Sinai Comprehensive Cancer Cenrer, Miami Beach, Florida 52. Principles of Neurosurgery
COXTItmUTIM. AD I'HORS
Roberto C. Heros, M.D., F.A.C.S. Professor, Co-Chairman, and Program Director, Department of Neurological Surgery, University of Miami School of Medicine, Miami, Florida 52. Principles of Neurosurgery Alan Hill, M.D., Ph.D. Professor and Head, Division of Neurology, British Columbia's Children's Hospital, Vancouver, Canada 86. Neurological Problems of the Newborn Fred H. Hochberg, M.D. Attending Neuro-Oncologist, Brain Tumor Center, Massachusetts General Hospital, Boston SHE. Cancer and the Nervous System: Management of Primary Nervous System Tumors in Adults James F. Howard, Jr., M.D. Chief, Neuromuscular Disorders Section, Department of Neurology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill 84. Disorders of Neuromuscular Transmission David J. Hunter, M.D., Sc.D. Professor of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 58A. Cancer and the Nervous System: Epidemiology of Primary Brain Tumors Padmaja Kandula, M.D. Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee SO. Principles of Pain Management Carlos S. Kase, M.D. Professor of Neurology, Boston University School of Medicine; Attending Neurologist, Boston University Medical Center, Boston, Massachusetts S7B. Vascular Diseases of the Nervous System: Intracerebral Hemorrhage Bashar Katirji, M.D., F.A.C.P. Professor of Neurology, Case Western Reserve University School of Medicine; Director, Electromyography Laboratory, and Chief, Neuromuscular Division, University Hospitals of Cleveland, Cleveland, Ohio 36B. Clinical Neurophysiology: Clinical Electromyography Daniel I. Kaufer, M.D. Associate Professor, Department of Neurology, and Director, Memory and Cognitive Disorders Program, The University of North Carolina Medical School, Chapel Hill 72, The Dementias
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Samia J. Khoury, M.D. Associate Professor of Neurology, Harvard Medical School; Director, Partners MS Center, Brigham and Women's Hospital, Boston, Massachusetts 45. Neuro immunology Howard S. Kirshner, M.D. Professor and Vice Chair, Department of Neurology, Vanderbilt University School of Medicine; Director, Stroke Service, Vanderbilt University Hospital, and Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consultant in Neurology, Nashville VA Medical Center, St. Thomas Hospital, Nashville, Tennessee 6. Approaches to Intellectual and Memory Impairments; 12A. Language and Speech Disorders: Aphasia; 12B. Language and Speech Disorders: Dysarthria and Apraxia of Speech Edwin H. Kolodny, M.D. Neurogenetics Unit, Department of Neurology and Pediatrics, New York University School of Medicine, New York 68. Inborn Errors of Metabolism of the Nervous System John F. Kurtzke, M.D. Professor Emeritus of Neurology, Georgetown University School of Medicine, Washington, D.C.; Distinguished Professor of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Consultant in Neurology and Neuroepidemiology, Neurology Service, Veterans Affairs Medical Center, Washington, D.C. 43. Neuroepidemiology Anthony E. Lang, M.D., F.R.C.P.C. Professor of Neurology, University of Toronto Faculty of Medicine; Director of Movement Disorders, The Toronto Western Hospital, Division of the University Health Network, Toroto, Canada 24. Movement Disorders: Diagnosis and Assessment Patrick J. M. Lavin, M.B., B.Ch., B.A.O., M.R.C.P.I. Professor of Neurology and Ophthalmology, Vanderbilt University Medical School, Nashville, Tennessee 16. Eye Movement Disorders: Diplopia, Nystagmus, and Other Ocular Oscillations; 39, Neuro-Ophthalmology: Ocular Motor System Ronald P. Lesser, M.D. Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 73. The Epilepsies Alan H. Lockwood, MD Professor of Neurology and Nuclear Medicine, State University of New York at Buffalo School of Medicine
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CONTRIBUTING AUTHORS
and Biomedical Sciences; Director of Operations, Center for Positron Emission Tomography, Veterans Administration Western New York Health Care System, Buffalo 62. Toxic and Metabolic Encephalopathies
School of Medicine at the University of California at Los Angeles 4. Delirium
Oscar L. Lopez, M.D. Associate Professor of Neurology and Psychiatry, University of Pittsburgh 72. The Dementias
David J. Michelson, M.D. Fellow in Child Neurology, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California 7. Global Developmental Delay and Developmental Regression
David N. Louis, M.D. Professor of Pathology, Molecular Pathology Unit, Harvard Medical School; Associate Chief of Pathology, Massachusetts General Hospital, Boston S8B. Cancer and the Nervous System: Pathology and Molecular Genetics of Nervous System Tumors
Van S. Miller, M.D. Texas Child Neurology, LLP, Piano, Texas 71. Neurocutaneous Syndromes
Betsy B. Love, M.D. Clinical Assistant Professor of Neurology, Indiana University School of Medicine, Indianapolis S7A. Vascular Diseases of the Nervous System: Ischemic Cerebrovascular Disease Robert G. Mair, Ph.D. Professor of Psychology, University of New Hampshire, Durham 20. Disturbances of Taste and Smell Donald W. Marion, M.D. Professor and Chairman, Department of Neurological Surgery, Boston University School of Medicine; Neurosurgeon-in-Chief, Boston Medical Center, Boston, Massachusets 56B. Trauma of the Nervous System: Craniocerebral Trauma Christopher J. Mathias, M.B.B.S., D.Phil., F.R.C.P. Professor of Neurovascular Medicine, Imperial College School of Medicine and University Department of Clinical Neurology, Institute of Neurology, University College London; Consultant Physician, Neurovascular Medicine Unit, St. Mary's Hospital; Consultant Physician, Autonomic Unit, The National Hospital for Neurology and Neurosurgery, London, United Kingdom 83. Disorders of the Autonomic Nervous System Michael J. McLean, M.D., Ph.D. Associate Professor, Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 49. Principles of Neuropharmacology and Therapeutics Mario F. Mendez, M.D., Ph.D. Director, Neurobehavior Unit, VA Greater Los Angeles Healthcare System; Professor of Neurology and Pyschiatry and Biobehavioral Sciences, David Geffcn
Karl E. Misulis, M.D., Ph.D. Clinical Professor of Neurology, Vanderbilt University School of Medicine, Nashville; Neurologist, SemmesMurphey Clinic, Jackson, Tennessee 26. Hemiplegia and Monoplegia; 31. Sensory Abnormalities of the Limbs, Trunk, and Tace; 34. Lower Back and Lower Limb Pain Hiroshi Mitsumoto, M.D., D.Sc. Wesley J. Howe Professor, Department of Neurology, Columbia University College of Physicians and Surgeons; Director, The Eleanor and Lou Gehrig MNA/ALS Research Center; Head, Neuromuscular Diseases Division, Columbia-Presbyterian Hospitals, New York 80. Disorders of Upper and Lower Motor Neurons Paul L. Moots, M.D, Associate Professor of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee SO. Principles of Pain Management Carlos T. Moracs, M.D. Associate Professor of Neurology and Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 69. Mitochondrial Disorders Brian Murray, M.B., B.Ch., B.A.O., M.Sc. Consultant Neurologist, Department of Neurology, Mater Misericordiac and University Hospital, Dublin, Ireland S6D. Trauma of the Nervous System: Peripheral Nerve Trauma; 80. Disorders of Upper and Lower Motor Neurons Ruth Nass, M.D. Professor of Clinical Neurology, New York University School of Medicine; Attending Pediatric Neurologist, New York University Medical Center, New York 67. Developmental Disabilities
CONTRIBUTING AUTHORS
Carissa Nehl, B.S. Graduate Research Assistant, Universiry of Iowa Hospitals and Clinics, Iowa City S. Behavior and Personality Disturbances Michael J. Olek, D.O. Assistant Professor of Neurology; Director, Multiple Sclerosis Center, University of California at Irvine, Irvine 60. Multiple Sclerosis and Other Inflammatory Demyelinating Diseases of the Central Nervous System Gregory M. Pastores, M.D. Assistant Professor, Neurology and Pediatrics, New York University School of Medicine, New York 68. Inborn Errors of Metabolism of the Nervous System Jane S. Paulsen, Ph.D. Professor, Departments of Psychiatry, Neurology, Psychology, and Neuroscicnces, Roy and Lucille Carver College of Medicine, The University of Iowa, Iowa City; Director, Psychology Division in Psychiatry, The University of Iowa Hospitals and Clinics, Iowa City S. Behavior and Personality Disturbances; 38. Neuropsychology Timothy A. Pedley, M.D. Henry and Lucy Moses Professor of Neurology and Chairman, Department of Neurology, Columbia University College of Physicians and Surgeons; Neurologist-in-Chief, The Neurological Institute of New York, ColumbiaPresbyterian Medical Center, New York 36A. Clinical Neurophysiology: Electroencephalography and Evoked Potentials Arie Perry, M.D. Associate Professor, Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine; Associate Professor of Pathology, Barnes-Jewish and St. Louis Children's Hospital, St. Louis, Missouri 58B. Cancer and the Nervous System: Pathology and Molecular Genetics of Nervous System Tumors Alan Pestronk, M.D. Professor of Neurology and Pathology, and Director, Neuromuscular Clinical Laboratory, Washington University School of Medicine, St. Louis, Missouri 29. Muscle Pain and Cramps Ronald F. Pfeiffer, M.D. Professor and Vice Chairman, Department of Neurology, Universiry of Tennessee Health Science Center, Memphis 13. Neurogenic Dysphagia
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David C. Preston, M.D. Professor of Neurology, Case Western Reserve University School of Medicine; Director of the Neuromuscular Service, University Hospitals of Cleveland, Cleveland, Ohio 28. Proximal, Distal, and Generalized Weakness Bruce H. Price, M.D. Assistant Professor in Neurology, Harvard Medical School, Boston; Assistant in Neurology, Massachusetts General Hospital, Boston; Chief, Department of Neurology, McLean Hospital, Belmont, Massachusetts 9. Depression and Psychosis in Neurological Practice Louis J. Ptacek, M.D. Investigator, Howard Hughes Medical Institute, and Professor, Department of Neurology, University of California at San Francisco, San Francisco 70. Channelopathies: V.pisodic and Electrical Disorders of the Nervous System Robert M. Quencer, M.D. Professor and Chairman of Radiology, Neurological Surgery and Ophthalmology, University of Miami School of Medicine/Jackson Memorial Medical Center, Miami, Florida 37A. Neuroimaging: Structural Neuroimaging Robert A. Ratcheson, M.D. Harvey Huntington Brown, Jr., Professor and Chairman of Neurological Surgery, Case Western Reserve UniversitySchool of Medicine; Director of Neurological Surgery, University Hospitals of Cleveland, Cleveland, Ohio 57C. Vascular Diseases of the Nervous System: Intracranial Aneurysms and Subarachnoid Hemorrhage; 57D. Vascular Diseases of the Nervous System: Arteriovenous Malformations Scott L. Rauch, M.D. Associate Chief of Psychiatry, Harvard Medical School; Director, Psychiatric Neuroimaging Research, and Associate Chief of Psychiatry for Neuroscience Research, Massachusetts General Hospital, Boston 37E. Neuroimaging: Functional Neuroimaging Michael Ronthal, M.B.B.Ch., F.R.C.P. Associate Professor of Neurology, Harvard Medical School; Deputy Chief of Neurology, Beth Isreal Deaconess Medical Center, Boston, Massachusetts 33. Arm and Neck Pain Richard B. Rosenbaum, M.D. Clinical Professor of Neurology, Oregon Health and Sciences University and Neurology Division, The Oregon Clinic, Portland 79. Disorders of Bones, Joints, Ligaments, and Meninges
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CONTRIBUTING AUTHORS
Bernd F. Remler, M.D. Professor of Neurology and Ophthalmology, Medical College of Wisconsin; Staff Physician, Department of Neurology, Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin 3. Falls and Drop Attacks E. Steve Roach, M.D. Professor of Neurology, Wake Forest University School of Medicine; Director, Comprehensive Epilepsy Program, Wake Forest University Baptist Medical Center, WinstonSalem, North Carolina 71. Neurocutaneous Syndromes Gary A. Rosenberg, M.D. Professor and Chairman of Neurology, Departments of Neurology, Neurosciences, Cell Biology and Physiology, University of New Mexico Health Sciences Center; Chief of Neurology Service, University of New Mexico Hospital, Albuquerque 65. Brain Edema and Disorders of Cerebrospinal Fluid Circulation Myrna R. Rosenfeld, M.D., Ph.D. Associate Professor of Neurology; Division Chief, NeuroOncology, University of Pennsylvania School of Medicine, Philadelphia 58H. Cancer and the Nervous System: Paraneoplastic Disorders of the Nervous System Leslie J. Gonzalez Rothi, Ph.D. Professor of Neurology, University of Florida, Gainesville; Research Career Scientist and Director, Brain Rehabilitation Research Center, VA Medical Center, Gainesville, Florida 10. Intentional Motor Disorders and the Apraxias Armando Ruiz, M.D. Voluntary Assistant Professor of Radiology, University of Miami School of Medicine, Miami, Florida 37A. Neuroimaging: Structural Neuroimaging; 37B. Neuroimaging: Computed Tomographic and Magnetic Resonance Vascular Imaging Marcin Sadowski, M.D., Ph.D. Assistant Professor of Neurology, New York University School of Medicine; Attending Physician, New York University Medical Center and Bellevue Hospital, New York 59G. Infections of the Nervous System: Prion Diseases Gaurav Saigal, M.B.B.S. Neuroradiology Fellow, University of Miami School of Medicine, Miami, Florida 37 B. Neuroimaging: Computed Tomographic and Magnetic Resonance Vascular Imaging
Donald B. Sanders, M.D. Professor of Medicine, Division of Neurology, Duke University Medical Center, Durham, North Carolina 84. Disorders of Neuromuscular Transmission Johnny S, Sandhu, M.D. Department of Radiology, University of Miami School of Medicine, Miami, Florida 37C. Neuroimaging; Neuroangiographic Anatomy and Common Cerebrovascular Diseases; 53. Principles of Endovascular Surgery Paul Santiago, M.D. Spine Fellow, Section of Neurological Surgery, University of Chicago, Chicago, Illinois 56C. Trauma of the Nervous System; Spinal Cord Trauma Cesar C. Santos, M.D. Associate Professor of Neurology and Pediatric Neurology; Section 1 lead, Pediatric Neurology, Wake Forest University School of Medicine; Chief, Section of Pediatric Neurology and Director, Neurology Training Program, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 71. Neurocutaneous Syndromes Harvey B. Sarnat, M.D., F.R.C.P.C. Professor of Pediatrics (Neurology) and Pathology (Neuropathology), David Geffen School of Medicine at UCLA; Director, Division of Pediatric Neurology and Neuropathologist, Cedars-Sinai Medical Center, Los Angeles, California 66. Developmental Disorders of the Nervous System David Schiff, M.D. Associate Professor of Neurology, Neurological Surgery, and Medicine; Co-director, Ncuro-Oncology Center, University of Virginia Medical Center, Charlottesville S8G. Cancer and the Nervous System: Nervous System Metastases James W. Schmidley, M.D. Professor of Neurology, University of Arkansas for the Medical Sciences, Little Rock S7G. Vascular Diseases of the Nervous System: Central Nervous System Vasculitis James M. Schumacher, M.D. Neurological Associates, P.A., Sarasota, Florida 52. Principles of Neurosurgery Neil E. Schwartz, M.D. Chief Resident, Department of Neurology, Stanford University Medical Center, Palo Alta, California 64C. Effects of Toxins and Physical Agents on the Nervous System: Neurotoxins of Animals and Plants; 64D. Effects of Toxins and Physical Agents on the Nervous System: Marine Toxins
CONTRIBUTING AUTHORS Warren R. Selman, M.D. Professor of Neurological Surgery, Case Western Reserve University School of Medicine; Vice Chairman, Department of Neurological Surgery, University Hospitals of Cleveland, Cleveland, Ohio 57C. Vascular Diseases of the Nervous System: Intracranial Aneurysms and Subarachnoid Hemorrhage; 57D. Vascular Diseases of the Nervous System: Arteriovenous Malformations D. Malcolm Shaner, M.D. Assistant Clinical Professor of Neurology, UCLA School of Medicine; Consultant in Neurology, Southern California Permanente Medical Group, Los Angeles 87. Neurological Problems of Pregnancy Kathleen M. Shannon, M.D. Associate Professor, Department of Neurological Sciences, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 77. Movement Disorders Barbara E. Shapiro, M.D., Ph.D. Associate Professor of Neurology, Case Western Reserve University School of Medicine; Director of Neuromuscular Research, University Hospitals of Cleveland, Cleveland, Ohio 28. Proximal, Distal, and Generalized Weakness Michael C. Sharts, M.D. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pennsylvania S6B. Trauma of the Nervous System: Craniocerebral Trauma Roger P. Simon, M.D. Adjunct Professor, Department of Pharmacology 6c Physiology and Neurology, Oregon Health Sciences University; Robert Stone Dow Chair of Neurology, and Director of Neurobiology Research, Legacy Clinical Research and Technology Center, Portland, Oregon 63. Deficiency Diseases of the Nervous System Sumit Singh, M.D. Assistant Professor, Department of Neurology, All India Institute of Medical Sciences, New Delhi 59D. Infections of the Nervous System: Parasitic Infections Evelyn M. L. Sklar, M.D. Professor of Clinical Radiology and Neurological Surgery, University of Miami School of Medicine; Professor of Clinical Radiology and Neurological Surgery, University of Miami-Jackson Memorial Medical Center, Miami, Florida 37A. Neuroimaging: Structural Neuroimaging
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Benn E. Smith, M.D. Assistant Professor of Neurology, Mayo Medical School, Rochester, Minnesota; Consultant in Neurology, Mayo Clinic, Scottsdale, Arizona 82. Disorders of Peripheral Nerves Bruce D. Snyder, M.D. Clinical Professor of Neurology, University of Minnesota Medical School, Minneapolis 61. Hypoxic/Anoxic and Ischemic Encephalopathies Yuen T. So, M.D., Ph.D. Associate Professor of Neurology and Neurosciences; Director, Neurology Clinics, Stanford University Medical Center, Stanford, California 63. Deficiency Diseases of the Nervous System; 64B. Effects of Toxins and Physical Agents on the Nervous System: Effects of Drug Abuse on the Nervous System; 64C. Effects of Toxins and Physical Agents on the Nervous System: Neurotoxins of Animals and Plants; 64D. Effects of Toxins and Physical Agents on the Nervous System: Marine Toxins Marylou V. Solbrig, M.D. Assistant Adjunct Professor of Neurology, University of California, Irvine, School of Medicine; Attending Neurologist, University of California, Irvine, Medical Center, Irvine 59A. Infections of the Nervous System: Bacterial Infections; 59B. Infections of the Nervous System: Viral Infections Jose I. Suarez, M.D. Assistant Professor of Neurology and Neurosurgery, Case Western Reserve University; Director, Neurosciences Critical Care Unit, University Hospitals of Cleveland, Cleveland, Ohio 51. Principles of Neurointensive Care S. H. Subramony, M.D. Professor and Vice Chairman, Department of Neurology, University of Mississippi School of Medicine; Attending Physician, University Hospitals and Clinics; Consulting Physician, Methodist Rehabilitation Center, Jackson, Mississippi 23. Ataxic Disorders; 78. Disorders of the Cerebellum, Including the Degenerative Ataxias Jeffrey L. Sunshine, M.D., Ph.D. Assistant Professor of Radiology, Neurology, and Neurosurgery, Case Western Reserve University School of Medicine; Assistant Director of MRI, University Hospitals of Cleveland, Cleveland, Ohio 57C. Vascular Diseases of the Nervous System: Intracranial Aneurysms and Subarachnoid Hemorrhage; 57D. Vascular Diseases of the Nervous System: Arteriovenous Malformations
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CONTRIBUTING AUTHORS
Jerry W. Swanson, M.D. Professor of Neurology, Mayo Medical School; Consultant, Department of Neurology and Chair, Headache Division, Mayo Clinic, Rochester, Minnesota 21. Cranial and Facial Pain; 75. Headache and Other Craniofacial Pain Patrick J. Sweeney, M.D., F.A.C.P. Department of Neurology, Case Western Reserve University School of Medicine; Director, Neurology Residency Program, The Cleveland Clinic Foundation, Cleveland, Ohio 76. Cranial Neuropathies Stephen J. Tapscott, M.D., Ph.D. Associate Member, Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 44. Clinical Neurogenetics Robert W. Tarr, M.D. Associate Professor of Radiology and Neurosurgery, Case Western Reserve University School of Medicine; Director of Interventional Neuroradiology, University Hospitals of Cleveland, Cleveland, Ohio S7C. Vascular Diseases of the Nervous System: Intracranial Aneurysms and Subarachnoid Hemorrhage; S7D. Vascular Diseases of the Nervous System: Arteriovenous Malformations Charles H. Tcgclcr, M.D. Professor of Neurology, Director, Neurosonology Laboratory, and Head, Section on Stroke and Cerebrovascular Disease, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 37D. Neuroimaging: Ultrasound Imaging of the Cerebral Vasculature Philip D. Thompson, M.B.B.S., Ph.D., F.R.A.C.P. Professor of Neurology, University Department of Medicine, University of Adelaide; Consultant Neurologist and Head, Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia 25. Gait Disorders Robert L. Tomsak, M.D., Ph.D Associate Professor of Ophthalmology and Neurology, Case Western Reserve University School of Medicine; Director, Division of Clinical Ncuro-ophrhalmology, University Hospitals of Cleveland, Cleveland, Ohio 14. Vision Loss; 40. Neuro-Ophthalmology: Afferent Visual System William H. Trescher, M.D. Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Kennedy Krieger Institute, Baltimore, Maryland 73. The Epilepsies
Manjari Tripathi, D.M. Assistant Professor of Neurology, Neurosciences Center, All India Institute of Medical Sciences, New Delhi 59C. Infections of the Nervous System: fungal Infections B. Todd Troost, M.D. Professor and Chairman of Neurology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 18. Dizziness and Vertigo; 19. Hearing Loss and Tinnitus without Dizziness or Vertigo; 41. Neuro-Otology Kenneth L. Tyler, M.D. Reuler-Lewin Family Professor of Neurology and Professor of Medicine, Microbiology, and Immunology, University of Colorado Health Sciences Center; Chief, Neurology Service, Denver Veterans Affairs Medical Center and Eastern Colorado Health Care System, Denver 46. Neurovirology; 59B. Infections of the Nervous System: Viral Infections Elizabeth C. Tyler-Kabara, M.D., Ph.D. Chief Resident, Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania S6B. Trauma of the Nervous System: Craniocerebral Trauma Edward Valenstein 10. Intentional Motor Disorders and the Apraxias Ashok Vcrma, M.D., D.M. Associate Professor of Neurology, University of Miami School of Medicine; Attending Neurologist and Neurology Training Program Director, Jackson Memorial Hospital Staff Neurologist, Miami VA Medical Center, University of Miami School of Medicine, Miami, Florida 59. Infections of the Nervous System; 59A. Infections of the Nervous System: Bacterial Infections; 59C. Infections of the Nervous System: Fungal Infections; 59D. Infections of the Nervous System: Parasitic Infections; 59E. Infections of the Nervous System: Neurological Manifestations of Human Immunodeficiency Virus Infections in Adults; 59F. Infections of the Nervous System: Neurological Manifestations of Human Immunodeficiency Virus Infections in Children; 59G. Infections of the Nervous System: Prion Diseases; 69. Mitochondrial Disorders Alfredo D. Voloschin, M.D. Neuro-Oncology Research Fellow, Massachusetts General Hospital and Harvard Medical School, Boston 5SP. Cancer and the Nervous System: Management of Primary Nervous System Tumors in Infants and Children
CONTRIBUTING AUTHORS
Waqar Waheed, M.D. Instructor in Neurology, Washington University School of Medicine, St. Louis, Missouri 29. Muscle Pain and Cramps Ajay K. Wakhloo, Ph.D. Professor of Radiology, Neurological Surgery, and BioMedical Engineering, University of Miami; Director, Neuro en do vascular Surgery &Z Interventional Neuroradiology, and Director, Center for Neuroendovascular Surgery and Stroke Research (CNS), University of Miami School of Medicine, Miami, Florida 37C. Neuroimaging: Neuroangiograpbic Anatomy and Common Cerebrovascular Diseases; 53. Principles of Endovascular Surgery Michael Wall, M.D. Professor of Neurology and Ophthalmology, University of Iowa College of Medicine; Staff Physician, University of Iowa Hospitals and Clinics and Veterans Administration Medical Center, Iowa City 22. Brainstem Syndromes Mitchell T. Wallin, M.D., M.P.H. Assistant Professor of Neurology, Georgetown University School of Medicine; M.S. Clinic Director and Chief, Neuroepidemiology, Neurology Service, VA Medical Center, Washington, D.C. 43. Neuroepidemiology
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Robert T. Watson, M.D. Professor of Neurology and Senior Associate Dean for Educational Affairs, University of Florida School of Medicine, Gaineseville 10. Intentional Motor Disorders and the Apraxias Stephen G. Waxman, M.D., Ph.D. Professor and Chairman of Neurology, Yale University School of Medicine, New Haven; Director, Paralyzed Veterans of America Neuroscience Research Center, Yale University School of Medicine; Rehabilitation Research Center, VA Hospital, West Haven, Connecticut 27. Paraplegia and Spinal Cord Syndromes Patrick Wen, M.D. Associate Professor of Neurology, Harvard Medical School, Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital and Center for Neuro-Oncology, Dana Farber Cancer Institute, Boston 58G. Cancer and the Nervous System: Nervous System Metastases Thomas Wisniewski, M.D. Associate Professor of Neurology, Pathology, and Psychiatry, New York University School of Medicine S9G. Infections of the Nervous System: Prion Diseases Osama O. Zaidat, M.D. Assistant Professor of Neurology, Case Western Reserve University; Neurointensivist, University Hospitals of Cleveland, Cleveland, Ohio 51. Principles of Neurointensive Care
Preface to the Fourth Edition When preparing the preface to the first edition of Neurology in Clinical Practice in 1990, we highlighted the principles upon which the new textbook was based. We wrote that we had long felt the need for a practical textbook of neurology that covered all the clinical neuroscienccs and provided not only a description of neurological diseases and their pathophysiology but also a practical approach to their diagnosis and management. We emphasized that neurology is intellectually challenging because of the complexity of the nervous system, and fascinating because of the insight that neurological disease provides into the workings of the brain and mind. We recognized the major technological and research advances that were coming, and looked with excitement to the nottoo-distant future when more of the neurological diseases would be completely understood, when many of the biochemical defects would be correctible, and when effective regeneration of the central and peripheral nervous systems might be possible. Nevertheless, we believed then, as we do now, that technology must remain the servant of the clinician and never become the master. Now, thirteen years later, those words are yet more relevant, the hopes are nearer to achievement, and we believe that the book remains true to the original principles. The first edition of Neurology in Clinical Practice won the Most Outstanding Book Award of the Association of American Publishers (Professional and ScholarlyPublication Division). At the time of publication of the third edition in 2000, we sadly lost David Marsden, a founder and co-editor of the first three editions. This fourth edition welcomes Joseph Jankovic as co-editor. This fourth edition has been completely rewritten, and almost half of the chapters were prepared by new authors. In addition, new chaprers are provided on cndovascular surgery and mitochondrial and ion channel disorders. This book is the amalgam of the scholarly contributions of all our colleagues who wrote the chapters and provided the illustrations and website material. We are deeply grateful to them for their selfless devotion to neurological education. A project of this magnitude would not have been possible without the encouragement and wisdom of Susan Pioli, Executive Publisher for Global Medicine at Elsevier. She was an active participant at every stage of the development of this book. Mary Beth Murphy, Senior Development Editor at Elsevier, was the key person
drawing this, product together. Additionally, we thank Joan Sinclair, Production Manager, and Kelly Mabie, Production Editor, without whose energy and efficiency this book would not have seen the light of day. Finally, we acknowledge the contributions of our readers, whose feedback on the NICP family of books and website has been invaluable in assisting us to improve this scries of educational instruments, Over these thirteen years, the Neurology in Clinical Practice family of publications has expanded to include the Pocket Companion, the Review Manual, several translations into other languages, and, most important, the website, www.nicp.com. Starting with the third edition of Neurology in Clinical Practice, we developed and launched this innovative and unique website. With this fourth edition, we will continue to expand this dynamic electronic edition of the book. The website publication provides what the print cannot: regularly posted updates on recent advances in clinical neurology; videos showing eye movements, movement disorders, EMG waveforms, and other material; expanded references to the literature; and additional depth of clinical material from other leading Elsevier neurology texts with e-commerce availability. The Pocket Companion to NICP, which is a true synopsis of the two volumes, will be published shortly after the fourth edition of Neurology in Clinical Practice. It continues to be a rewritten, condensed, and accessible version ol the most clinically needed material derived from the "parent" two volumes. This companion is a portable quick reference that will lead the reader back to the two volumes for more in-depth coverage. The Review Manual for Neurology in Clinical Practice, written by Karl Misulis and edited by the four Editors, will also be published shortly after the fourth edition of Neurology in Cltntcal Practice. This question-and-answer workbook is organized according to the chapters of the fourth edition of Neurology in Clinical Practice. The questions are useful in preparing for the Resident InService and Board examinations, and the answers provide explanations and referrals to the main two volumes for more complete consideration of the subject matter. Walter G. Bradley, DM., F.R.C.P. Robert B. Daroff, M.D. Gerald M. Fenichel, M.D. Joseph jankovic, M.D.
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Parti Approach to Common Neurological Problems
Parti Approach to Common Neurological Problems
Chapter 1 Diagnosis of Neurological Disease Walter G. Bradley, Robert B. Daroff, Gerald M. Fenichel, and Joseph Jankovic
The Neurological Interview Chief Complaint History of Present Illness Review of Patient-Specific Information Review of Systems History of Previous Illnesses Family History The Examination Neurological Examination
4 4 4 5 5 5 6 d 6
The neurological diagnosis in a patient is sometimes easy, but at other times it may be quite challenging, requiring specialized skills. If a patient shuffles into the doctor's office and has a pill-rolling tremor of the hands and loss of facial expression, it is not difficult to come to a diagnosis of Parkinson's disease. However, it is important to remember that while it is very satisfying to make such a spot diagnosis, the patient may actually he coming for help with a totally different neurological problem, and therefore an evaluation of the whole problem is necessary. In all branches of medicine, the history of the symptoms and the clinical examination of the patient are the keys to achieving a diagnosis. This is particularly true in neurology. The standard practice in neurology is to record the patient's chief complaint and take a history of the development of the symptoms, followed by the history of illnesses and surgeries, the family history, the personal and social history, and a review of any symptoms involving the main body systems. The neurologist then performs a neurological examination, and constructs a differential diagnosis of the possible causes of the patient's symptoms. Although this process is also used in making general medical and surgical diagnoses, whar is unique to neurology is the extreme attention to "localization." When a patient presents to an internist or surgeon with abdominal or chest symptoms, the localization is practically established by the symptoms, and the etiology then becomes the primary concern. However, a neurological patient with a weak hand may have a lesion localized to the muscles, the neuromuscular junction,
General Physical Examination Assessment of the Cause of the Patient's Symptoms Anatomical Localization Differential Diagnosis Laboratory Investigations Management of Neurological Disorders The Experienced Neurologist's Approach to the Diagnosis of Common Neurological Problems
7 8 9 9 9
nerve or nerves in the upper limb, brachial plexus, spinal cord, or brain. The neurological examination is essential in determining the site (localization) of the offending lesion. In general, the history provides the best clues fot etiology and the examination is essential for localization. This diagnostic process consists of a series of steps (Figure 1.1). Although the standard teaching is that the patient should be allowed to provide the history in his or her own words, each step of the process involves active questioning of the patient by the neurologist. At each step, the neurologist should consider rhe possible anatomical localizations, and particularly the etiology of the symptoms (see Figure 1.1). From rhe patient's chief complaint and a detailed history, an astute neurologist can derive clues that lead first to a hypothesis about the location, and then to a hypothesis about the etiology of the neurological lesion. From these hypotheses, the experienced neurologist can predicr what abnormal neurological signs should he present and what should be absent, thereby allowing confirmation of the site of the dysfunction. Alternatively, analysis of the history may suggest two or more possible anatomical locations and diseases, each with a different predicted consrellation of abnormal neurological signs. The findings on neurological examination can be used to determine which of these various possibilities is the most likely. To achieve a diagnosis, the neurologist needs not only to have a good knowledge of the anatomy, physiology, and biochemistry of the nervous system, but also of the clinical features and pathology of the neurological diseases. .1
4
APPROACH TO COMMON NEUROLOGICAL PROBLEMS Task
Goal
the diagnosis, and to cure the disease. Sometimes the patient comes hoping that something is not present ("Please tell me that my headaches are not caused by a brain tumor!"). Sometimes the patient says that other doctors "never told me anything" (which may be true, although in many cases the patient cither did not hear or did not like what was said).
CHIEF COMPLAINT The chief complaint (or the several main complaints) is the usual starting point of the diagnostic process. An example might be a patient presenting with the triad of complaints of headache, clumsiness, and double vision. The complaints serve to focus attention on the questions to be addressed while taking the history and provide the first clue to the anatomy and etiology of the disease underlying the complaints. In this case, the neurologist would be concerned that the patient might have a tumor in the posterior fossa affecting the cerebellum and brainstem. The mode of onset is critically important in determining the etiology. For example, a sudden onset usually indicates a vascular etiology such as a cerebral infarction or hemorrhage. A course characterized by exacerbations and remissions may suggest multiple sclerosis, whereas a slowly progressive course indicates a neoplasm. Paroxysmal episodes suggest the possibility of seizures; migraines; or some paroxysmal dyskinesias, ataxias, or periodic paralyses.
HISTORY OF PRESENT ILLNESS THE NEUROLOGICAL INTERVIEW The neurologist is often an intimidating figure for many patients. To add to the stress of the neurological interview and examination, the patient may already have a preconceived notion that the disease causing the symptoms is horrible and life threatening. Because of this background, the neurologist should do everything possible to put the patient at case, and to be empathetic. It is important to introduce oneself to the patient and exchange social pleasantries before leaping into the interview. A few opening questions can break the ice. "How old are you?" "What type of work have you done most of life?" "Who is your doctor, and who would you like me to write to?" "Are you right- or left-handed?" After this, it is easier to ask the first important question: "What brings you to see me? What is your main problem?" Another technique is to begin by asking the patient, "How can I help you?" This establishes that the doctor is there to ptovide a service and allows patients to express their expectations for the consultation. It is important for the physician to get a sense of patient's expectations from the visit. Usually they want the doctor to find or confirm
Often the patient will give a very clear history of the temporal development of the complaints, the location and severity of the symptoms, and the current level of disability. However, some patients, particularly the elderly, are tangential and insist on telling what other doctors did or said, rather than relating their own symptoms. Direct questioning is often needed to clarify the symptoms, but it is important not to lead the patient. Patients are all too ready to give a positive response to an authority figure, even if it is patently incorrect. It is important to consider whether the patient is reliable. Reliability depends on the patient's intelligence, memory, language function, educational and social status, and whether there are secondary gain issues, such as a disability claim or pending lawsuit. One should suspect a somatofotm disorder in any patient who claims to have symptoms involving multiple organ systems. Getting information from an observer other than the patient is important for characterizing many neurological conditions, such as seizures and dementia. Taking a history from a child is complicated by shyness with strangers, a different sense of time, and a limited vocabulary. In children, the history is always the composite perceptions of the child and the parent.
DIAGNOSIS OF NEUROLOGICAL DISEASE Patients and physicians may use the same word to mean very different things. If the physician accepts the word at face value, without ensuring that the patient uses the word in the same way as the doctor, misinterpretation may lead to misdiagnosis. For instance, patients often describe a limb as being "numb" when it is actually paralyzed. Patients often use the term "dizziness" to refer to confusion or weakness and not vertigo. A patient may describe vision as being "blurred" when further questioning reveals diplopia. "Blackouts" may be loss of consciousness, loss of vision, or simply confusion. "Pounding" or "throbbing" headaches are not necessarily pulsating. The neurologist must understand fully the nature, onset, duration, and progression of each symptom and the temporal relationship of one symptom to another. Are the symptoms getting better, staying the same, or getting worse? What relieves them and what makes them worse? In infants and young children, temporal sequence also includes the timing of developmental milestones; failure to achieve a milestone is as important as loss of achievement. An example may clarify how the history leads to diagnosis. A 28-year-old woman presents with a 10-year history of recurrent headaches associated with her menses. The unilateral quality of pain in some attacks and the association of flashing lights, nausea, and vomiting points to the diagnosis of migraine. On the other hand, if the same patient has a progressively worsening headache upon wakening, has new onset seizures, and is developing a hemiparesis, this suggests an intracranial space-occupying lesion. Both the absence of expected features and the presence of unexpected features may assist in the diagnosis. A patient with numbness of the feet might have a peripheral neuropathy, but the presence of backache and loss of sphincter control suggests that a spinal cord or cauda equina lesion is more likely. Patients may arrive for a neurological consultation with a folder of previous laboratory tests and neuroimaging studies. They often dwell on these tests and their interpretation by other physicians. Be wary of accepting the opinions of other doctors; they may have been wrong! The careful neurologist takes a new history and makes a new assessment of the prohlem. The history of how the patient or the caregiver responded to the symptoms may be important. A pattern of overreaction may be of help in evaluating the significance of the complaints. However, a night visit to the emergency department for a new-onset headache should not be dismissed without investigation. Conversely, the child who was not brought to the hospital despite hours of seizures is likely to be the victim of child abuse, or at least of neglect.
5
and surgical illnesses; current medications and allergies; a review of symptoms in non-neurological systems of the body; the personal history in terms of occupation, marital status, and alcohol, tobacco, and illicit drug use; and the medical history of the parents, siblings, and children, looking for evidence of familial diseases. The order in which these items are considered is not important but consistency avoids something being forgotten. In the outpatient office, the patient can be asked to complete a form with a series of questions on all of these matters before starting the consultation with the physician. This expedites the interview, although more details are often needed. What chemicals is the patient exposed to at home and at work? Did the patient ever use alcohol, tobacco, or prescription or illegal drugs? h thete excessive stress at home, in school, or in the workplace, such as divorce, death of a loved one, or loss of employment? Are there hints of abuse or neglect of children or spouse? Sexual preference is important information in this era of human immunodeficiency virus infection. The doctor should question children and adolescents away from their parents if there is a need to obtain mote accurate information about sexual activity and substance abuse.
Review of Systems The review of systems should include the elements of nervous system function that did not surface in taking the history. The neurologist should have covered the following: cognition, personality and mood change; hallucinations; seizures and other impairments of consciousness; ortho static faintness; headaches; special senses; speech and language function; swallowing; limb coordination; slowness of movement; involuntary movements; strength and sensation; pain; gait and balance; and sphincter, bowel, and sexual function. A positive response m.iy help clarih a diagnosis. For instance, if a patient complaining of ataxia and hemiparesis admits to unilateral deafness, this may suggest an acoustic neuroma. Headaches in a patient with pataparesis suggest a parasagittal meningioma rather than a spinal cord lesion. The developmental history must be assessed in children and may also be of value in adults whose illness started during childhood. The review must include all the organ sysrems. Neurological function is adversely affected by dysfunction of many systems, including the liver, kidney, gastrointestinal tract, heart, and blood vessels. Several neurological diseases are characterized by multi-organ involvement, such as vasculitis, sarcoidosis, mitochondrial disorders, and storage diseases.
REVIEW OF PATIENT SPECIFIC INFORMATION History of Previous Illnesses Information about the patient's background often greatly helps the neurologist make a diagnosis of the cause of the symptoms. This information includes the history of medical
Items in the patient's medical and surgical history may help explain the present complaint. For instance, seizures and
6
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
worsening headaches in a patient who previously had surgery for lung cancer suggest a brain metastasis. Chronic low-back pain in a patient complaining of numbness and weakness in the legs on walking half a mile suggests neurogenic claudication from lumbar canal stenosis. The record of the history should include dates and details of all surgical procedures; significant injuries, including head trauma and fractures; hospitalizations; and conditions requiring medical consultation and medications. For pediatric patients, information on the pregnancy and state of the infant at birth should be recorded. Certain features in the patient's history should always alert the physician to the possibility that they may be responsible for the neurological complaints. Gastric surgery may lead to vitamin B12 deficiency. Sarcoidosis may cause Bell's palsy, diabetes insipidus, ophthalmoplegia, and peripheral neuropathy. Disorders of the liver, kidney, and small bowel can be associated with a wide variety of neurological disorders. Systemic malignancy can cause direct and indirect (paraneoplastic) neurological problems. Do not be surprised if the patient fails to remember previous medical or surgical problems. It is common to find abdominal scars on a patient who described no surgical procedures until questioned about the scars. Medications are often the cause of neurological disturbances, particularly chemotherapy drugs. Isoniazid may cause a peripheral neuropathy. Lithium carbonate may produce tremor and ataxia. Neuroleptic agents can produce a parkinsonian syndrome or dyskinesias. Most patients do not think of vitamins, oral contraceptives, non-prescription analgesics, and herbal compounds as medications, and specific questions about these agents are necessary.
Family History Many neurological disorders are hereditary. Hence a history of similar disease in family members or of consanguinity may be of diagnostic importance. However, the expression of a gene mutation may be quite different from one family member to another with respect not only to the severity of neurological dysfunction but also to the organ systems involved. For instance, the mutations of the gene for Mach ado-Joseph disease (SCA 3) can cause several phenotypes. A patient with Charcot-Marie-Tooth disease (hereditary motor-sensory neuropathy) may have a severe peripheral neuropathy, whereas relatives may have only pes cavus. Reported diagnoses may be inaccurate. In families with dominant muscular dystrophy, affected individuals in earlier generations are often said to have had "arthritis" that put them into a wheelchair. Some conditions, such as epilepsy, may be "family secrets." Therefore, one should be cautious in accepting a patient's assertion that there is no family history of a similar disorder. If there is a possibility that the disease is inherited it is helpful to obtain information from
parents and grandparents and to examine relatives at risk. Minimum data for all first- and second-degree relatives should include age (currently or at death), cause of death, and any significant neurological or systemic diseases.
T H E EXAMINATION Neurological Examination A description of the neurological examination may be found in several excellent textbooks (see References), Trainees must be able to perform and understand the complete neurological examination, in which every central nervous system region, peripheral nerve, muscle, sensory modality, and reflex is tested. However, the full neurological examination is too lengthy to perform in practice. Instead, the experienced neurologist uses the focused neurological examination to examine in detail the neurological functions that are relevant to the history, and performs a screening neurological examination to check the remaining parts of the nervous system. This approach should confirm, refute, or modify the initial hypotheses of disease location and causation derived from the history (see Figure 1.1). Both the presence and absence of abnormalities may be of diagnostic importance. For instance, if a patient's symptoms suggest a left hemiparesis, the neurologist searches carefully for a left homonymous hemianopia; evidence that the blink or smile is slowed on the left side of the face; that rapid, repetitive movements are impaired in the left limbs; that the tendon reflexes are more brisk on the left than the right; that the left abdominal reflexes are absent; and that the left plantar response is extensor. Along with testing the primary modalities of sensation on the left side, the neurologist may examine the higher integrative aspects of sensation, including graphesthesia, stereognosis, and sensory extinction with double simultaneous stimuli, The presence or absence of some of these features can separate a left hemiparesis arising from a lesion in the right cerebral cortex or from one in the left cervical spinal cord. The screening neurological examination {Table 1.1) is designed for quick evaluation of the mental status, cranial nerves, motor system (strength, muscle tone, presence of involuntary movements and postures), coordination, gait and balance, tendon reflexes, and sensation. More complex functions are tested first; if these are performed well, then it may not be necessary to test the component functions. The patient who can walk hccl-to-toe (tandem gait) does not have a significant disturbance of the cerebellum or of joint position sensation. Similarly, the patient who can do a pushup, rise from the floor without using the hands, and walk on toes and heels will have normal limb strength when each muscle group is individually tested. Asking the patient to hold the arms extended in supination in front of the body with the eyes open allows evaluation of strength and posture. It may also reveal involuntary movements such as tremor, dystonia,
DIAGNOSIS OV NKUKOl OG1CAI iNSl-ASK Table 1.1:
Outline of the screening neurological examination
Mental status: Assess while recording the history. Cranial nerves: I: Not tested II: Gross visual acuity each eye: Visual fields by confrontation, including double simultaneous stimuli Rmduscopy III, IV, VI; Horizontal and vertical eye movements Pupillary response to light Presence of nystagmus V: Pinprick and touch sensation on face, corneal reflex VII: Close eyes, show teeth VIII: Perception of whispered voice in each car or rubbing of fingers. If impaired, look in external auditory canals, and use tuning fork for lateralization and hone versus air sound conduction. IX, X: Palate lifts in midline, gag reflex present XI: Shrug shoulders XI!: Protrude tongue Limbs: Each limb tested separately: Presence of involuntary movements Muscle mass (atrophy, hypertrophy) and look for fascidilations Muscle tone in response to passive flexion and extension Power of main muscle groups Coordination; finger-to-nose and hccl-to-shin testing, performance of rapid alternating movements Tendon reflexes Plantar responses Pinprick and light touch on hands and feet Double simultaneous stimuli on hands and feet Joint position sense in hallux and index finger Vibration sense at ankle and index finger Gait and balance Romberg test myoclonus, or chorea. A downward or pronator drift of a weak arm is expected. Repeating the maneuver with the eyes closed allows assessment of joint position sensation. The screening neurological examination may miss important neurological abnormalities. For instance, a bitemporal visual field defect may not be detected when the fields of both eyes are tested simultaneously. It is necessary to test each eye separately. Similarly, a parietal lobe syndrome may go undiscovered unless visuospatial function is assessed. It is sometimes difficult to decide whether a physical finding is normal or abnormal, and only experience prevents the neurologist from misinterpreting as a sign of disease something that is the result of normal variation. Every person has some degree of asymmetry. Moreover, what is abnormal in young adults may be normal in the eldetly. Loss of the ankle reflex and loss of vibration sense at the big toes are common findings in patients older than 60 years. Conversely, children cannot detect the distal stimuli when the hand and face are simultaneously touched on the same side of the body until they are 7 years old. The experienced neurologist understands the normal range of neurological variation, while the beginner frequently records mild impairment of a number of different functions. These include isolated deviation of the tongue or
7
uvula to one side and minor asymmetries of reflexes or sensation. Such soft signs may be incorporated into the overall synthesis of the disorder if they are consistent with other parts of the history and examination; otherwise, they should be disregarded. If an abnormality is identified, all features that are usually associated should be sought. For instance, ataxia of a limb may result from a corticospinal tract lesion, sensory defect, or cerebellar lesion. If the limb incoordination is due to a cerebellar lesion, there will be ataxia on finger-to-nose and hccl-to-shin testing, abnormal rapid alternating movements of the hands (dysdiadochokinesia), and often nystagmus and ocular dysmetria. If some of these signs of cerebellar dysfunction are missing, examination of joint position sense, limb strength, and reflexes may demonstrate that this incoordination is due to something other than a cerebellar lesion. At the end of the neurological examination, the abnormal physical signs should be classified as definitely abnormal (bard signs) or equivocally abnormal (soft signs). The hard signs, when combined with symptoms from the history, allow the neurologist to develop a hypothesis about the anatomical site of the lesion or at least about the neurological pathways involved. The soft signs can then be reviewed to determine if they conflict with or support the initial conclusion. Remember that the primary purpose of the neurological examination is to reveal functional disturbances that localize abnormalities. The standard neurological examination is less effective when used to monitor the course of a disease or its temporal response to treatment. Special quantitative functional tests and rating scales are needed to measure change in neurological function over time.
General Physical Examination The nervous system is damaged in so many general medical diseases that a general physical examination is an integral pan ol the examination ol patients with neurological disorders. For instance, atrial fibrillation, valvular heart disease, or an atrial septal defect may cause embolic strokes in the central nervous system. Hypertension increases the risk for all types of stroke. Signs of malignancy raise the possibility of metastatic lesions of the nervous system or paraneoplastic neurological syndromes, such as a subacute cerebellar degeneration or progressive multifocal leukocnccphalopathy. In addition, some diseases such as vasculitis and sarcoidosis affect both the brain and other organs.
ASSESSMENT OF T H E CAUSE OF T H E PATIENT'S SYMPTOMS Anatomical Localization At the completion of the history, the experienced neurologist should attempt the first assessment of the anatomical
8
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
location of the lesion or the neurological systems involved, and of the pathophysiology of the disorder (see Figure 1.1). The experienced neurologist then uses the examination to localize the lesion before trying to determine its cause. The initial question is whether the disease is in the brain, spinal cord, peripheral nerves, neuromuscular junctions, or muscles. Then it must be established whether the disorder is focal, multifocal, or a system disorder. A system disorder is a disease that causes degeneration of one part of the nervous system, while it spares other adjacent ncutological systems. For instance, degeneration of the corticospinal tracts and spinal motor neurons with sparing of the sensory pathways of the central and peripheral nervous systems is the hallmark of the system degeneration termed motor neuron disease or amyotrophic lateral sclerosis. Another example of a system degeneration is multiple system atrophy, manifested by slowness of movement (parkinsonism), ataxia, and dysautonomia. The first step in localization is to translate the patient's symptoms and signs into abnormalities of a nucleus, tract, ot system. For instance, loss of pain and temperature sensation on one-half of the body, excluding the face, indicates a lesion of the contralateral spinothalamic tract in the high cervical spinal cord. A left sixth nerve palsy, with weakness of left face and right limbs, points to a left pontine lesion, A left homonymous hemianopia indicates a lesion in the right optic tract, optic radiations, or occipital cortex. The neurological examination plays a crucial role in localizing the lesion. A patient complaining of tingling and numbness in the feet might initially be thought to have a peripheral neuropathy. If examination shows hyperreflcxia in the arms and legs, and no vibration sensation below the clavicles, the lesion is likely to be in the spinal cord, and the many causes of peripheral neuropathy can be dropped from consideration. A patient with a history of weakness of the left arm and leg who is found on examination to have a left homonymous hemianopia has a right cerebral lesion, not a cervical cord problem. The neurologist must decide if the symptoms and signs could all arise from one focal lesion or whether several anatomical sites must be involved. The principle of parsimony, or Occam's razor, requires that we strive to hypothesize only one lesion. The differential diagnosis for a single focal lesion is significantly differenr from that for multiple lesions. Thus a patient complaining of loss of leftsided vision and left-sided weakness is likely to have a lesion in the right cerebral hemisphere, possibly caused by stroke or rumor. On the other hand, if the visual difficulty is due to a central scotoma in the left eye, and if the upper motor neuron weakness affects the left limbs but spates the lower cranial nerves, there must be two lesions: one in the left optic nerve and one in the left corticospinal tract below the medulla, as seen, for example, in multiple sclerosis. If a patient with symptoms of slowly progressive slurring of speech and difficulty walking is found to have ataxia of the arms and legs, bilateral extensor plantar responses, and
optic atrophy, the lesions must either be multifocal (affecting brainstem and optic nerves, and hence probably multiple sclerosis) or a system disorder, such as a spinocerebellar degeneration. The complex vascular anatomy of the brain can sometimes cause multifocal neurological deficits to tesult from only one vascular abnormality. For instance, a patient with occlusion of one vertebral artery may suffer a srroke producing a midbrain lesion, a hemianopia, and an amnestic syndtome. Synthesis of symptoms and signs into the anatomical localization of a lesion requires a good knowledge of neuroanatomy, including the location of all major pathways in the nervous system and their inter-relationships at different levels. In making this synthesis, the ttainee will find it helpful to refer to diagrams that show transverse sections of the spinal cord, medulla, pons, and midbrain; the brachial and lumbosacral plexuses; and the dermaromes and myotomes. Knowledge of the functional anatomy of the cerebral cortex and the blood supply of the brain and spinal cord is also essential. Symptoms and signs may arise not only from disturbances caused at the focus of an abnormality (focal localizing signs) but also at a distance. One example is the damage that results from the shift of intracranial contents produced by an expanding supra tentorial tumor. This may cause a palsy of the third or sixth cranial nerve, even though the tumor is far from the cranial nerves. Clinical features caused by damage far from the primary site of abnormality are called false localizing signs. The term derives from the era before neuroimaging studies when clinical examination was the major means of lesion localization. In fact, these are not false signs but rarher rhe signs that the inttacranial shifts arc marked, alerting the clinician to the latge size of the tumor.
DIFFERENTIAL DIAGNOSIS Once the likely site of the lesion is identified, the next step is to generate the differential diagnosis, that is, the list of diseases that may be responsible for a parienr's symptoms and signs (see Figure 1.1). The experienced neurologist automatically first considers the most likely cause of the symptoms, followed by less common causes. The beginner is happy to generate a list of the main causes of the symptoms in whatever order comes to mind. Experience indicates the most likely causes, based on the specific features of rhe patient, the parts of the nervous system affected, and the relative frequency of each disease. Remember that rare presentations of common diseases are more common than common presentations of rare diseases. Sometimes only a single disease can be incriminated, but usually there are several candidate diseases. The list of possibilities should take into account both the temporal features of the patient's symptoms and the pathological
DIAGNOSIS OF NEUROLOGICAL DISEASE processes known to affect the relevant area of the nervous system. For example, in a patient with signs indicating a lesion of the internal capsule, the cause is likely to be stroke if the hemiplegia had a sudden onset. If there was progression over weeks or months, the cause is likely an expanding tumor. Another example is a patient with signs of multifocal lesions. If symptoms have relapsed and remitted over several years, the diagnosis is likely to be multiple sclerosis or multiple strokes (depending on the patient's age, sex, and risk factors). If symptoms appeared only recently and progressed, multiple metastases should be considered. Again, the principle of parsimony or Occam's razor should be applied when constructing the differential diagnostic list. Consider a patient with a 3-week history of a progressive spinal cord lesion who suddenly experiences aphasia. Perhaps he or she had a tumor compressing the spinal cord and has incidentally developed a small stroke. However, parsimony would suggest a single disease, probably cancer with multiple metastases. Another example is a patient with progressive atrophy of the small muscles of the hands for 6 months before the appearance of a pseudobulbar palsy. She or he could have bilateral ulnar nerve lesions and recent bilateral strokes, but amyotrophic lateral sclerosis is more likely. However, remember that nature does not always obey the rules of parsimony. The differential diagnosis generally starts with pathological processes, such as a stroke, a tumor, or an abscess. H;ich pathological process may result from several different diseases. Thus a clinical diagnosis of an intracranial neoplasm generates a list of the different types of tumors thar arc likely to be responsible for the clinical manifestations in this particular patient. Similarly, in a patient with a stroke the clinical history may help separate hemorrhage, embolism, thrombosis, vascular spasm, or vasculitis. The skilled diagnostician is justly proud of placing the correct diagnosis at the top of the list, but it is more important to ensure that all possible diseases are considered. If a disease is not considered, it is unlikely to be diagnosed. Treatable disorders should always be considered, even when there is a very low probability. This is especially true if they may mimic more common incurable neurological disorders, such as Alzheimer's disease or amyotrophic lateral sclerosis.
LABORATORY INVESTIGATIONS Sometimes the neurological diagnosis can be made without any laboratory investigations. This is true for a clear-cut case of Parkinson's disease, myasthenia gravis, or multiple sclerosis. Nevertheless, even in these situations, appropriate laboratory documentation is important for other physicians who will see the patient in the future. In other cases the cause of the disease will only be elucidated by the use of laboratory tests. These tests may in individual cases include hematological and biochemical blood studies;
9
neurophysiological testing (Chapter 36); neuroimaging (Chapter 37); organ biopsy; and bacteriological and virological studies. The use of laboratory tests in the diagnosis of neurological diseases is considered more fully in Chapter 35.
MANAGEMENT OF NEUROLOGICAL DISORDERS Not all diseases arc curable. However, even if a disease is incurable the physician will be able to reduce the patient's discomfort and assist the patient and the family in managing the disease. The understanding of neurological diseases is a science. The diagnosis of neurological disease is a combination of science and experience. The management of neurological disease is an art, an introduction to which is provided in Chapter 48.
T H E EXPERIENCED NEUROLOGIST'S APPROACH TO THE DIAGNOSIS OF C O M M O N NEUROLOGICAL PROBLEMS The skills of a neurologist are learned. Seeing many cases of a disease teaches the neurologist which symptoms and signs should he present, and, just as important, which should not be present. Although there is no substitute for experience and pattern recognition, the trainee can learn the clues used by the seasoned practitioner to achieve a diagnosis. Part I of this book covers the main symptoms and signs of neurological disease. These chapters describe how an experienced neurologist approaches common presenting problems, such as a movement disorder, a speech disturbance, or diplopia, to arrive at the correct diagnosis. Part II of this book comprises rhe major fields of investigation and management of neurological disease. Part III provides a compendium of the neurological diseases themselves.
REFERENCES Brazis, P. W., Masdeu, J, C, & Biller, J. 1996, Localization in Clinical Neurology, 3rd cd, Little Brown, Boston DeMycr, W. F„ 1995, Technique of the Neurological Examination, 4th ed, McGraw-Hill, New York Fenichel, G. M. 1993, "The neurological examination of the newborn." Bram Dev, vol. 15, pp. 403-410 Haerer, A. F. 1992, The Neurological Examination, 5th ed, Lippincort Raven, Philadelphia Marsden, C. D. St Fowler, T.J. 1997, Clinical Neurology, Edward Arnold, London Plum, F. &C Posner, J. B. 19K2, The Diagnosis of Stupor and Coma, 3rd ed, Davis, Philadelphia Rolak, L. A. (ed) 2001, Neurology Secrets, 3rd cd, Hanley & Bdfus, Philadelphia Swaiman, K. F. 1994, Pediatric Neurology: Principles and Practices, 2nd cd, Mosby, St. Louis
)
Chapter 2 Episodic Impairment of Consciousness Joseph Bruni Syncope History and Physical Examination Causes of Syncope Miscellaneous Causes of Syncope Investigations of 1'aticnts with Syncope Seizures Hisroty and Physical Examination
11 12 13 16 17 17 17
Temporary loss of consciousness may be caused by impaired cerebral perfusion (syncope, fainting), cerebral ischemia, migraine, epileptic seizures, metabolic disturbances, sudden increases in intracranial pressure, or sleep disorders. Anxiety attacks, psychogenic seizutes, panic disorder, and malingering may be difficult to distinguish from these conditions. At times, the diagnosis may not be clatified without detailed laboratory examinations and prolonged periods of observation. Syncope may result from decreased cardiac output secondary to cardiac arrhythmias, outflow obstruction, hypovolemia, orthostatic hypotension, or decreased venous return. Cerebrovascular disturbances from transient ischemic attacks of the posterior or anterior cerebral circulations or cerebral vasospasm from migraine, subarachnoid hemorrhage, or hypertensive encephalopathy may tesult in temporary loss of consciousness. Metabolic disturbances caused by hypoxia, drugs, anemia, and hypoglycemia may result in frank syncope or, more frequently, may present with the sensation of an impending faint (ptesyncope). Absence seizures, generalized tonic-clonic seizures, and complex partial seizures are associated with alterations of consciousness and, in most cases, can be easily distinguished from syncope. Epileptic seizutes may be difficult to distinguish from pseudoseizures (psychogenic seizures), panic attacks, and malingering. In children, breath-holding spells, a form of syncope that is discussed latet in the chapter, can cause a transitory alteration of consciousness that may mimic epileptic seizures. Although sudden increases of intracranial pressure (which may result from intermittent hydrocephalus, severe head trauma, brain tumors, inttacerebral hemorrhage, or Reye's syndrome) may produce sudden loss of consciousness, these patients frequently have other neurological manifestations that lead to this diagnosis.
Absence Seizures Tonic-Clonic Seizures Complex Partial Seizures Investigations of Seizures Psychogenic Seizures or Pseudoseizures (Nonepileptic Seizures) Miscellaneous Causes of Altered Consciousness
18 IS IS 18 19 20
In patients with episodic impaitment of consciousness, a diagnosis relies heavily on the clinical history described by the patient and observers. Laboratory investigations, however, may provide useful information. In a small number of patients, a cause for the loss of consciousness may not be established, and these patients may require longer periods of observation. Tabic 2.1 compares the clinical features of syncope and seizures.
SYNCOPE The pathophysiologic basis of syncope is the gradual failure of cerebral perfusion with a reduction in cerebral oxygen availability. Syncope is often preceded by a symptom complex (presyncopc) characterized by lightheadedness, generalized muscle weakness, giddiness, visual blurring, tinnitus, and gastrointestinal symptoms. The patient may appear pale and feel cold and sweaty. The onset of loss of consciousness is generally gradual but may be rapid, without prcsyncopal symptoms, if related to certain conditions, such as a cardiac arrhythmia. The gradual onset may allow patients to protect themselves from falling and injury. A simple faint is usually precipitated by emotional stress, unpleasant visual stimuli, prolonged standing, or pain. Although the duration of unconsciousness is brief, it may vary from seconds to minutes. During the faint, the patient may be motionless or display myoclonic jerks. Urinary incontinence is uncommon but not rare. The pulse is weak and often slow. Urea thing may be shallow and the blood pressure barely obtainable. As the fainting episode cotrects itself (e.g., by the patient becoming horizontal), the color returns, breathing becomes more regular, and the pulse and blood pressure return to normal. After the faint, there is some residual weakness, hut unlike II
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS Table 2.1:
Comparison of clinical features of syncope and seizures
Features
Syncope
Seizure
Relation to posture Time of day Precipitating factors
Common Diurnal Emotion, injury, pain, crowc s, heat
Skin color Aura or premonitory symptoms Convulsion injury
Pallor Long Rare Rare
Urinary incontinence Postictal confusion Postictal headache Focal neurological signs Cardiovascular signs Abnormal electroencephalogram recording
Rare Rare No No Common ( ;ardiac syncope) Rare (may show generalized slowing during the event)
No Diurnal or nocturnal Sleep loss, drug/alcoliol withdrawal Cyanosis or normal Brief Common Common (with convulsive seizures) Common Common Common Occasional No Common
Table 2.2:
Classification of syncope
Cardiac arrhythmias Bradyarrhythmias Tachyarrhythmias Reflex arrhythmias Decreased cardiac output Cardiac outflow obstruction Inflow obstruction Cardiomyopathy Hypovolemia Hypotension Drug use Dysautonomia Carotid sinus Vertebrobasilar disease Vasospasm Takayasu's arteritis Metabolic Hypoglycemia Anemia Anoxia Hyperventilation Vasovagal (vasodepressor; neurocardiogenic; neural mediated) Cardiac syncope Cough, micturition Multifactorial
with seizures, confusion, headaches, and drowsiness are uncommon sequelae. Nausea may be noted when the patient regains consciousness. The causes of syncope are generally classified according to the pathophysiological mechanism involved (Table 2.2), but the final common pathway is cerebral hypoperfusion.
History and Physical Examination The history and physical examination are the most important parts of the initial evaluation of syncope. There
are sit mificant age and sex differences in the frcq
the various types of syncope. Syncope occurring in children and young adults is most commonly due to hyperventilation or vasovagal (vasodepressor) attacks and less commonly due to congenital heart disease (Lewis and Dhala 1999). Fainting associated with benign tachycardias without underlying organic heart disease may also appear in the younger age-groups. Syncope caused by basilar migraine is more common in young females. When repeated syncope begins in later life, organic disease of the cerebral circulation or cardiovascular system is usually responsible. In establishing the cause of syncope, the most important step is a careful history. The diagnosis often can be made from the patient's description. The previously described presyncopal symptoms and certain clues in the history may help establish the cause. The neurologist should always obtain a full description of the first faint. The clinical features should be established, with emphasis on precipitating factors, posture, type of onset of the faint and whether it was abrupt or gradual, position of head and neck, the presence and duration of preceding and associated symptoms, duration of loss of consciousness, rate of recovery, and sequelae. If possible, an observer should be questioned about clonic movements, color changes, diaphoresis, pulse, respiration, urinary incontinence, and the nature of recovery. Clues in the history that suggest cardiac syncope include a history of palpitations or a fluttering sensation in the chest before losing consciousness. These symptoms are common in arrhythmias. In vasodepressor syncope and orthostatic hypotension, preceding symptoms of lightheadedness may be common. Episodes of cardiac syncope are generally briefer than vasodepressor syncope, and the onset is usually rapid. Episodes caused by cardiac arrhythmias occur independent of position, whereas in vasodepressor syncope and syncope caused by orthostatic hypotension, the patient is usually standing.
EPISODIC IMPAIRMENT OF CONSCIOUSNESS Attacks of syncope precipitated by exertion suggest a cardiac etiology. Exercise may induce arrhythmic syncope or syncope caused by decreased cardiac output secondary to blood flow obstruction, such as may occur with aortic or subaortic stenosis. Exercise-induced syncope may also be caused by cerebrovascular disease, aortic arch disease, congenital heart disease, pulseless disease (Takayasu's disease), pulmonary hypertension, anemia, hypoxia, and hypoglycemia, but often no cardiac disease is uncovered (Colivicchi et al. 2002). A family history of sudden cardiac death, especially in females, might suggest the long QT syndrome. Because many drugs can induce orthostatic hypotension or produce cardiac arrhythmias, a careful and complete medical and medication history is mandatory (Goldschlager et al. 2003). The neurologist should inquire about the frequency of attacks of loss of consciousness and the presence of cerebrovascular or cardiovascular symptoms between episodes. The patient should be questioned about whether all the episodes are similar, because some parienrs experience more than one type of attack. With an accurate description of the attacks and familiarity with clinical features of various types of syncope, the physician should be able to correctly diagnose most patients. Some seizure types that have to be distinguished from syncope include orbitofronral complex partial seizures, which can be associated with autonomic changes, and complex partial seizures that are associated with sudden falls and altered awareness followed by confusion and gradual recovery (temporal lobe syncope). Features that distinguish syncope from seizures and other alterations of consciousness are discussed later in this chapter. After a complete history, the physical examination is of next importance. Examination during the episode is very informative but frequently impossible unless presyncopal symptoms can be reproduced by a Valsalva maneuver or by recrearing the circumstances of the attack, such as by position change. In the patient with suspected cardiac syncope, particular attention should be paid to the vital signs and determination of supine and erect blood pressure. Normally, upon standing the systolic blood pressure rises and the pulse rate may increase. An orthostatic drop in blood pressure greater than 15 mm Hg may suggest autonomic dysfunction. Blood pressure should be assessed in both arms if cerebrovascular disease, subclavian steal, or Takayasu's arteritis is suspected. During syncope caused by a cardiac arrhythmia, a heart rate faster than 140 beats per minute usually indicates an ectopic cardiac rhythm, whereas a bradycardia with a heart rate of less than 40 beats per minute suggests complete atrioventricular (AV) block. Supraventricular tachycardias can be terminated abruptly by carotid sinus massage, whereas a ventricular tachycardia shows no response. However, this technique is no longer advised because of the risk of cerebral embolism from atheroma in the carotid
13
artery wall. Stokes-Adams attacks may be of longer duration and may be associated with audible atrial contraction and a variable first heart sound. Heart disease as a cause of syncope is more common in the elderly patient (Brady and Shen 2002). The patient should undergo cardiac auscultation for the presence of cardiac murmurs and abnormalities of the heart sounds. There may be the murmur of aortic stenosis, subaortic stenosis, or mitral valve disease. An intermittent posture-related murmur may be heard with an atrial myxoma. A systolic click in a young person suggests mitral valve prolapse. A pericardial rub suggests pericarditis. All patients should undergo observation of the carotid pulse and auscultation of the neck. The degree of aorticstenosis may at times be reflected in a delayed carotid upstroke. Carotid, ophthalmical, and supraclavicular bruits suggest underlying cerebrovascular disease. Carotid sinus massage may be useful in older patients suspected of having carotid sinus syncope, but it is important to keep in mind that up to 2 5 % of asymptomatic subjects may have some degree of carotid sinus hypersensitivity. Carotid sinus massage should be avoided in patients with suspected cerebrovascular disease, and when performed, it should be done in properly controlled conditions with electrocardiogram (ECG) and blood pressure monitoring.
Causes of Syncope Cardiac
Arrhythmias
Both bradyarrhythmias and tachyarrhythmias may result in syncope, and abnormalities of cardiac rhythm resulting from dysfunction from the sinoatrial (SA) node to the Purkinje network may be involved. Arrhythmias are a common cause of syncope and must be considered in all cases in which an obvious mechanism is not known. Syncope caused by cardiac arrhythmias generally occurs more quickly than syncope from other causes and may be more prolonged. Cardiac syncope may occur in any position, may occasionally be induced by exercise, and may occur in both congenital and acquired heart disease. Although some patients experience palpitations during some arrhythmias, others are not aware of any cardiacsymptoms, The most common arrhythmias causing syncope are AV block, SA block, and paroxysmal supraventricular and ventricular tachyarrhythmias. AV block describes disturbances of conduction occurring in the AV conducting system, which include the AV node to the bundle of His and the Purkinje network. SA block describes a failure of consistent pacemaker function of the SA node. Paroxysmal tachycardia refers to a rapid heart rate secondary to an ectopic focus outside the SA node; this may be supraventricular or intraventricular,
14
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Atrioventricular
Block
AV block is probably the most common cause of arrhythmic cardiac syncope. The term Stokes-Adams attack describes disturbances of consciousness occurring in association with a complete AV block, which occurs primarily in elderly patients. The onset of a Stokes-Adams attack is generally sudden, although a number of visual, sensory, and perceptual premonitory symptoms may be experienced. During the syncopal attack, the pulse disappears and no heart sounds are audible. The patient is pale and, if standing, falls down, often with resultant injury. If the attack is sufficiently prolonged, respiration may be labored and urinary incontinence and clonic muscle jerks may occur. Prolonged confusion and neurological signs of cerebral ischemia may be present. Regain of consciousness is generally rapid. The clinical features of complete AV block include a slow-collapsing pulse and elevation of the jugular venous pressure, sometimes with cannon waves. The firsr heart sound is of variable intensity, and heart sounds related to atrial contractions may be audible. The diagnosis is confirmed by ECG, which demonstrates the independence of atrial P waves and ventricular QRS complexes. During Stokes-Adams attacks, ECG recordings generally show ventricular standstill, but ventricular fibrillation or tachycardia may also occur. Sinoatrial Block SA block may result in dizziness, lightheadedness, and syncope. It is most frequent in rhe elderly. Palpitations are common, and the patient appears pale. Patients with SA node dysfunction frequently have other conduction disturbances, and certain drugs, such as verapamil, digoxin, and beta blockers, may further impair SA node function, On examination, the patient's pulse may be regular between attacks. During an attack, the pulse may be slow or irregular, and a number of rhythm disturbances may be present. Paroxysmal
Tachycardia
Supraventricular tachycardias include atrial fibrillation with a rapid ventricular response, atrial flutter, and Wo Iff-Park in son-White syndrome. These arrhythmias may suddenly reduce cardiac output enough to cause syncope. Ventricular tachycardia or ventricular fibrillation may result in syncope if the heart rate is sufficiently fast and if the arrhythmia lasts longer than a few seconds. Patients are generally elderly and usually have evidence of underlying cardiac disease. Ventricular fibrillation may be part of long QT syndrome in association with congenital deafness in children. In most patients with long QT syndrome, episodes begin in the first decade of life, but onset may be much later. Exercise may precipitate an episode of cardiac
syncope. Long QT syndrome may be acquired and may present in adults as epilepsy. Acquired causes include cardiac ischemia, mitral valve prolapse, myocarditis, and electrolyte disturbances (Ackerman 1998), as well as many drugs (Goldschlager et al. 2002). Brugada's syndrome may produce syncope as a result of ventricular tachycardia or ventricular fibrillation. The ECG demonstrates an incomplete right bundle branch block in leads V, and V 2 with ST-segment elevation in the right precordial leads (Goldschlager et al, 2003). Reflex
Cardiac
Arrhythmias
A hypersensitive carotid sinus may be a cause of syncope in the elderly, mosr commonly in men. Syncope may result from a reflex sinus bradycardia, sinus arrest, or AV block; peripheral vasodilation with a decrease in arterial pressure; or from a combination of both. Although 10% of the population older than 60 years may have a hypersensitive carotid sinus, not all such patients experience syncope. Accordingly, this diagnosis should be considered only when the clinical history is compatible. Carotid sinus syncope may be initiated by a tight collar or by carotid sinus massage on clinical examination. When syncope occurs, the patient is usually upright and the duration of the loss of consciousness is generally a few minutes. When consciousness is regained, the patient is mentally clear. Unfortunately, there are no accepted diagnostic criteria for carotid sinus syncope, and the condition is overdiagnosed. Syncope induced by unilateral carotid massage or compression may also be caused by partial occlusion, usually atherosclerotic, of the contralateral carotid or a vertebral artery, or it may be due to the release of atheromatous emboli. Because of these risks, carotid artery massage is no longer recommended. The rare syndrome of glossopharyngeal neuralgia is characterized by intense paroxysmal pain in the throat and neck and is accompanied by bradycardia or asystole, severe hypotension, and, if prolonged, seizures. Episodes of pain may be initiated by swallowing but also by chewing, speaking, laughing, coughing, shouting, sneezing, yawning, or talking. The episodes of pain always precede the loss of consciousness (see Chapter 75), Rarely, cardiac syncope may be due to bradyarrhythmias consequent to vagus nerve irritation caused by esophageal diverticula, tumors and aneurysms in the region of the carotid sinus, mediastinal masses, or gallbladder disease. Decreased
Cardiac
Output
Syncope may occur as a result of a sudden and marked decrease in cardiac output. Both congenital and acquired conditions may be causal. Tetralogy of Fallot, the most common congenital malformation causing syncope, does so by producing hypoxia caused by right-to-left shunting.
EPISODIC IMPAIRMENT OF CONSCIOUSNESS Other congenital conditions associated with cyanotic heart disease may also cause syncope. Ischemic heart disease and myocardial infarction, aortic stenosis, idiopathic hypertrophic subaortic stenosis, pulmonary hypertension, and other causes of obstruction of pulmonary outflow, atrial myxoma, and cardiac tamponade may sufficiently impair cardiac output to cause syncope. Exercise-induced or effort syncope may occur in aortic or subaortic stenosis and other states in which there is reduced cardiac output and associated peripheral vasodilation induced by the exercise. Exercise-induced cardiac syncope may also be related to exercise-induced cardiac arrhythmias. In patients with valvular heart disease, syncope may be related to arrhythmias. Syncope may also be due to reduced cardiac output secondary to myocardial failure, to mechanical prosthetic valve malfunction, or to thrombus formation. Mitral valve prolapse is generally a benign condition, but rarely cardiac arrhythmias can occur. The most significant arrhythmias are ventricular. In atrial myxoma or with massive pulmonary embolism, a sudden decrease in left ventricular output may occur. In atrial myxoma, syncope is often positional and occurs when the tumor falls into the AV valve opening during a change in position of the patient, thereby causing obstruction of the left ventricular inflow. Decreased cardiac output may also be secondary to conditions that result in inflow obstruction or reduced venous return. These include superior and inferior vena cava obstruction, tension pneumothorax, constrictive cardiomyopathies, constrictive pericarditis, and cardiac tamponade. Syncope associated with aottic dissection may he due to cardiac tamponade but may also be secondary to hypotension, obstruction of cerebral circulation, or a cardiac arrhythmia. Hypovolemia Acute blood loss, usually due to gastrointestinal tract bleeding, may cause weakness, faintness, and syncope if sufficient blood is lost. Blood volume depletion by dehydration may cause faintness and weakness, but true syncope is uncommon, unless the dehydration is combined with exercise.
15
The common faint may or may not be associated with bradycardia. The patient experiences impairment of consciousness, with loss of postural tone. Signs of autonomic hyperactivity are common, including pallor, diaphoresis, nausea, and dilated pupils. After recovery, patients may have persistent pallor, sweating, and nausea; if they get up too quickly, they may black out again. The common faint may he preceded by presyncopal symptoms of lethargy and fatigue, nausea, weakness, a sensation of an impending faint, and yawning. It is more likely to occur in certain circumstances, such as a hot crowded room, especially if the person is tired or hungry and upright or sitting. The episode of fainting may be brought on by venipuncture, the sight of blood, or a sudden painful or traumatic experience. When the patient regains consciousness, there usually is no confusion or headache, although weakness is commonly described. As in other causes of syncope, if the period of cerebral hypoperfusion is long enough, urinary incontinence and a few clonic movements may be observed (convulsive syncope). Orthostatic syncope occurs when autonomic factors that compensate for the upright posture are inadequate. This can result from a variety of clinical disorders. Blood volume depletion or venous pooling may result in syncope when the individual assumes an upright posture. Orthostatic hypotension resulting in syncope may also occur with drugs that impair sympathetic nervous system function. Diuretics, antihypertensive medications, nitrates, arterial vasodilators, calcium-channel blockers, phenothiazincs, L-dopa, alcohol, and tricyclic antidepressants may all result in orthostatic hypotension. Autonomic nervous sysrem dysfunction resulting in syncope caused by orthostatic hypotension may be a result of primary autonomic failute caused by Shy-Drager syndrome or Riley-Day syndrome. Neuropathies that affect the autonomic nervous system include those of diabetes mellitus, amyloidosis, Guillain-Barre syndrome, acquired immunodeficiency syndrome, chronic alcoholism, hepatic porphyria, and beriberi. Rarely, subacute combined degeneration, syringomyelia, and other spinal cord lesions may damage the descending sympathetic pathways, producing orthostatic hypotension. Cerebrovascular
Ischemia
Hypotension A number of conditions cause syncope by producing a decrease in arterial pressure. The cardiac causes were already discussed. The common faint (designated variously as vasovagal, vasodepressor, neurocardiogenic, or neuraliy mediated syncope) is rhe most common cause of a transient decrease in blood pressure resulting in syncope (Grubb and Kanjwal 2003). It is often recurrent, tends to occur in relation to emotional stimuli, and may affect 2 0 - 2 5 % of young people. Less commonly, it occurs in older patients with cardiovascular disease (Fenton et al. 2000).
Syncope may occasionally result from reduction of cerebral blood flow in either the carotid or the vertebrobasilar system. Most commonly, the underlying condition is atherosclerosis of the cerebral vessels, but reduction of cerebral blood flow resulting from cerebral embolism, mechanical factors in the neck (e.g., severe osteoarthritis), and arteritis (e.g., Takayasu's or cranial arteritis) may be responsible. In the subclavian steal syndrome, a very rare impairment of consciousness is associated with upper extremity exercise and resultant diversion of cerebral blood flow to the peripheral circulation. Occasionally,
16
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
cerebral vasospasm secondary to basilar migraine or subarachnoid hemorrhage may be responsible. Insufficiency of the cerebral circulation often causes other neurological symptoms, depending on the circulation involved. Reduction in blood flow in the carotid circulation may lead to loss of consciousness, lightheadedness, giddiness, and a sensation of an impending faint. Reduction in blood flow in the vertebrobasilar system may also lead to loss of consciousness, but dizziness, lightheadedness, drop attacks without loss of consciousness, and bilateral motor and sensory symptoms are more common. Dizziness and lightheadedness alone, however, should not be considered symptoms of vertebrobasilar insufficiency. Syncope resulting from compression of the vertebral artery during certain head and neck movements may be associated with episodes of vertigo, disequilibrium, or drop attacks. Patients may describe blackouts when looking upward suddenly or when turning their heads quickly to one side. Generally, symptoms persist for several seconds after the movement stops. In Takayasu's arteritis, there may be major occlusion of blood flow in the carotid and vertebrobasilar systems; in addition to fainting, other neurological symptoms are common. Pulsations in the neck and arm vessels are usually absent, and blood pressure in the arms is unobtainable. The syncopal episodes characteristically occur with mild or moderate exercise and with certain head movements. Cerebtal vasospasm may result in syncope, particularly if the postetior circulation is involved. In basilar artery migraine, usually seen in young women and children, a variety of brainstem symptoms may also be experienced, and a pulsating headache is associated. The loss of consciousness is usually gradual, but a confusional state may last for hours (see Chapter 75). Metabolic
Disorders
A number of metabolic disturbances, including hypoglycemia, anoxia, and hyperventilation-induced alkalosis, may predispose to syncope, but usually only lightheadedness and dizziness ate experienced. The abruptness of onset of loss of consciousness depends on the acuteness and reversibility of the metabolic disturbances. Syncope caused by hypoglycemia generally develops gradually, The patient has a sensation of hunger; there may be a relationship to fasting, a history of diabetes mellitus, and a prompt response to ingestion of food. Symptoms are unrelated to posture but may be aggravated by exercise. During the syncopal attack, there is no significant change in blood pressure or pulse. Anoxia may produce syncope because of the lack of oxygen or through the production of a vasodepressor type of syncope. Symptoms of lightheadedness are common, but true syncope is less common. Patients with underlying cardiac or pulmonary disease are susceptible. In patients
with chronic anemia or certain hemoglobinopathies that impair oxygen transport, similar symptoms may occur. Syncopal symptoms may be more prominent with exercise or physical activity. Hyperventilation-induced syncope usually has a psychogenic origin. During hyperventilation, the patient may experience paresthesia of the face, hands, and feet; a buzzing sensation in the head; lightheadedness; giddiness; blurring of vision; mouth dryness; and occasionally tetany. Patients often complain of tightness in the chest and a sense of panic. Symptoms can occur in the supine or erect positions and are gradual in onset. The symptoms of hyperventilation may be helped by having the patient rebreathc into a paper bag. During hyperventilation, a tachycardia may be present, but blood pressure generally remains normal.
Miscellaneous Causes of Syncope In certain types of syncope, more than one mechanism may be responsible for the loss of consciousness. In the common faint, both vasodepressor and cardioinhibitory factors may be operational. In cardiac syncope, a reduction of cardiac output may be due to a single cause, such as obstruction to inflow or outflow or a cardiac arrhythmia, but multiple factors are common. Cough or tussive syncope and micturition syncope are special cases of reflex syncope for which the mechanisms are poorly understood and probably multifactorial. In cough syncope, loss of consciousness occurs after a paroxysm of severe coughing. This is most likely to occur in obese men, usually smokers or patients with chronic bronchitis. The syncopal episodes occur suddenly, generally after repeated coughing but occasionally after a single cough. Before losing consciousness, the patient may feel lightheaded. The individual's face often becomes congested and then pale. Diaphoresis may be present, and there may be loss of muscle tone. Syncope is generally brief, lasting only seconds, and recovery is rapid. Several factors are probably operational in causing cough syncope. The most significant is blockage of venous return by raised intrathoracic pressure. In weight-lifting syncope, a similar mechanism is operational. Micturition syncope most commonly occurs in men during or after micturition, usually after arising from bed to urinate in the erect position in the middle of the night. There may be a history of drinking alcohol before going to bed. The syncope may result from sudden reflex peripheral vasodilation caused by the release of intravesicular pressure and bradycardia. The relative peripheral vasodilation from recent alcohol use and a supine sleeping position arc contributory because blood pressure is lowest in the middle of the night. The syncopal propensity may increase with fever. Rarely, micturition syncope with headache may result from a pheochromocytoma in the bladder wall.
EPISODIC IMPAIRMENT OF CONSCIOUSNESS
Defecation syncope is uncommon, hut it probably shares the underlying pathophysiological mechanisms responsible for micturition syncope. Convulsive syncope is an episode of syncope of any etiology, sufficiently prolonged to result in a few clonic jerks; the other features arc typically syncopal and should not be confused with epileptic seizures.
Investigations of Patients with Syncope In the investigation of the patient with episodic impairment of consciousness, the diagnostic tests performed depend on the initial differential diagnosis (Kapoor 2002). Investigations should be individualized, but some, such as measurement of the hematocrit and blood glucose levels, as well as ECG recordings, are indicated in most patients. A resting ECG recording may reveal an abnormality of cardiac rhythm or the presence of underlying ischemic or congenital heart disease. In the patient suspected of cardiac syncope, a chest x-ray film may show evidence of cardiac hypertrophy, valvular heart disease, or pulmonary hypertension. Other noninvasive investigations include radionuclcotide catdiac scanning, echocardiography, and prolonged I lolrer monitoring for the detection of cardiac arrhythmias. Echocardiography is useful in the diagnosis of valvular heart disease, cardiomyopathy, atrial myxoma, prosthetic valve dysfunction, pericardial effusion, aortic dissection, and congenital heart disease. Holter monitoring detects twice as many ECG abnormalities as a routine ECG and may detect an arrhythmia at the time of a syncopal episode, 1 lolrer monimi'ing is commonly performed for 24 hours, although longer periods of recording may be required. Continuous loop recordings may be used in longterm monitoring and may be useful in a small number of patients (Krahn et al. 1999). Exercise testing and electrophysiological studies are carried out in a select group of patients. Exercise testing may be useful in detecting coronary artery disease, and exercise-related syncopal recordings may help localize the site of conduction disturbances. Tilt testing may be useful in the evaluation of patients with syncope of unknown origin, although false-positive results occur. Tilt testing commonly employs pharmacological agents such as nitroglycerin or isoproterenol. The specificity of tilt-table testing is approximately 9 0 % . In patients suspected of syncope from cerebrovascular causes, noninvasive diagnostic studies, including Doppler flow studies of the cerebral vessels and magnetic resonance imaging (MRI) or magnetic resonance angiography, may provide useful information. Occasionally, cerebral angiography may be indicated. Electroencephalography (EEG) is useful in differentiating syncope from epileptic seizure disorders. An EEG should be obtained only when a seizure disorder is suspected. Despite multiple investigations, in approximately 3 7 % of patients, the cause is unknown (Soteriades ct al. 2002),
17
SEIZURES Sudden, unexplained loss of consciousness in a child or adult may be caused by an epileptic seizure, which must be distinguished from syncope. An epileptic seizure is defined as a transient neurological dysfunction resulting from an excessive abnormal electrical discharge of cerebral neurons. The clinical manifestations are numerous, including disturbances of consciousness, changes in emotions, changes in sensation, abnormal movements, and changes in visceral functions or behavior. Epileptic seizures may be classified according to clinical manifestations and EEG findings (Chaptet 73). This section discusses only seizures associated with an alteration of consciousness. Both generalized seizures (absence and tonic-clonic) and complex partial seizures have alteration of consciousness as part of their clinical manifestations. Atonic seizures usually present as drop attacks and loss of consciousness is extremely brief. In most patients, a correct diagnosis can be made on the basis of the history, physical examination, and EEG findings.
History and Physical Examination The most definitive way to diagnose epilepsy and the type of seizure is clinical observation of the seizure, although this is often not possible, except when seizures are frequent. The history of an episode, as obtained from the patient and an observer, is of paramount importance. The neurologist should obtain a family history and should inquire about birth complications, central nervous system infection, head trauma, and previous febrile seizures, because they may all have relevance. The neurologist should obtain a complete description of the episode and should inquire about any warning before the event, possible precipitating factors, and other neurological symptoms that may suggest an underlying structutal cause. Important considerations are the age at onset, frequency, and diurnal variation of the events. Seizures are generally brief and have stereotyped patterns, as desctibed previously. With complex partial seizures and tonic-clonic seizures, a period of postictal confusion is highly characteristic. Unlike some types of syncope, seizures are unrelated to posture and generally last longer. In a tonic-clonic seizure, cyanosis is often present, pallor is uncommon, and breathing may be stertorous. Absence seizures have onset between ages 5 and 15 years in most patients, and a family history of seizures is present in 2 0 - 4 0 % of patients. Tonic-clonic and complex partial seizures may begin at any age from infancy to late adulthood, although infants may not demonstrate the typical features because of incomplete development of the nervous system. The neurological examination may reveal an underlying structural disturbance responsible for the seizure disorder. Birth-related trauma may result in asymmetries of physical
18
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
development; cranial bruits may indicate an arteriovenous malformation; and space-occupying lesions may result in papilledema or in focal motor, sensory, or reflex signs. In the pediatric age-group, mental retardation may be found in association with birth injury or metabolic defects. The skin should be examined for abnormal pigment changes and other dysmorphic features characteristic of some of the neurodegenerative disorders. If absence seizures are suspected, the diagnosis can often be made in the office by having the patient hyperventilate for $-4 minutes, which often induces an absence seizure. If the patient is examined immediately after a suspected tonicclonic seizure, the neurologist should search for abnormal signs, such as focal motor weakness and reflex asymmetry, and for pathological reflexes, such as Babinski's sign. These may help to confirm that the attack was a seizure and suggest a possible lateralization or location of the seizure focus.
sustained muscle contraction lasting 10-20 seconds. This phase is followed by a clonic phase that lasts approximately 30 seconds and is characterized by recurrent muscle contractions. During a tonic-clonic seizure, a number of autonomic changes may be present, including an increase in blood pressure and heart rate, apnea, mydriasis, urinary or fecal incontinence, piloerection, cyanosis, and diaphoresis. Injury may result from a fall or tongue biting. In the postictal period, consciousness is regained slowly. The patient may remain lethargic and confused for a variable period. Pathological reflexes may be elicited. Some generalized motor seizures with transient alteration of consciousness may have only tonic or only clonic components. Tonic seizures consist of an increase in muscle tone, and the alteration of consciousness is generally brief. Clonic seizures are characterized by a brief impairment of consciousness and bilateral clonic movements. Recovery may be rapid, but if the seizure is more prolonged, a postictal period of confusion may be noted.
Absence Seizures Complex Partial Seizures The absence seizure is a well-defined clinical and EEG event. The essential feature is an abrupt, brief episode of decreased awareness without any warning, aura, or postictal symptoms. At the onset of the absence seizure, there is an interruption of activity. A simple absence seizure is characterized only by an alteration of consciousness. A complex absence seizure is characterized by an alteration of consciousness and other signs, such as minor motor automatisms. During a simple absence seizure, the patient remains immobile, breathing is normal, no color changes are observed, there is no loss of postural tone, and there are no motor manifestations. After the seizure, the patient immediately resumes the previous activities and may be unaware of the attack. An absence seizure generally lasts 10-15 seconds, but it may be shorter or as long as 40 seconds. Complex absence seizures have additional manifestations, such as diminution of postural tone, which may cause the patient to fall; an increase in postural tone; minor clonic movements of the face or extremities; minor face or extremity automatisms; or autonomic phenomena, such as pallor, flushing, tachycardia, piloerection, mydriasis, or urinary incontinence.
Tonic-CIonic Seizures The tonic-clonic seizure is the most dramatic manifestation of epilepsy and is characterized by motor activity and loss of consciousness. Tonic-clonic seizures may be the only manifestation of epilepsy or may be associated with other seizure types. In a primary generalized tonic-clonic seizure, the patient generally has no warning or aura, although some patients may experience a few myoclonic jerks. The seizure begins with a tonic phase, during which there is
In a complex partial seizure, the first seizure manifestation may be an alteration of consciousness, but the patient commonly experiences an aura or warning. The seizure may have a simple partial onset, which may include motor, sensory, visceral, or psychic symptoms. The patient may initially experience hallucinations or illusions; affective symptoms, such as fear or depression; cognitive symptoms, such as a sense of depersonalization or unreality; or aphasia. The complex partial seizure generally lasts 1-3 minutes but may be shorter or longer. A complex partial seizure may become generalized and evolve into a tonic-clonic convulsion. During a complex partial seizure, automatisms, generally more complex than those in absence seizures, may be noted. The automatisms could involve continuation of the patient's activity before the onset of the seizure, or they may be new motor acts. The automatisms are varied but frequently consist of chewing or swallowing movements, lip smacking, grimacing, or automatisms of the extremities, including fumbling with objects, walking, or trying to stand up. Rarely, patients with complex partial seizures have drop attacks and the term temporal lobe syncope is often used. The duration of the postictal period after a complex partial seizure is variable, with a gradual return to normal consciousness and normal response to external stimuli. Table 2,3 provides a comparison of absence seizures and complex partial seizures.
Investigations of Seizures In the initial investigations of the patient with tonic-clonic seizures or complex partial seizures, a complete blood cell count, urinalysis, biochemical screening, blood glucose
EPISODIC IMPAIRMENT OF CONSCIOUSNESS Tabic 2.3:
19
Comparison of absence and complex partial seizures
Feature
Absence seizure
Complex partial seizure
Age at onset Aura or warning Onset Duration Automatisms Provocation by hyperventilation Termination Frequency Postictal phase KkvtrovncephalogtMm
Childhood or adolescence No Abrupt Seconds Simple Common Abrupt Possibly multiple seizures per day No Generalized spike and wave
Ncuroimaging
Usually normal
Any age Common Gradual Up to minutes Mure complex Uncommon Gradual Occasional Confusion, fatigue Focal epileptic discharges or nonspecific lesions May demonstrate focal lesions
level, serum calcium concentration, and serological test fot syphilis should be obtained. Laboratory investigations generally are not helpful in establishing a diagnosis of absence seizures. In infants and children, biochemical screening for amino acid disorders should be considered. MRI is the imaging modality of choice for the investigation of patients with suspected seizures. It is superior to computed tomographic scanning and increases the yield of focal structural disturbances. MRI can reveal tumors, cerebral atrophy, hydrocephalus, cerebral hemorrhage, infarction, subdural hematoma, cystic lesions, and vascular malformations. Although childten with absence seizures may have some abnormalities on MRI, this procedure is generally not required for diagnosis or management. Cerebrospinal fluid (CSF) examination is not necessary in every patient with a seizure disotder and should be reserved for the patient whose recent seizure may be related to an acute central nervous system infection. The role of the EFLG is to provide laboratory support for a clinical impression and to help classify the type of seizure. Epilepsy is a clinical diagnosis; therefore, EEG cannot produce a diagnosis with certainty unless the patient has a clinical event during the recording. A normal EEG does not exclude epilepsy, and minot nonspecific abnormalities do not confirm epilepsy. Some patients with clinically documented seizures show no abnormality even after serial EF.G recordings, sleep recordings, and special activation techniques. The EEG is most often helpful in the diagnosis of absence seizures. EEG evaluation can be supplemented with simultaneous video monitoring for the documentation of ictal events, allowing for a strict correlation between EEG changes and clinical manifestations. Simultaneous EEG and video monitoring is also useful in distinguishing epileptic seizures from noncpileptic phenomena. Although an accurate diagnosis can be made in most patients on the basis of the clinical history and the foregoing investigations, some patients ptesent a diagnostic dilemma. A 24-hour ambulatory EEG recording can make more definite a diagnosis of an epileptic seizure rather than nonepileptic phenomena or a clearer classification of the specific type of seizure.
Psychogenic Seizures or Pseudoseizures (Noncpileptic Seizures) Pscudoepileptic seizutes are paroxysmal episodes of altered behavior that superficially resemble epileptic seizures but lack the expected EEG epileptic changes (Ettinger et al. 1999). However, approximately 4 0 % of patients with pscudoepileptic or nonepileptic seizures also experience true epileptic seizures. A diagnosis is often difficult to establish based on initial history alone (Devinsky 1998). Often, a correct diagnosis can be made only after witnessing the patient's clinical episodes. Noncpileptic seizures occur in children and adults and are more common in females. Most commonly, they superficially resemble tonic-clonic seizures. They generally are abrupt in onset, occur in the presence of othct people, and do not occur during sleep. Motor activity is uncoordinated, but urinary incontinence is rare, and physical injury is uncommon. They tend to be more prolonged than true tonic-clonic seizures. Pelvic thrusting is often a manifestation of pseudoseizures. During and immediately after the seizure, the patient may not respond to verbal or painful stimuli. Cyanosis is not observed. Postictally, there are no focal neurological signs or pathological reflexes. In the patient with known epilepsy, the diagnosis of nonepileptic seizures should be considered when previously controlled seizures become medically refractory. For the diagnosis of nonepileptic seizures, the patient should have a psychological assessment because the majority of such patients have other psychiatric disturbances. In this patient group, there is a high frequency of hysteria, depression, and personality disturbances. At times, a sccondaty gain can be identified. In some patients with psychogenic seizures, the clinical episodes can frequently be precipitated by suggestion and by certain clinical tests, such as hyperventilation, photic stimulation, intravenous saline infusion or tactile (vibration) stimulation, or pinching the nose to induce apnea. It is important to keep in mind that hyperventilation and photic stimulation may also induce true epileptic seizures, but their clinical features arc usually distinctive. Some physicians avoid the use of placebo
20
APPROACH TO COMMON NEUROLOGICAL PROBLEMS Table 2.4:
Comparison of psychogenic and epileptic seizures
Feature
Psychogenic seizure
Epileptic seizure
Stereotypy of attack
May be variable May be prolonged Daytime Rare Rare Rare Prolonged, uncoordinated; pelvic thrusting Rare
Usually stereotyped Brief Nocturnal or daytime Can occur with tonic-clonic seizures Can occur with tonic-clonic seizures Common Automatisms or coordinated tonic-cIonic seizures Common Usually related Frequently abnormal Abnormal Uncommon Uncommon
Duration Diurnal variation Injury
Tongue biting Urinary incontinence Motor activity Postictal confusion Relation to medication changes Interictal KEG Ictal EEG Presence of secondary gain Psychiatric disturbances
Unrelated
Normal Normal Common Common
EEG = electroencephalogram,
procedures because of the possibility that the patient may feel tricked and this could have an adverse effect on the doc tor-patient relationship (Parra et al. 1998). The interictal EEG in patients with pseu do seizures is normal and remains normal during the clinical episode, demonstrating no evidence of a cerebral dysrhythmia. With the introduction of long-term ambulatory KEG monitoring, the episodic behavior of a patient can be correlated with EEG recordings; thus psychogenic seizures can be distinguished from true epileptic seizures. Table 2.4 compares the features of psychogenic seizures wirh those of epileptic seizures. As an auxiliary investigation of suspected psychogenic seizures, plasma prolactin concentrations may provide additional supportive data. Plasma prolactin concentrations are commonly elevated after tonic-clonic seizures and less frequently after complex partial seizures. Serum prolactin levels are almost invatiably normal after psychogenic seizures, although such a finding does not exclude the diagnosis of true epileptic seizures. Elevated prolactin levels, however, may also be present after syncope and with the use of drugs such as antidepressants, estrogens, bromocriptine, ergots, phenothiazines, antiepileptic drugs, and others.
Miscellaneous Causes of Altered Consciousness In children, alteration of consciousness may accompany breath-holding spells (see Chapter 55B) and metabolic disturbances (see Chapter 68), Breath-holding spells must be distinguished from epilepsy. Most spells start at 6-28 months of age, but they may occur as early as the first month of life; they usually disappear by 5 or 6 years of age. Breath-holding spells may occur several times per day and may manifest cither cyanosis or pallor. In cyanotic breath-holding spells, loss of consciousness is triggered by a sudden injury or fright, anger, or frustration. The child is initially provoked, cries vigorously for a few breaths, and
then holds his or her breath in expiration, whereon cyanosis develops. Consciousness is lost because of hypoxia. Although stiffening, a few clonic movements, and urinary incontinence are occasionally observed, these episodes can be clearly distinguished from epileptic seizures on the basis of the history of provocation and by noting that the apnea and cyanosis occur before any alteration of consciousness. In these children, the neurological examination and EEG recordings are normal. Pallid breath-holding episodes are generally provoked by a mild painful injury or a startle. The infant cries initially, then becomes pale and loses consciousness. As in the cyanotic type, stiffening, clonic movements, and urinary incontinence may occur. In the pallid infant syndrome, loss of consciousness is secondary to excessive vagal tone, resulting in bradycardia and subsequent cerebral ischemia, similar to a vasovagal attack. A number of pediatric metabolic disorders may have clinical manifestations of alterations of consciousness, lethargy, or seizures (see Chapter 68), These include disorders of amino acid metabolism, such as phenylketonuria, Hartnup disease, and maple syrup urine disease; the various disorders of the urea cycle; and miscellaneous metabolic disorders, such as hyperglycinemia and disorders of pyruvate metabolism. Neurological abnormalities in these patients may be seen at birth or later in infancy and childhood. Metabolic screening of urine and blood should be considered in an infant who presents with neurological disorders early in life; these include examination of the urine for the detection of aminoaciduria, excess urinary ketones, and urea excretion. Biochemical screening of the serum should also be considered for the infant or child who presents with transienr lethargy, apneic episodes, syncope, or seizures. Increased intracranial pressure may result from a number of causes, including periodic obsttuction of the circulation of CSF, as in aqueductal stenosis or colloid cyst of the third ventricle. These patients are subject to paroxysmal increases of intracranial pressure rhat may last up to
EPISODIC IMPAIRMENT OF CONSCIOUSNESS 20 minutes. These episodes may occur spontaneously or may be related to postural changes or Valsalva's maneuver. If sufficient to impair cerebral perfusion, the plateau waves of Lundberg may result in sudden, severe headaches, which may be followed by loss of consciousness. Occasionally, this is accompanied by opisthotonos and clonic movements. In intermittent obstruction of CSF circulation, leg buckling and atonic episodes may occur with changes in head position. Tinnitus is a common accompanying symptom. Syringomyelia of the cervical spine, often associated with a Chiari malformation (see Chapter 79), is occasionally associated with repeated episodes of syncope in children and adults {Woelfle et al. 1998). In the patient who presents with an apparent loss of consciousness, the neurologist must also consider the possibility of malingering or some other underlying psychogenic cause. However, it is always important to exclude organic causes first. The neurologist should also distinguish sleep disorders, such as cataplexy and other causes of drop attacks, from alterations of consciousness. These nonsyncopal spells include drop attacks of the elderly, narcolepsy, systemic mastocytosis, carcinoid syndrome, and pheochromocytoma. Systemic mastocytosis, carcinoid syndrome, and pheochromocytoma may also cause true syncope secondary to rapid changes in blood pressure.
REFERENCES Ackerman, M. J. 1998, "The long QT syndrome: Ion channel diseases of the heart," Mayo Clin Proc, vol. 73, pp. 250-269 Brady, P. A. Sc Shen, W. K. 2002, "When is intracardiac electrophysiologic data indicated in the older or very elderly patient? Complication rates and data," Clin Geriatr Med, vol. 18, pp. 339-360 Colivicchi, F., Ammirati, F., Biffi, A., et al. 2002, "Exercise-related syncope in young competitive athletes without evidence of
21
structural heart disease. Clinical presentation and long-term outcome," Eur Heart J, vol. 23, pp. 1125-1130 Devinsky, O. 1998, "Nonepileptic psychogenic seizures: Quagmires of pathophysiology, diagnosis, and trearmenr," Epilepsia, vol. 59, pp. 458-462 Ettinger, A. B., Devinsky, O., Weisbrot, D. M., et al. 1999, "A comprehensive profile of clinical, psychiatric and psychosocial characteristics of patients with psychogenic non-epileptic seizures," Epilepsia, 1999, vol. 40, pp. 1292-1298 Fenton, M., Hammill, S. C, Rea, R. F„ et al. 2000, "Vasovagal syncope," Ann Intern Med, vol. 133, pp. 714-725 Goldschlager, H, Epstein, A. E., Grubb, B. P„ et a). 2003, "Etiological considerations in the patient with syncope and apparently normal heart," Arch Intern Med, vol. 163, pp. 151-162 Crubb, B. Si Kaujwal, Y. 2003, "Neurocardiogenic syncope: A review of pathophysiology, diagnosis, and management," in Encyclopedia of the Neurological Sciences, eds M. J. Aminoff & R. B. Daroff, Academic Press/Elsevier Science, San Diego Kapoor, W. N. 2002, "Current evaluation and management of syncope," Circulation, vol. 106, pp. 1606-1609 Krahn, A. D., Klein, G. J., Yee, R., et al. 1999, "Use of an extended monitoring strategy in patients with problematic syncope," Circulation, vol. 99, pp. 406-410 Lewis, D. A., Dhala, A. 1999, "Syncope in the pediatric patient. The cardiologist's perspective," Pediatr Clin North Am, vol, 46, pp. 205-219 Parra, J., Kanner, A. M., Iriarce, J., et al. 1998, "When should induction protocols be used in the diagnostic evaluation of patients with paroxysmal events?" Epilepsia, vol. 39, pp. 863-867 Soteriades, E. S., Evans, J. C, Larson, M. G., et al. 2002, "Incidence and prognosis of syncope," N Engl J Med, vol. 347, pp. 878-885 Woelfle, J., Haverkamp, F., & Kreft, B. 1998, "Repeated syncopes and extended paediatric hydrosyringomyelia/Chiari I malformation; Relation or coincidence?" / Neurol Neurosurg Psychiatry, vol. 64, pp. 278-279
Chapter 3 Falls and Drop Attacks Bernd F. Remler and Robert B. Daroff Loss of Consciousness Syncope Seizures Transient Ischemic Attacks Vertebrobasilar Insufficiency Anterior Cerebral Artery Ischemia Third Ventricular and Posterior Fossa Tumors Motor and Sensory Impairment of the Lower Limbs Disorders of the Basal Ganglia
23 23 24 24 24 24 24 25 25
Everyone occasionally loses balance and, infrequently, falls. When falls occur repeatedly or without a prior sense of imbalance, the patient may have a neurological problem. Various disease states and neurological impairments cause falls and drop attacks. Associated loss of consciousness implies syncope or seizures (see Chapter 2). Transient ischemic attacks (TIAs) in the posterior circulation or the anterior cerebral artery distribution can cause monosymptomatic drops. Third-ventricular or posterior fossa tumors may also be associated with abrupt drops. Patients with lower-extremity weakness, spasticity, rigidity, sensory loss, or ataxia frequently fall. Narcoleptics experience cataplexy, and patients with Meniere's disease occasionally fall as a result of otolithic dysfunction. Middle-aged women may fall with no discernible cause. Finally, the elderly, with their inevitable infirmities, fall frequently. These associations permit a classification of falls and drop attacks, as presented in Table 3.1, We use the words falls and drops interchangeably. The term drop attacks, on the other hand, describes sudden falls occurring without warning, that are primarily due to intracranial causes, such as midline tumors and transient ischemic attacks. Seizures and vestibular disorders arc much less common causes of drop attacks. The medical history is essential in evaluating patients with falls and drop attacks. The situational and environmental circumstances of the event must be ascertained. On the basis of the causes listed in Table 3.1, basic questions must be asked of the patient or witnesses. Did the patient lose consciousness? If so, for how long? Did lightheadedness or palpitations precede the event? Is there a history of a seizure disorder? Were there previous symptoms suggestive of TIAs? Does the patient have headaches? Are there symptoms of distal sensory loss, limb weakness, or stiffness? Has the patient had excessive daytime sleepiness,
Neuromuscular Disorders (Myopathy and Neuropathy) Myelopathy Cerebral or Cerebellar Disorders Cataplexy Vestibular Disorders (Otolithic Crisis) Cryptogenic Falls in Middle-Aged Women The Aged State Summary
25 25 25 26 26 26 26 27
and are the falls precipitated by strong emotions, such as elation or laughter? Is there a history of visual impairment, hearing loss, vertigo, or tinnitus? Given the tendency for middle-aged women and the elderly to fall, the patient's age and gender are imporranr to the evaluation. The neurological examination is particularly relevant in ascertaining that falling might be related to disorders of the central or peripheral nervous system. Does the patient have motor or sensory deficits in the lower limbs; the rigidity and tremor of Parkinson's disease (PD); the ophthalmoparesis of progressive supranuclear palsy (PSP); ataxia, spasticity, or other signs compatible with multiple sclerosis? Patients with normal neurological examinations and no history of associated neurological or cardiac symptoms present a special challenge. If the falling is recurrent, magnetic resonance imaging (MRI) should be considered to rule out an otherwise silent midline cerebral neoplasm or malformation. Patients who frequently experience nearfalls without injuries may have a psychogenic disorder of station and gait.
LOSS OF CONSCIOUSNESS Syncope The manifestations and causes of syncope are described in Chapter 2, Severe ventricular arrhythmias and hypotension lead to cephalic ischemia, loss of consciousness, and falling. If there is a sudden third-degree heart block (Stokes-Adams attack), the patient loses consciousness and falls without warning. Less severe causes of decreased cardiac output, such as bradyarrhythmias or tachyarrhythmias, are associated with a prodromal sensation of faintness before the 2.1
24
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 3.1:
Causes and types of falls and drops
LIBS ot consciousness
Syncope Seizures Transient ischemic attacks (drop attacks) Vertebrobasilar Anteriot cerebral Third ventricular and posterior fossa tumors (drop attacks) Motor and sensory impairment of lower limbs Basal ganglia disorders Parkinson's disease Progressive supranuclear palsy Neuromuscular disorders (myopathy and neuropathy) Myelopathy Cerebral or cerebellar disorders Cataplexy Vestibular disorders Cryptogenic falls in middle-aged women Aged state
loss of consciousness. Elderly patients with cardioinhibitory ("sick") sinus syndrome, however, often describe dizziness and falling, rather than faintness (Kapoor 2000). Orthostatic hypotension conveys a markedly increased risk of falling in the elderly and confounds other factors contributing to falls. Hypotension is almost always associated with a presyncopal syndrome of progressive lightheadedness, faintness, dimming of vision, and rubbery legs before consciousness is lost. Orthostatic hypotension is particularly problematic in the frail elderly, who have many other risk factors for falling (Heitterachi et al. 2002) (see The Aged State, later in this chapter).
with lamotriginc (Faught 1999). Paradoxically, some antiseizure drugs can precipitate drop attacks, such as carbamazepine in Rolandic epilepsy (Genton 2000).
Transient Ischemic Attacks Drop attacks secondary to TIAs arc sudden falls occurring without warning or obvious explanation (e.g., tripping). There is no, or only momentary, loss of consciousness; the sensorium and lower-limb strength arc intact immediately or shortly after the patient hits the ground. The neurological examination should not reveal lower-limb motor or sensory dysfunction between episodes. If such abnormalities are present, it can be impossible to distinguish drop attacks from the falls associated with sensorimotor impairment of the lower limbs. The vascular distributions of drop attacks from TIAs are the posterior circulation and the anterior cerebral arteries.
Vertebrobasilar Insufficiency Drop attacks caused by posterior circulation insufficiency result from transient ischemia to the corticospinal tracts or the paramedian reticular formation. They are rarely an isolated symptom of vertebrobasilar insufficiency because most patients have a history of TIAs, including the more common symptoms of vertigo, diplopia, ataxia, weakness, and hemisensory loss. Occasionally, a drop attack may herald progressive thrombosis of the basilar artery, hours before major and permanent neurological signs evolve.
Seizures Anterior Cerebral Artery Ischemia Epileptic drop attacks are caused by asymmetrical tonic contractions of limb and axial muscles, loss of tone of postural muscles (Tinuper et al. 1998), and seizure-related cardiac arrhythmias. The arrhythmias mimic cardiogenic syncope and, like temporal lobe drop attacks, are typically associated with a period of altered consciousness after the drop. Video-EEG monitoring of epileptic patients with a history of falls permits the characterization of the various motor phenomena that cause loss of posture. For the clinician, however, the precise nature of these events is less important than establishing a diagnosis of seizures. This is often simple in patients with long-standing epilepsy, but falls in patients with poststroke hemiparesis may be falsely attributed to motor weakness rather than to new-onset seizures. Further confusion may result from the difficulties involved in differentiating the destabilizing extensor spasms of spasticity from focal seizures. Epileptic drop attacks in young patients with severe childhood epilepsies may respond favorably to callosotomy (Maehare and Shimizu 2001). Falling as a consequence of the tonic axial component of startle-induced seizures may be controllable
Anterior cerebral artery ischemia causes drop attacks by impairing perfusion of the parasagittal prcmotor and motor cortex controlling the lower extremities. Derivation of both anterior cerebral arteries from the same internal carotid artery—a common vascular variant, with an approximate frequency of 20%—anatomically predisposes to this syndrome. In such patients, an embolus may lodge in the single anterior cerebral artery root and produce bilateral parasagittal ischemia with a consequent drop attack.
Third Ventricular and Posterior Fossa Tumors Drop attacks can be manifestations of colloid cysts of the third ventricle or mass lesions within the posterior fossa. With colloid cysts, unprovoked falling is the second most common symptom, after position-induced headaches. This history may be the only clinical clue to the diagnosis because the neurological examination may be entirely normal. Abrupt neck flexion may precipitate drop attacks in
FALLS AND DROP ATTACKS
otherwise asymptomatic patients who are harboring posterior fossa tumors. Drop attacks occur in 2 - 3 % of patients with Chiari malformations (Ziegler and Mallonce 1999). Drops induced by rapid head turning were considered pathognomonic of cysticercosis of the fourth ventricle in the early 20th century (Brun's sign). Other intracranial mass lesions, such as parasagittal meningiomas, foramen magnum tumors, or subdural hematomas, are usually associated with baseline abnormalities of gait and motor functions, and falling occurs consequent to these impairments (see Table 3.1) tather than to true drop attacks.
M O T O R AND SENSORY IMPAIRMENT OF THE LOWER LIMBS A wide variety of neurological disorders impair motor functions, coordination, and balance. Such conditions are frequent causes of falls. Disorders of the Basal Ganglia Parkinson's
Disease
Patients with PD frequently fall. Aggravating risk factors include previous falls, demenria, disease duration, benzodiazepine use, and poor performance on the Romberg test (Wood et al. 2002). Although many patients with PD have postural instability and often fall backward, the office testing of retropulsion is not reliable in predicting falls (Bloem et al. 2001), Patients with PD may also, without warning, drop directly to the ground. This is most commonly related to dopamine-induced motor fluctuations, particularly peak-dose dyskinesias and off periods (see Chapter 77). PD is also associated with a forward-flexed posture that diminishes the ability of patients to compensate for further shifts of the center of gravity. In particular, muscular rigidity and bradykinesia prevent rapid muscle activation and weight shifts when balance is offset, Progressive Supranuclear Palsy Patients with PSP (see Chapter 77) are characterized by parkinsonian features, axial rigidity, nuchal dystonia, spasticity, and ophthalmoparesis. They are more likely to fall backward than PD patients, even with equivalent functional impairment. Furthermore, loss of downgaze impairs their ability to avoid obstacles during ambulation. Idiopathic rapid eye movement sleep behavior disorder (sec Chapter 74) is a precursor of PSP as well as a cause of nocturnal falls in the elderly (Morfis er al. 1997). Clonazepam is usually effective in the treatment of this parasomnia and provides reliable prophylaxis for the associated falls. Similar mechanisms to those described with PD and PSP contribute to falls in patients with related
25
neurodegenerative disorders causing parkinsonism. Recurrent falls are a prominent feature of diffuse Lewy body disease (Imamura et al. 1999), multiple system atrophy, the pure akinesia syndrome, and cortical-basal ganglionic degeneration (sec Chapter 77).
NEUROMUSCULAR DISORDERS (MYOPATHY AND NEUROPATHY) Myopathies characteristically involve proximal muscles and increase the tendency to fall. The multiple causes of myopathy and neuropathy (genetically determined or acquired) arc discussed in Chapters 82 and 85. Most neuropathies arc mixed (i.e., motor and sensory) in type, Regatdless of cause, neuropathies predispose the patient to falling because of lower-limb weakness and impaired afferent sensations from feet, joints, and muscles. Sensory neuropathies delay or reduce the relay of sensory signals from the lower limbs and promote falling when postural imbalance occurs. Falling may herald the onset of acute polyneuropathies, such as Guillain-Barre syndrome. Polio survivors, who are now reaching middle age and older, have a high annual frequency of falling that may exceed 6 0 % (Silver and Aiello 2002!.
Myelopathy Patients with spinal cord disease (see Chapter 27) are at a particularly high risk of falling because all descending motor and ascending sensory tracts traverse the cord. Aside from weakness, spasticity, and impaired sensory input from the lower limbs, there is disruption of vestibulospinal and cerebellar pathways. This precludes adequate corrections for sudden shifts in the center of gravity,
CEREBRAL OR CEREBELLAR DISORDERS Motor, sensory, vestibular, and cerebellar dysfunction occur in isolation, or in any combination, in patients with central nervous system disease. Patients with acute basal ganglia lesions may show a slow, contralateral, tilting movement, causing falls. Strokes, as would be expected, increase the subsequent fall risk at least twofold. Right hemispheric stroke location, depression, and reduced arm function put these patients at particularly high risk (Jorgensen et al. 2002; Ugur et al. 2000). Metabolic encephalopathies cause characteristic transienr loss of the postural tone (asterixis). If this is extensive and involves the axial musculature, episodic loss of the uptight posture can mimic drop attacks in chronic uremic patients. Cerebellar disease causes gait ataxia, a prime cause of postural instability and falling. Moreover, patients with degenerative (see Chapter 78) or demyelinating (see Chapter 60)
26
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
cerebellar disease often have coexisting brainstem, spinal cord, or cerebral involvement.
Cataplexy Cataplexy, the sudden loss of lower-limb tone, is a part of the tetrad of narcolepsy that also includes excessive daytime sleepiness, hypnagogic hallucinations, and sleep paralysis (see Chapter 74). Consciousness is preserved during a cataplectic attack, which varies from slight lower-limb weakness to complete flaccid paralysis and abrupt falling. Once on the ground, the patient is unable to move but continues breathing. The attacks usually last less than 1 minute and only rarely exceed several minutes. Cataplectic attacks are provoked by laughter, anger, surprise, and startle. Occasionally, they interrupt or follow sexual orgasm. During the attack, there is electromyographic silence in antigravity muscles, and deep tendon reflexes and the Hreflex (see Chapter 36B) cannot be elicited. Cataplexy occurs in the absence of narcolepsy when associated with cerebral disease (symptomatic cataplexy), as in NicmannPick disease, Nome's disease, or brainstem lesions. It may occur rarely as an isolated problem in normal individuals, which may be familial (Aldrich 1998). A liquid formulation of gamma hydroxybutyrate (sodium oxybatc), an agent infamous for its use in date rape, is available for the treatment of cataplexy.
that their legs suddenly gave way. As soon as they get to their feet, walking continues normally. It occurs in more than 3% of women; the disorder develops in 7 5 % of these women after the age of 40. Twenty percent have at least one close relative (mother, aunt, or sister) with the condition. The falling frequency is quite variable. Most patients fall between 2 and 12 times per year. Only one fourth fall more than once per month or have clusters of frequent falls with prolonged asymptomatic intervals. Rarely, head trauma and significant intracranial injury results. Causal factors for this strictly female condition have been elusive. Footwear, specifically high heels, is not the cause. Occasional patients date the onset of the disorder to early in a pregnancy, before abdominal distention would be expected to alter postural stability. When falls begin during pregnancy, the women invariably continue falling even after delivery. The perimenstrual period makes some women with this condition more vulnerable. There is no relationship between falling and body weight. The most reasonable explanatory postulate is a prolonged long-loop (transcortical) reflex in women that delays the generation of sufficient quadriceps tension to decelerate a falling trunk. The diagnosis is made in a middle-aged woman with inexplicable falls, a normal neurological examination, and no evidence of any other known cause of falling (see Table 3.1). There is no available pharmacological therapy. All that can be done is to reassure the patient and prevent injury by using protective knee and elbow padding. Some women, fearing falls, can become agoraphobic and should be treated with behavioral intervention,
Vestibular Disorders (Otolithic Crisis) During attacks of vertigo, patients often lose balance and fall. In contrast, Meniere's disease (see Chapter 18) may be complicated by drop attacks unassodated with preceding or accompanying vertigo (Tumarkm's otolithic crisis) (Kentala et al. 2001; Ishiyama et al. 2001). Presumably, stimulation of otolithic receptors in the saccule triggers inappropriate reflex postural adjustments, via vestibulospinal pathways, leading to the falls. The patients, without warning, feel as if they are being thrown to the ground. They may fall straight down or be propelled in any direction. Indeed, one of the authors (RBD) had a patient who suddenly saw and felt her legs moving forward in front of her as she did a spontaneous back-flip secondary to an otolithic crisis. This condition occurs only in patients with Meniere's disease.
THE AGED STATE
CRYPTOGENIC FALLS IN MIDDLE-AGED W O M E N
The normal aging process is associated with a decline in multiple physiological functions that diminish the ability to compensate for external stressors that challenge the upright posture. Decreased proprioception, loss of muscle bulk (Pavol et al. 2002), arthritis of the knee and ankle joints, cardiovascular disturbances (Kario et al. 2001), deteriorating vision and ocular motor functions (Di Fabio et al,
Enigmatically, women older than 40 years of age have a tendency to fall. The fall is usually forward and occurs, without warning, while walking. There is no loss of consciousness, dizziness, or even a sense of imbalance. The patients are convinced that they have not tripped but
Most patients presenting to neurologists with a chief complaint of falling are elderly and chronically impaired. As the chance of falling increases with age, so does the severity of injury and the number of chronic disabilities predisposing to falls (Tideiksaar and Fillit 1997). Next to fractures, falls are the single most disabling condition leading to nursing home admission. As would be expected, elderly in sheltered accommodations have the highest frequency of falls; this may affect up to 5 0 % . Many of these patients fall repeatedly, with elderly women bearing the highest risk. In the very old, falls constitute the leading source of injury-related deaths. This, and estimated annual health care expenditures of $20 billion for the consequences of falls, underscores their significance as a major health problem (KannuS et al. 1999).
l-'AU.S AND DROP ATTACKS 2002), cognitive impairment, and failing postural reflexes (prcsbyastasis) summate and increase the risk of falling. Even the healthy elderly have a pronounced age-related decline in the ability to compensate for simulated forward falling. White matter abnormalities on brain MRIs correlate with postural instability and mobility impairment in the elderly (Kwa et al. 1998; Benson et al. 2002). Some elderly individuals without a discernible neurological disorder lose their ability to restitute when their center of gravity is displaced backward. They retropulsc when gently pushed in the chest, and sometimes fall back when simply asked to stand up straight. They may adapt a compensatory tendency to stoop forward when upright, and walk cautiously, with a wide base and short steps. Most of the falling elderly have one or, more commonly, several pathological predisposing conditions, and the chance of falling increases markedly with the number of identified risk factors (Tinctti 2003). In predisposed patients, a large proportion of these falls is accidental, reflecting an interaction between a debilitated patient and potential environmental hazards. This is in contrast to endogenous falls related to loss of consciousness, which are less frequent. Among tin1 important conditions associated with tails arc dementia, metaholic and toxic encephalopathies, depression, arthritis (Tinetti 2003), cerebral infarcts, parkinsonism, neuropathy, and gait disorders (see Chapter 25). Walking and postural recovery require more extensive attentional resources in the elderly (Brown et al. 1999). Accordingly, patients with Alzheimer's disease, when compared with healthy elderly, have slower walking speed, more difficulty clearing obstacles, and further deterioration of gait properties when asked to perform a simultaneous cognitive task, such as talking. Applying this paradigm to elderly patients in general, the observation of gait interruptions while speaking ("stops walking when talking," I.undin-Olsson et al. 1997) has a high predictive value for falling. The clinical evaluation should aim at identifying predisposing medical conditions and differentiating accidental from endogenous falls. A detailed medication history is essential. Antidepressants, anticonvulsants, antihypertensives, antiarrhythmics, benzodiazepines and other tranquilizers, and neuroleptics increase the risk of falls (Tinetti 2003). Finally, a description of contributing environmental factors should be obtained, either from the patients or from others rami liar with their living circumstances. Therapeutic ami risk reduction intervention for the falling elderly patient requires (1) treatment of correctable conditions, (2) provision of rehabilitative services and assistive devices, and (3) prevention by controlling environmental hazards. Pacemakers, supportive stockings, and medications may be helpful for patients experiencing autonomic dysfunction, cardiac dysrhythmias, and pharmacologically treatable movement disorders, but all unnecessary medications that increase the risk of falling (see the previous discussion) should be discontinued. Proper spectacle lenses
27
and orthotic and other assistive devices, such as walkers, canes, and crutches, can return a progressively immobilized falling patient to a safer and more independent lifestyle. Women should be encouraged to wear sturdy low-heeled shoes. The risk of fall-related fractures may further be reduced by using specifically designed joint protectors (Kannus et al. 2000). A variety of exercise programs, particularly rhose stressing muscle strengthening and balance, reduce the risk of falls (Campbell et al. 1997; Gillespie et al. 2000). Rehabilitative efforts are indicated for those patients in whom, after a few falls, a postfall syndrome develops consisting of phobic avoidance and restrictive behavior (Friedman et al. 2002). Controlling environmental hazards include lighting hallways, stairs, and entrances; anchoring rugs and using non-skid mats; and installing handrails in bathrooms, halls, and stairways. In addition, climbing ladders, or even stepladders, should be avoided.
SUMMARY A careful history and physical examination should, in most cases, uncover the cause of falls and drop attacks. Unfortunately, with middle-aged women and the elderly, the cause may be merely a function of gender or age. Patients with fixed motor or sensory impairments must be advised honestly about their almost unavoidable tendency to fall. Nevertheless, environmental adjustments and use of protective devices can reduce the frequency of falls and related injuries.
REFERENCES Aldrich, M. S. 199%, "Diagnostic aspects of narcolepsy," Neurology, vol. 50, Suppl. 1, pp. S2-S7 Benson, R. R., Guttmann, C. R. G., Wei, X., et al. 2002, "Older people with impaired mobility have specific loci of periventricular abnormality on VI Rl," Neurology, vol. 58, pp. 48-55 Bloem, B. R., Grimbergen, Y. A. M., Cramer, M., et al. 2001, "Prospective assessment of falls in Parkinson's disease," J Neurol, vol. 248, pp. 950-958 Brown, L. A., Shumway Cook, A., 6c Woollacott, M. H. 1999, "Attentional demands and postural recovery: The effect of aging," J Gerontology Series A-Biologic Sciences Medical Sciences, vol. 54, pp. M165-171 Campbell, A. J., Robertson, M. C, Gardner, M. M., et al. 1997, "Randomised controlled trial of a general practice programme of home based exercises to prevent falls in elderly women," BMJ, vol. 315, pp. 1065-1069 Di Fabio, R. P., Greany,J. F., Emasithi, A., & Wyman, J. F. 2002, "Eye-head coordination during postural perturbation as a predictor of falls in community-dwelling elderly women," Arch Pbys Med Rebabil, vol. 83, pp. 942-951 Faught, E. 1999, "t.amotrigine for startle-induced seizures," Seizure, vol. 8, pp. 361-363
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Friedman, S. M., Munoz, R„ West, S. K., et al. 2002, "Falls and fear of falling: Which comes first? A longitudinal prediction model suggests strategies for primary and secondary prevent i o n , " / Am Geriatric Soc, vol. 50, pp. 1329-1335 Gentoii, P. 2000, "When antiepileptic drugs aggravate epilepsy," Brain Dev, vol. 22, pp. 75-80 Gillespie, L. D., Gillespie, W. J., Robertson, M. C, et al. 2 0 0 1 , "Interventions for preventing falls in elderly people," Cochrane Database Syst Rev, no. 3, CD000340 Heitterachi, E., Lord, S. R., Meyerkort, P., et al. 2002, "Blood pressure changes on upright tilting predict falls in older people," Age Ageing, vol. 3 1 , pp. 181-186 Imamura, T., Hirino, N., Hashimoto, M., et al. 1999, "Fall-related injuries in dementia with Lewy bodies (DLB) and Alzheimer's disease," Eur } Neurol, vol. 7, pp. 77-79 Ishiyama, G., Ishiyama, A., Jacobson, K„ Sc Baloh, R. W. 2 0 0 1 , "Drop attacks in older patients secondary to an otologic cause," Neurology, vol. 57, pp. 1103-1106 Jorgensen, L., Engstad, T., & Jacobsen, B. K. 2002, "Higher incidence of falls in long-term stroke survivors than in population controls: Depressive symptoms predict falls after stroke," Stroke, vol, 3 3 , pp. 542-547 Kannus, P., Parkkari, J., Koskinen, S., et al. 1999, "Fall-induced injuries and deaths among older adults," JAMA, vol. 2 8 1 , pp. 1895-1899 Kannus, P., Parkkari, J,, Niemi, S., et al. 2000, "Prevention of hip fracture in elderly people with use of a hip protector," N Engl] Med, vol. 343, pp. 1506-1513 Kapoor, W. N. 2000, "Syncope," N Engl ] Med, vol. 343, pp. 1856-1862 Kario, K., Tobin, J. N., Wolfson, L. 1., et al. 2001, "Lower standing systolic blood pressure as a predictor of falls in the elderly: A community-based prospective study," / Am Coll Cardiol, vol. 38, pp. 246-252 Kcntala, E., Havia, M., 8i Pyykko, I. 2001, "Short-lasting drop atracks in Meniere's disease," Otolaryngol Head Neck Surg, vol. 124, pp. 526-530
Kwa, V. 1. H., Zaal, L. H., Verbeeten, B. Jr., et al. 1998, "Disequilibrium in patients with atherosclerosis. Relevance of pontine ischemic rarefaction," Neurology, vol. 5 1 , pp. 570-573 Lundin-Olsson, L., Nyberg, I.., & Gustafson, Y, 1997, "'Stops walking when talking' as a predictor of falls in elderly people," Lancet, vol. 349, p. 617 Maehara, T. & Shimizu, H. 2 0 0 1 , "Surgical outcome of corpus caliosotomy in patients with drop attacks," Epilepsia, vol. 42, pp. 67-71 Morfis, 1.., Schwartz, R. S., Si Cistuli, P. A. 1997, "REM sleep behaviour disorder: A treatable cause of falls in elderly people," Age Ageing, vol. 26, pp. 43-44 Pavol, M. J., Owings, T. M., Foley, K. T., & Grabiner, M. D. 2002, "Influence of lower extremity strength of healthy older adults on the outcome of an induced trip," ] Am Geriatric Soc, vol. 50, pp. 256-262 Silver, J. K, Sc Aiello, D. D. 2002, "Polio survivors: Falls and subsequent injuries," Am ] Phys Med Kebab, vol. 8 1 , pp. 567-570 Tideiksaar, R. & Fillit, H. 1997, "Falls in the elderly," in Seizures and epilepsy in the elderly, cds. A. J. Rowan £c R. E. Ramsay, Butterworth-Heinemann, Boston Tinetti, M. E. 2003, "Preventing falls in elderly persons," N Engl] Med, vol. 348, pp. 42-49 Tinuper, P., Cerullo, A., Marini, C., et al. 1998, "Epileptic drop attacks in partial epilepsy; Clinical features, evolution, and prognosis," / Neurol Neurosurg Psychiatry, vol. 64, pp. 231-237 Ugur, C., Guciiyencr D., Uzuner, N., et al. 2000, "Characteristics of falling in patients with stroke," / Neurol Neurosurg Psychiatry, vol. 69, pp. 649-651 Wood, B. H., Bilclough, J. A., Bowron, A., &; Walker, R. W. 2002, "Incidence and prediction of falls in Parkinson's disease: A prospective multidisciplinary study," ] Neurol Neurosurg Psychiatry, vol. 72, pp. 721-725 Ziegler, D. K. & Mallonee, W. 1999, "Chiari-1 malformation, migraine, and sudden death," Headache, vol. i9, pp. 38-41
Chapter 4 Delirium Mario F. Mendez and David N. Gershfield
Clinical Characteristics Acute Onset with Fluctuating Course Attention a 1 Deficits Disorganized Thinking Altered Level of Consciousness Perceptual Disturbances Disturbed Sleep-Wake Cycle Altered Psychomotor Activity Disorientation and Memory Impairment Other Cognitive Deficits Kehavioral and Emotional Abnormalities
29 30 30 30 30 30 31 31 31 31 32
Delirium is a ncurobehavioral disorder characterized by an acute mental status change, fluctuating course, and abnormal attention. Delirium is a common disorder among hospitalized patients, occurring in 10-30% of medically ill patients and among 14-56% of patients 65 years of age and older (Brown and Boyle 2002; Elie et al. 2000; Inouye et al. 1998). Delirium may be the most common presentation of disease in the elderly (Bucht, Gustafson, and Sandberg 1999). The consequences of delirium are serious: They include longer hospitalizations, increased mortality, high rates of discharge to institutions, and more than $4 billion of annual Medicare expenditures in the United States (Inouye et al. 1999). Physicians have known about this disorder since antiquity. Hippocrates referred to it as pbrenitis, the origin of our word frenzy. In the first century AD, Celsus introduced the term delirium from the Latin for "out of furrow," meaning derailment of the mind, and Galen observed that delirium was often due to physical diseases that affected the mind "sympathetically." In the nineteenth century, Gowers recognized that these patients could he either lethargic or hyperactive. Bonhoeffer, in his classification of organic behavioral disorders, established that delirium is associated with clouding of consciousness. Finally, Kngel and Romano described alpha slowing and delta and thcta intrusions on electroencephalograms (LLCs) and correlated these changes with clinical severity. They noted that treating the medical cause resulted in reversal of both the clinical and the EEG changes of delirium. Despite this long history, clinicians often fail to diagnose delirium. They often miss this syndrome more from lack of recognition than from misdiagnosis as something else. The elderly, in particular, may have a "quieter," more subtle presentation of delirium. Adding to the confusion about
Pathophysiology Diagnosis of Delirium History Mental Status Examination Diagnostic Scales and Criteria Physical Examination Laboratory Tests Differential Diagnosis Management Prognosis
32 33 33 34 34 IS 3i
!3 38 40
delirium are the many terms used to describe this disorder: acute brain failure, acute brain syndrome, acute cerebral insufficiency, acute confusional state, acute organic syndrome, delirium, exogenous psychosis, metabolic encephalopathy, organic psychosis, toxic encephalopathy, toxic psychosis, and others. One of the problems in recognizing delirium is defining the disorder. Delirium often reflects a global failure of brain metabolism from a large variety of medical etiologies, yet it is difficult to judge the impact of medical conditions on the brain. Most delirium in the elderly is superimposed on dementia, yet several investigators question the reversibility of delirium and its distinction from dementia. In sum, the definition of delirium must emphasize an acute behavioral decompensation with fluctuating attention, regardless of etiology or the presence of baseline cognitive impairments. In addition, we must carefully define the terms used with these disorders. Attention is the ability to focus on specific stimuli to the exclusion of others. Arousal, a basic prerequisite for attention, indicates responsiveness or excitability into action. Coma, stupor, wakefulness, and alertness arc states of arousal. Consciousness, a product of arousal, means clarity of awareness of the environment.
CLINICAL CHARACTERISTICS The essential elements of delirium are summarized in Tables 4.1 and 4.2. Among the American Psychiatric Association's criteria (American Psychiatric Association 2000) for these disorders are an acute onset with fluctuations over the course of a day, reduced ability to focus and sustain attention, disorganized thinking, and evidence of a neurological or medical cause. Furthermore, 24
30
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 4,1:
Clinical characteristics of delirium
Acute onset of mental status change with fluctuating course Attentional deficits Disorganized thinking Altered level of consciousness Perceptual disturbances Disturbed sleep-wake cycle Altered psychomotor activity Disorientation and memory impairment Other cognitive deficits behavioral and emotional abnormalities
attention indiscriminately, trivial ones often getting mote attention than important ones. All components of attention ate disturbed, including selectivity, sustainability, processing capacity, case of mobilization, monitoring of the environment, and the ability to shift attention when necessary. Although many of the same illnesses result in a spectrum of disturbances from mild inattention to coma, delirium is not the same as disturbance of arousal.
Disorganized Thinking Table 4.2: Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Revised, criteria for delirium A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. B. A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual dis turbance that is not better accounted for by pre-existing, established, or evolving demenria. C. The disturbance develops over a short period (usually hours to days) and tends to fluctuate during the course of the day. D. There is evidence from the history, physical examination, or laboratory findings rhat the disturbance is caused by rhe direct physiological consequences of a general medical condition. Source: Modified with permission from American Psychiatric Association. 2000, Diagnostic and Statistical Manual of Me/ital Disorders, 4th ed, revised text, American Psychiatric Associatioti, Washington, DC. delirious patients have disorganized thinking and altered level of consciousness, perceptual disturbances, disturbance of the sleep-wake cycle, increased or decreased psychomotor activity, disorientation, and memoty impairment. Other cognitive, behavioral, and emotional disturbances may also occur as part of the spectrum of delirium.
Acute Onset with Fluctuating Course Delirium develops rapidly over hours or days but tarely over more than a week, and fluctuations in the course occur throughout the day. There are lucid intervals interspersed with the daily fluctuations. Gross swings in attention, arousal, or both occur unpredictably and irregularly and become worse at night. Because of potential lucid intervals, medical personnel may be misled by patients who exhibit improved attention and awareness unless the patients are evaluated over time,
Attentional Deficits A disturbance of attention is the cardinal symptom of delirium. Patients are distractible, and stimuli may gain
The stream of thought is disturbed in delirium. There are multiple intrusions of competing thoughts and sensations, and patients are unable to order symbols, carry out sequenced activity, and organize goal-directed behavior, Confusion refers to this inability to maintain the stream of thought with accustomed clarity, coherence, and speed. The patient's speech reflects this jumbled thinking. Speech shifts from subject to subject and is rambling, tangential, and circumlocutory, with hesitations, repetitions, and perseverations. Decreased relevance of the speech content and decreased tcading comprehension are characteristic of delirium. Confused speech is further characterized by an abnormal rate, frequent dysarthria, and nonaphasic misnaming, particularly of words related to stress or illness, such as those referable to hospitalization.
Altered Level of Consciousness Consciousness, or clarity of awareness, may be disturbed. Most patients have lethargy and decreased arousal. Others, such as [IIDM- with delirium tremens, arc hypcralerl and easily aroused. In hyperalert patients, the extreme arousal does not preclude attentional deficits because patients are indiscriminate in their alertness, are easily distracted by irrelevant stimuli, and cannot sustain attention. The two exttemes of consciousness may overlap or alternate in the same patient or may occur from the same causative factor.
Perceptual Disturbances The most common perceptual disturbance is decreased perceptions pet unit of time; patients miss things that are going on around them. Illusions and other misperceptions result from abnormal sensory discrimination. Perceptions may be multiple, changing, or abnormal in size or location. Hallucinations also occur, particularly in younger patienrs and in those in the hyperactive subtype. They ate most common in the visual sphere and arc often vivid, threedimensional, and in full color. Patients may see lilliputian animals or people that appear to move about. Hallucinations are generally unpleasant, and some patients attempt to fight them or run away with fear. Some
DELIRIUM
hallucinatory experiences may be release phenomena, with intrusions into wakefulness of dreams or of visual imagery. Psychotic auditory hallucinations, with voices commenting on the patient's behavior, are unusual.
31
are "replaced" in this condition. In general, delirious patients tend to mistake the unfamiliar for the familiar. For example, they tend to relocate the hospital closer to their homes. In a form of reduplicative paramnesia known as Capgras' syndrome, however, a familiar person is mistakenly thought to be an unfamiliar impostor.
Disturbed Sleep-Wake Cycle Disruption of the day-night cycle causes excessive daytime drowsiness and reversal of the normal diurnal rhythm. "Sundowning"—with restlessness and confusion during the night—is common, and delirium may be manifest only at mght. Nocturnal peregrinations can result in a serious problem when the delirious patient, partially clothed in a hospital gown, has to be retrieved from the hospital lobby or from the street in the middle of the night. This is one of the least specific symptoms and also occurs in dementia, depression, and other behavioral conditions. In delirium, however, disruption of circadian sleep cycles may result in rapid eye movement or dream-state overflow into wakin».
Altered Psychomotor Activity There are two subtypes of delirium, based on changes in psychomotor activity. The hypoactive-hypoalert subtype is characterized by psychomotor retardation. These are the patients with lethargy and decreased arousal. The hyperactive-hyperalert subtype is usually hyperalert and agitated and has prominent overactivity of the autonomic nervous system. Moreover, the hyperactive type is more likely to have delusions and perceptual disorders, such as ha 11 Lie illations. About half of patients with delirium manifest elements of both subtypes or fluctuate between the two. Only about 1 5 % are strictly hyperactive. In addition to the patients being younger, the hyperactive subtype has more drug-related causes, a shorter hospital stay, and a better prognosis.
Other Cognitive Deficits Disturbances occur in visuospatial abilities and in writing. Higher visual-processing deficits include difficulties in visual object recognition, environmental orientation, and organization of drawings and other constructions. Writing disturbance is the most sensitive language abnormality in delirium. The most salient characteristics are abnormalities in the mechanics of writing: The formation of letters and words is indistinct, and words and sentences sprawl in different directions (Figure 4.1). There is a reluctance to write, and there are motor impairments, such as tremors or micrographia, and spatial disorders (e.g., misalignment or leaving insufficient space for the writing sample). Sometimes the writing shows perseverations of loops or aspects of the writing. Spelling
FINISHING
Disorientation and Memory Impairment Disturbances in orientation and memory are related. Patients are disoriented first to time of day, followed by other aspects of time, and then to place. They may perceive abnormal juxtapositions of events or places. Disorientation to person—in the sense of loss of personal identity—is rare. Disorientation is one of the most common findings in delirium. Disorientation is not specific for delirium, however, and it occurs in dementia and amnesia as well. Among patients with delirium, recent memory is disrupted in large part by the decreased registration caused by attentional problems. In delirium, reduplicative paramnesia, a specific memoryrelated disorder, results from decreased integration of recent observations with past memories. Persons or places
PRESIDENT (top is cursive,bottom is printing)
32
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
and syntax are also disturbed, with spelling errors particularly involving consonants, small grammatical words (prepositions and conjunctions), and the last letters of words. Writing is easily disrupted in these disorders, possibly because it depends on multiple components and is the least-used language function.
Behavioral and Emotional Abnormalities Behavioral changes include poorly systematized delusions, often with persecutory and other paranoid ideation and personality alterations. Delusions, like hallucinations, are probably release phenomena and are generally fleeting, changing, and readily affected by sensory input. These delusions are most often persecutory. Some patients exhibit facetious humor and playful behavior, lack of concern about their illness, poor insight, impaired judgment, and confabulation. There can be marked emotional lability. Sometimes patients are agitated and fearful, or depressed, or quite apathetic. Dysphoric (unpleasant) emotional states arc the more common, and emotions are not sustained. Up to one half of elderly delirious patients display symptoms of depression with low mood, loss of interests, fatigue, decreased appetite and sleep, and other feelings related to depression, Thete may be mood-congruent delusions and hallucinations. The mood changes of delirium are probablydue to direct effects of the confusional state on the limbic system and its regulation of emotions, Finally, more elementary behavioral changes may be the principal symptoms of delirium. This is especially the case in the elderly, in whom decreased activities of daily living, urinary incontinence, and frequent falls are among the major manifestations of this disorder,
PATHOPHYSIOLOGY The pathophysiology of delirium is not entirely understood, but it depends on a widely distributed neurological substrate. Normal attention requires both the ascending reticular activating system (ARAS) in the upper brainstem and polymodal association areas of the cortex. Stimulation of the ARAS elicits arousal, and lesions of the ARAS may result in sleep, coma, or akinetic mutism rather than attentional problems or delirium (see Chapters 5 and 74). The ARAS primes the cortex for stimulus reception, whereas the polymodal association cortex controls and focuses this arousal energy for attention. Certain brain areas may be particularly involved in attention: bilateral or right prefrontal cortex in attcntional maintenance and executive control, the temporoparietal junction region in disengaging and shifting attention, the thalamus in engaging attention, and the upper brainstem structures in moving the focus of attention. Cortical blood
FIGURE 4.2 A proposed schema for the attention system. The important polymodal areas arc the prefrontal cortex and the temporal-parietal junction, particularly in the right hemisphere. A sensory signal leads to alerting and localization as it is relayed from the thalamus to the primary sensory cortex. Upon transmission to the temporal-parietal cortex, attention is disengaged from its current focus and moved to engage the sensory event. Environmental monitoring and the '"gate" function of attention may occur through feedback from the polymodal cortical areas to the nucleus reticularis of the thalamus (external thalamic ring), a modulator of sensory input.
flow studies suggest that the polymodal cortical areas and their limhic connections arc the "attentional gate" for sensory input through feedback to the reticular nucleus of the thalamus (Figure 4.2). The thalamic nuclei are uniquely positioned to further screen sensory information from the ARAS, and small lesions in the thalamus may cause delirium. As part of thalamofrontal circuits, the thalamic nuclei influence and regularc the activity of cerebral and limbic cortices. In addition, there is evidence that the right hemisphere is dominant for attention, although split-brain studies clearly point out the need for bihemispheric cooperation in maintaining attention. A second explanation for delirium is alterations in neurotransmitters, particularly a cholinergic-dopaminergic imbalance. Anticholinergic agents can induce the clinical and EEC changes of delirium, which are reversible with the administration of cholinergic medications, such as physostigmine. The beneficial effects of tacrine and donepezil, acetylcholinesterase inhibitor medications used for Alzheimer's disease, may be partly due to an activating or attentionenhancing role, Moreover, cholinergic neurons project from the pons and the basal forebrain to the cortex and make cortical neurons more responsive to other inputs, A decrease in acetylcholine results in decreased perfusion in the frontal cortex. Hypoglycemia, hypoxia, and other metabolicchanges may differentially affect acetylcholinc-mediated functions. Other neurotransmitters may be involved in delirium, including dopamine, serotonin, norepinephrine, y-aminobutyric acid, glutamine, opiates, and histamine.
1)1 I .lltll.M
Dopamine appears to function in a reciprocal fashion to acetylcholine, hence the delirium-producing effects of i.-dopa and other antiparkinsonism medications. Opiates may induce the effects by increasing dopamine and glutamate activity. Future studies may show a role for inflammatory cytokines in the pathogenesis of delirium. Any explanation of delirium must take into account not only specific structural lesions and neurotransmitter changes but also the diffuse metabolic causes that can result in the same disturbances of attention. The diffuse causes, the universal susceptibility to developing delirium, and the minimal or nonspecific pathologic changes suggest an impairment of some common metabolic pathways in nerve cells. Metabolic pathways involving the ARAS and i he poly modal cortex may he vulnerable because these lira areas have the most polysynaptic chains.
DIAGNOSIS OF DELIRIUM Diagnosis is a two-step process. The first step is the recognition of delirium, which requires a thorough history, a bedside mental status examination focusing on attention, and a review of established diagnostic scales or criteria for delirium. The second step is to identify the cause from a large number of potential diagnoses. Because the clinical manifestations offer few clues to the cause, crucial to the differential diagnosis are the general history, the physical examination, and the laboratory assessment. In addition, the clinician should thoroughly review the patient's medication list.
History An abrupt decline in mentation, particularly in the hospital, should be presumed to be delirium. Although patients may state that they cannot think straight or concentrate, family members or other good historians should be available to describe the patient's behavior and medical history. The observer may have noted early symptoms of delirium, such as inability to perform at a usual level, decreased awareness of complex details, insomnia, and frightening or vivid dreams. Furrhermore, it is crucial to obtain accurate information about systemic illnesses, drug use, recent trauma, occupational and environmental exposures, malnutrition, allergies, and any preceding symptoms leading to a confusional state. The patient's risk factors for delirium should be carefully assessed (Table 4.3). Of the risk factors that predispose to incident delirium in the hospital, the most important are advanced age, pre-existing cognitive dysfunction or dementia, and chronic medical illnesses (Johnson 2001). Advanced age itself seems to be an independent risk factor, especially for those older than 80 years. Many of these elderly parients predisposed to delirium have cerebral
Table 4.3:
."
Risk factors for delirium
Elderly, especially SO years or older Dementia, cognitive impairment, or other brain disorder Fluid and electrolyte disturbances and dehydration Other metabolic disturbance, especially elevated blood urea nitrogen level, or hepatic insufficiency Number and severity of medical illnesses including cancer Infections, especially urinary tract, pulmonary, and acquired immunodeficiency syndrome Malnutrition, low serum albumin level Cardiorespiratory failure or hypoxemia Prior stroke or other nondementia brain disorder Polypharmacy and use of analgesics, psychoactive drugs, or anticholinergics Drug abuse, alcohol or sedative dependency Sensory impairment, especially visual Sensory overstimulation and "intensive care unit psychosis" Sensory deprivation Sleep disturbance Functional impairment Fever, hypothermia Physical trauma or severe burns Fractures Male gendef Depression Specific operations Cardiac, especially open heart surgery Orthopedic, especially femoral neck and hip fractures, bilateral knee replacements Ophthalmologics], especially cataract surgery Noneardiac thoracic surgery and aortic aneurysmal repairs Transurethral resection of the prostate
atrophy or white matter and basal ganglia ischemic changes on neuroimaging. Among the elderly, those with dementia are five times more likely to develop delirium than those without dementia (Elie et al. 1998). As many as one half of hospitalized patients with delirium have an underlying dementia, and many of the remainder have mild cognitive impairment, A third factor is the severity of the illness and the degree of physical impairment. Additional risk factors include vision impairment (
Helps to undress, listens to stories with pictures Pretends in play, helps put things away Helps in dressing Plays with other children, uses toilet alone Asks about word meanings, domestic role playing
of developmental pathophysiology, increased imaging resolution, and availability of genetic testing {Shevell ct al. 2000). Establishing the cause of a retardation syndrome may not always alter medical management but does ptovide a family with important information regarding prognosis and recurrence risk for future pregnancies, and it also limits the need for further testing. A child's development depends on the complex interplay of biological, social, and environmental influences. Table 7.2 summarizes the biological conditions associated with developmental disability and organizes examples by presumed time of onset and disease category. (The interested reader is referred to the appropriate chapters of this textbook for detailed descriptions of these conditions.)
History The caregiver's report of a child's past developmental history is the first step in estimating the degree and scope of developmental delay. Questions should address the child's current level of function and possible associated medical problems, seizures, or difficulties with feeding, sleeping, or behavior. Prior medical records, past and current classroom placements, and reports from teachers provide corroboration. A family history of similar illness suggests a genetic syndrome and should be pursued in detail, including consanguinity, ethnicity, relatives with neurological impairments, and early postnatal deaths. Although family history is becoming increasingly difficult as families spread
Stands alone, uses a thumb-finger pineer grasp Walks alone, stoops and recovers Walks up steps with hand held, imitates scribbling Runs well, makes circular scribbles, copies a horizontal line Climbs stairs with alternate feet, copies a vertical line Rides a tricycle, stands on one foot briefly, copies a circle Hops on one foot, uses scissors to cut out pictures, copies a square and a cross Skips, copies a triangle
geographically, information should be sought from both parents and from both sets of grandparents. An equally detailed prenatal, birth, and postnatal history may reveal those risk factors that arc associated with neurological injury (Table 7.3).
Physical Examination Observing a child's interactions with parents and with ageappropriate toys allows an initial assessment of motor skill and dexterity; curiosity, impulsivity, and artcntion span; and social skills, eye contact, and communicative intent. The hands-on physical examination should be as complete as a child will allow, focusing on possible etiological clues such as growth parameters; abnormalities of the eyes, skin, and hair; dysmorphic features; abnormal tone, posture, movements, and reflexes; signs of cerebellar or peripheral nerve dysfunction; and organomegaly. Findings that suggest specific syndromes are listed in Tables 7.4 and 7.5.
Diagnostic Testing An evidence-based and stepwise search for an underlying cause is preferable to the use of a large panel of screening tests. One stepwise approach is presented in Figure 7.1.
GLOBAL DEVELOPMENTAL DELAY AND DEVELOPMENTAL REGRESSION Table 7.2:
77
Etiology of developmental delay by time of onset
Prenatal/perinatal
Examples.
Congenital malformations of the CNS Ch romos om a 1 a bn orma 1 ities Endogenous toxins from maternal organs Exogenous toxins from maternal use Fetal infection Prematurity and/or fetal malnutrition Perinatal trauma Perinatal asphyxia
Lissencephaly, Chiari malformation Down syndrome, Turner's syndrome Maternal hepatic or renal failure Alcohol, anticonvulsants, anticoagulants, drugs of abuse Congenital infections (toxoplasmosis, rubella, cytomegalovirus, HIV, and syphilis) Periventricular leukomalacia, intraventricular hemorrhage Intracranial hemorrhage, spinal cord injury H y pox ic-i sch e mic en c e ph a lo pa thy
Postnatal Inborn errors of metabolism Abnormal storage of metabolites Abnormal postnatal nutrition Endogenous toxins from organ failure Exogenous toxins Endocrine organ failure CNS infection
Examples Aminoacidopathies, mitochondrial diseases, urea cycle defects Lysosomal storage diseases, glycogen storage diseases Vitamin or calorie deficiency 1 k-paiic or renal failure, kern icterus Prescription drugs, illicir substances, lead Neonatal or acquired hypothyroidism, hypoadrenocorticism (Addison's disease) Meningitis, cerebral abscess, viral meningoencephalitis, HIV encephalopathy, subacute sclerosing panencephalitis Nonaccidental trauma, traumatic brain injury Infiltration, edema, hydrocephalus, radiarion Neurofibromatosis, tuberous sclerosis, incontinentia pigmenti, Sturgc-Weber syndrome Congenital muscular dystrophy, congenital myotonic dystrophy, congenital myopathies Systemic lupus erythematosus, moyamoya disease, stroke, venous sinus thrombosis Autism, uncontrolled epilepsy, severe mood disorder, schizophrenia
CNS trauma Neoplasia Neurocutaneous syndromes Neuromuscular disorders with CNS involvement Vascular conditions Other
CNS = central nervous system; HIV = human immunodeficiency virus. Source: Adapted with permission from Shevell, M. I. & Swaiman, K. F. 1999, "Global developmental delay and mental retardation," in Pediatric Neurology, Principles and Practice, eds K. F. Swaiman & S. Ashwal, Mosby, St. Louis.
Metabolic
Testing
Universal n e w b o r n screening in the United States, particularly the use of t a n d e m mass spectroscopy, identifies m a n y of the m o r e c o m m o n metabolic disorders. M e t a b o l i c screening of children w i t h unexplained global developmental delay has a less than 1% yield. T h e yield r e m a i n s
Table 7.3:
less t h a n 5% even w h e n a metabolic etiology is suggested by history or e x a m i n a t i o n . Screening these children with basic m e t a b o l i c tests before o r d e r i n g specific metabolic tests m a y increase t h e yield to 1 4 % (Papavasiliou et al. 2 0 0 0 ) . T h y r o i d studies are n o t indicated in children w i t h global d e v e l o p m e n t a l delay w h o h a v e already been screened as n e w b o r n s unless clinical features a r e also present.
Perinatal risk factots for neurological injury
Material Up renatal
Natal
Postnatal
Age less than 16 or more than 40 yr Cervical or pelvic abnormalities Infection Diabetes mellitus Drug addiction Malnutrition I [ypertension or toxemia Thyroid disease Hemorrhagic shock Polyhydramnios or oligohydramnios Low socioeconomic status Prior miscarriages or stillbirths Vaginal bleeding after first trimester Prior placental abnormalities
Cesarean section after a trial of labor Firstborn male Premature twins Cyanosis Need for resuscitation Low Apgar score Gestational age less than 30 wk Hypoxic-ischemic encephalopathy Midforceps delivery Breech presentation Placental abruption Umbilical prolapse
Abnormal sucking or feeding Abnormal crying Asymmetrical face or extremities Dysmorphic features Hyperbilirubinemia Hypotonia Birth injuries Seizures Fever Need for an incubator or oxygen Poor weight gain Malnutrition
Source: Adapted with permission from Shevell, M. I. &: Swaiman, K. F, 1999, "Global developmental delay and mental retardation," in Pediatric Neurology, Principles and Practice, eds K. F. Swaiman & S. Ashwal, Mosby, St. Louis.
-s
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 7.4:
Ocular findings associated with selected syndromic developmental disorders
Finding
Examples
Cataracts Chorioretinitis Corneal opacity
CerebrotendinouS xanthomatosis, galactosemia, Lowe's, LSD, Wilson's Congenital infections Cockayne's, Lowe's, LSD, xeroderma pigmentosa, Zellweger's Lowe's, mucopolysaccharidoses, Sturge-Weber, Zellweger's Homocystinuria, sulfite oxidase deficiency LSD, multiple sulfatase deficiency Aminoacidopathies, AT, CDG, Chediak-Higashi, Friedrich's ataxia, Leigh's, Marinesco-Sjogren, metachromatic leukodystrophy, neuroaxonal dystrophy, Pelizaeus-Merzbacher, SCD AT, Basscn-Kornzwcig, LSD, mitochondrial diseases Alpers', Leber's optic atrophy, leukodystrophies, LSD, neuroaxonal dystrophy, Pelizaeus-Merzbacher, SCD Cockayne's, Hartnup's, homocystinuria AT, Bassen-Kornzweig, Cockayne, CDG, Hallervorden-Spatz, Laurence-Moon-Beidl, LSD, mitochondrial diseases, Refsum's, Sjogren-La rsscn, SCD
Glaucoma
Lens dislocation Macular cherry-red spot Nystagmus
Ophthalmoplegia Optic atrophy Photophobia Retinitis pigmentosa or macular degeneration
AT = ataxia-telangiectasia; CDG = congenital disorders of glycosylation; LSD = lysosomal storage diseases; SCD = spino-cerehellar degeneration. Source: Adapted with permission from Shevell, M. 1. & Swaiman, K. F. 1999, "Global developmental delay and mental retardation," in Pediatric Neurology, Principles and Practice, eds K. F. Swaiman & S. Ashwa!, Moshy, St. I.ouis. Metabolic testing should he considered w h e n the history or physical e x a m i n a t i o n is suggestive of a metabolic disorder or w h e n n e w b o r n screening results are n o t available. Tests to consider include a capillary blood g a s , scrum lactate a n d pyruvate (energy metabolism), serum a m m o n i a ( a m i n o a c i d o p a t h i e s a n d urea cycle defects), serum a m i n o acids ( a m i n o a c i d o p a t h i e s ) , urine o r g a n i c acids (organic acidopathies), s e r u m creatine kinase (myopathies), serum very-long-chain fatty acids (peroxisomal disorders), urine m u c o p o l y s a c c h a r i d e s a n d oligosaccharides (mucopolysaccharidoses), a n d thyroid function tests, Genetic
Testing
Cytogenetic study of children with g l o b a l d e v e l o p m e n t a l delay, using k a r y o t y p i n g at the 5 0 0 - b a n d level of resolution, has a yield of a b o u t 3 . 5 % . For children w i t h multiple minor dysmorphic features of the face and limbs, the yield is up to 2 0 % ( G r a h a m a n d Selikowitz 1993). D o w n s y n d r o m e , recognizable by its characteristic d y s m o r p h i c features and h y p o t o n i a , is the most c o m m o n c h r o m o s o m a l a b n o r m a l i t y found, a c c o u n t i n g for 2 5 - 5 0 % of severe retardation. T h e fragile X m u t a t i o n ( F M R - 1 ) is t h e m o s t c o m m o n inherited cause of mental r e t a r d a t i o n . Its p r e valence a m o n g developmental!;- delayed children is 2 . 5 - 5 , 0 % . T h e yield of F M R - 1 testing in p o s t p u h e r t a l males increases to 7 . 6 % w h e n c o m m o n clinical features are used for selection (DeVries et al. 1999) (Table 7.6). T h e X1 inked Rett's s y n d r o m e m u t a t i o n (McCP2) is the m o s t c o m m o n cause of m e n t a l r e t a r d a t i o n in females after D o w n s y n d r o m e . T h e features at presentation arc listed in Table 7,7. In one study, the Rett's m u t a t i o n was found in 2 . 5 % of institutionalized female children (Vorsanova ct al. 2 0 0 1 ) . T h e prevalence of the m u t a t i o n in males a n d in m o r e
mildly affected females is u n k n o w n . Using fluorescence in situ hybridization (FISH) a n d microsatellitc m a r k e r s to screen for the m o r e subtle subtelomeric c h r o m o s o m a l r e a r r a n g e m e n t s m a y h a v e a yield as high as 8 . 5 % in m o d e r a t e l y to severely affected children (Baker et al. 2 0 0 2 ) . R o u t i n e cytogenetic testing s h o u l d be performed on all developmentally delayed children. Testing for the fragile X m u t a t i o n should also be considered, a l t h o u g h clinical preselection can be used to exclude s o m e p o s t p u h e r t a l males. Rett's s y n d r o m e testing should be considered for all m o d e r a t e l y to severely delayed females, especially those d e m o n s t r a t i n g typical clinical features. Subtelomeric testing s h o u l d be considered in children w h o s e m o d e r a t e to severe delay r e m a i n s u n e x p l a i n e d . FISH testing for o t h e r less c o m m o n single gene m u t a t i o n s a n d c o n t i g u o u s gene deletions are w a r r a n t e d w h e n clinical features of those s y n d r o m e s a r e present (Table 7.8).
Imaging
Studies
R o u t i n e imaging with c o m p u t e d t o m o g r a p h y (CT) yields t h e etiology in 3 3 % of unselccted p o p u l a t i o n s of children with g l o b a l d e v e l o p m e n t a l delay. T h i s yield increases to 6 5 % w h e n magnetic r e s o n a n c e imaging (MRI) i s used because M R I is m o r e sensitive for cerebral dysgenesis and w h i t e m a t t e r a b n o r m a l i t i e s , the most c o m m o n radiological findings (Dcmaerel, Kingsley, and Kendall 1 9 9 3 ) . Yields are higher still in patients with cerebral palsy, focal n e u r o logical deficits, or microcephaly. Brain i m a g i n g w i t h M R I should b e r o u t i n e i n children with d e v e l o p m e n t a l disability. CT still h a s a place in the evaluation of children w i t h suspected calcifications (as from congenital infections or t u b e r o u s sclerosis) or craniosynostosis.
GLOBAL DEVELOPMENTAL DELAY AND DEVELOPMENTAL REGRESSION Table 7.5:
79
Other findings associated with selected syndromic developmental disorders
binding
Examples
Cerebellar dysfunction
Aminoacidopathics, AT, Bassen-Kornzwcig, CDG, cercbrotendinous xanthomatosis, Chediak-Higashi, Cockayne's, Friedreich's ataxia, Lafora's disease, LSD, Marim-sco Sjogren's, mitochondrial disease, neuroaxonal dystrophy, Pelizaeus-Merzbacher, Ramsay Hunt syndrome, SCD, Wilson's
Hair abnormalities Synophrys Fine hair Kinky hair
Hirsutism Balding Gray hair Hearing abnormalities Hyperacusis Conductive loss Sensorineural loss Infantile hypotonia Limb abnormalities Mkromelia Broad thumbs Macroccphaly Microcephaly Movement disorders Odors Cat urine Maple Musty
Rancid butter Sweaty feet Organomegaly Peripheral neuropathyShort stature Seizures Skin abnormalities Hyperpigmentation Hypopigmentation Nodules Thick skin Thin skin
Cornelia de Lange's Homocysrinuria, hypothyroidism Argininosuccinic aciduria, Menkc's LSD Leigh's, progeria AT, Chediak-Higashi, Cockayne's, progeria LSD, Subacute sclerosing panencephalitis, sulfite oxidase deficiency Mucopolysaccharidoses Adn.'r1t>l::i.ikudvMrlividiis ft Ion i>ri testins: Aphasic errors Sundown ing Referred by others
BEHAVIOR AND PERSONALITY DISTURBANCES Frontotemporal
FIGURE R.3 Neuropsychiatric inventory subseale scores for apathy and depression. AD = Alzheimer's disease; FTD = frontotemporai dementia; PD = Parkinson's disease; PSP = pr og re ss i vc supranuclear palsy; HD = Huntington's disease. (Reprinted with permission from Levy, M. L., Gummings, J. L., Fairbanks, L. A., et al. 1998, "Apathy is not depression,"/ Neuropsychiatry Clin Neurosci, vol. 10, pp. 314-319.) without these symptoms (Rao and Lyketsos 1998). For example, compared with patients with AD without psychotic symptoms, neuropsychological studies indicated that patients with AD with delusions were more impaired on an abstraction task and were more perseverative. Using survival analyses, wc recently found that lower scores on measures of fluency, grooved pegboard, trail making, and digit span wete predictors (p < .05) of future psychosis in AD. In addition, greater worsening on the Dementia Rating Scale (DRS), attention and construction subscales, total DRS, and fluency scores were associated with a twofold to threefold increase in the risk of developing psychosis. For instance, for every one z-score change in fluency, the risk of psychosis increased threefold. Atypical antipsychotics are the preferred method of treatment for psychosis in AD because of the lowered anticholinergic and hypotensive effects. Although few treatment studies have been performed, the National Institutes of Health is currently supporting a multisite study of atypical antipsychotics (e.g., quetiapine, olanzapine, risperidone, and citalopram) in AD.
89
Dementia
FTD, previously called Pick's disease, is composed of at least three syndromes: semantic dementia, progressive nonfluent aphasia, and frontal lobe degeneration of nonAlzheimer type (FLD). The term FTD therefore describes a heterogeneous group of disorders. Clinical presentation of FTD may vary significantly. A distinct neuropsychological profile of FTD has not yet emerged; as a result, some have described FTD as a ncurobehavioral disorder rather than ;i neuropsychological disorder. Recent consensus criteria for diagnosis of FTD have been reported and primary criteria relate to the presence of behavioral change (Table 8.9). Behavioral Disruption. As the name suggests, FTD syndromes are marked by progressive atrophy of the frontal and temporal lobes. Atrophy within the frontal lobes leads to disruption of the frontal-subcortical circuits and the associated behavioral syndromes described earlier, Individuals with FTD exhibit symptoms of orbitofrontal syndrome, such as disinhibition, poor impulse control, tactlessness, and poor judgment. In addition, loss of empathy, mental inflexibility, and stereotyped behaviors are common. Individuals with FLD frequently have impaired social relationships and inappropriate social interactions. Symptoms associated with Kliiver-Bucy syndrome, such as byperorality and hypersexuality, may occur in late stages of FTD. Patients may develop a propensity for sweets. Disruption of the anterior cingulate circuit may also occur, resulting in symptoms of apathy and lack of motivation, which may be the earliest signs of FTD. In addition, these individuals may show little concern for personal hygiene, appearing unkempt. Finally, disruption of the dorsolateral circuit in FTD is associated with impaired planning and organization. The inability to demonstrate basic and social emotions is also common. Often, the family members and caregivers are the ones who report these behavioral disturbances because many patients with FTD experience a lack of insight into their current difficulties. Although no large-scale clinical trials have been conducted, evidence suggests that behavioral disturbances, such as disinhibition, overeating, and compulsions, may respond to treatment with SSRIs, Studies have attempted to distinguish FTD from AD based on behavioral symptoms. Disinhibition, apathy, aberrant motor behavior, and euphoria are more common in FTD than AD, as illustrated in Figure 8.5. Others have noted that lack of insight and emotion, food cramming, indifference, and impulsivity are more common in FTD than vascular dementia (VaD). Psychiatric Disturbances. Although the more classic psychiatric syndromes, such as depression, anxiety, and psychosis, are observed in FTD, symptoms are rarely severe enough to meet criteria for diagnosis. Depression in FTD is associated with irritability, increased appetite with weight
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 8.8:
Psychotic symptoms in Alzheimer's disease vs. schizophrenia in elderly patients
Incidence Bizarre or complex delusions Misidentification of caregivers Common form of hallucinations Schneiderian first-rank symptoms Active suicidal ideation History of psychosis Eventual remission of psychosis Need for many years of maintenance on antipsychotics Average optimal daily dose of an antipsychotic
Psychosis in AD
Schizophrenia in the elderly
30-50% Rare
90%)
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patients with PSP show high levels of apathy, whereas about half of patients with PSP exhibit a change in personality and less than half suffer from depression. Disinhibition, or loss of control for emotions, is noted in 3 0 - 3 6 % of patients with PSP. Huntington's
Disease
Psychiatric and behavioral symptoms are common in Huntington's disease (HD) and have been reported as the presenting disease manifestations in up to 7 9 % of patients. Research on the incidence of psychiatric symptoms in HD is variable though, encumbered by limitations within and across studies. Some limitations of the available research are as follows: (1) affected people are often medicated to minimize abnormal involuntary movements; such treatment may mask psychiatric and behavioral symptoms; (2) most available tieuropsychiatrie assessment tools use conventional psychiatric terminology based on idiopathic psychiatric illness, which fails to distinctly reflect the symptoms associated with striatal deterioration; and (3) most research has emphasized the motor and cognitive impairments associated with HD, despite family reports that psychiatric disturbances are most strongly associated with stress, disability, and placement decisions. Data from 1857 Huntington Study Group (HSG) subjects with a diagnosis of symptomatic HD arc presented in Table 8.10. Subjects are grouped into disease stages according to ratings obtained on the Total Functional Capacity Scale. Depression. Depression is one of the most common concerns for individuals and families with HD, occurring in up to €3>% of patients. It has been suggested that depression can precede the onset of neurological symptoms in HD by 2 to 20 years, although large-scale empirical research has been minimal. Recent data from the HSG indicate that depression is most common immediately before diagnosis, when neurological soft signs and other subtle abnormalities become evident. Following a definite diagnosis of HD, however, depression is most prevalent in the middle stages of the disease (i.e., Shoulson-Fahn stages 2 and 3) and may diminish in the later stages. Positron emission tomography (PET) studies indicate that patients
Table 8.10: Percentage of patients with Huntington's disease endorsing psychiatric symptoms by TFC stage Symptom
(n = 4.U)
(n = 660)
(n = 520)
(n = 221)
(n = 84)
Depression Suicide Aggression Obsessions Delusions Hallucinations
57.5% 6.0% 39.5% 13.3% 2.4% 2.3%
62.9% 9.7% 47.7% 16.9% 3.5% 4.2%
59.3% 10.3% 51.8% 25.5% 6.1%
ill'!-,, 9.9% 54.1% 28.9% 9.9% 11.2%
42.2% 5.5% 54.4% 13.3% 2.2% 3.3%
mime could lie associated with a disconnection between language and motor areas such that the left hemisphere that mediates comprehension of the verbal command could not influence the right hemisphere's motor areas that are responsible for controlling the left hand. This patient, however, could also nor imitate gestures or correctly use actual tools or objects. Therefore a lan^iLi^-inmiii' disconnection could 1101 account tor these findings. Thus Liepmann and Mass posited that the left hemisphere of right handers contains movement formulas and that the callosal lesion in this patient disconnected these movement formulas from the right hemisphere's motor areas. Gazzaniga et al. (1967) also found that their patients with callosal disconnection could not correctly pantomime to command with their left hand, but unlike the patient described by Liepmann and Mass, their patients could imitate and correctly use actual tools and objects with their left hand. The preserved ability to imitate and use actual tools and objects suggests that the inability to gesture to command in these patients with callosal lesions was induced by a language-motor disconnection, rather than a movement formula-motor disconnection. In addition, a disconnection between movement formula and motor areas should produce spatial and temporal errors, but many of the errors made by the patient discussed by Liepmann and Mass appeared to be content errors. Watson and Heilman (1983), however, described a patient with an infarction limited to the body of the corpus callosum, Watson and Heilman's patient had no weakness in her right hand and performed all tasks flawlessly with her right hand. In contrast, with her left hand, she could not correctly pantomime to command, imitate, or use actual tools. Immediately after her cerebral infarction, she made some content errors, but subsequently she made primarily spatial and temporal errors. Her performance indicated that not only language but also movement representations were stored in her left hemisphere and her callosal lesion disconnected these movement formulas from the right hemisphere's motor areas. Lesions of the Inferior Parietal Lobe. It has been proposed by Heilman et al. (1982) that the movement re presentations or movement formulas are stored in the left parietal lobe of right handers and that destruction of the left parietal lobe should induce not only a production deficit (apraxia) but also a gesture comprehension-discrimination disorder. Apraxia induced by (1) premotor lesions, (2) lesions of the pathways that connect premotor areas to motor areas, and (3) lesions of the pathways that lead to the premotor areas from the parietal lobe may also cause production deficits. In contrast to parietal lesions, however, these premotor lesions should not induce gesture comprehension and discrimination disorders. Patients with anterior and posterior lesions have been tested (Heilman et al. 1982); although both groups of patients were apraxic, the patients
with a damaged parietal lobe had comprehension and discrimination disturbances, but those without parietal lesions did not. Liepmann and Mass (1907) proposed that handedness was related to the hemispheric laterality of the movement representations. However, it is not unusual to see righthanded patients with left hemisphere lesions who are not apraxic. Although it is possible that such patients' lesions did not destroy one of the left hemispheric areas important for praxis, many of these patients' lesions arc large and do involve the parietal lobe and other critical left hemisphere areas. As we discussed, not all callosal lesions cause an IMA of the left hand. These results suggest that not all right handers have movement formulas entirely represented in their left hemisphere. Some people may have cither bilateral movement representations or even right hemisphere representations. Apraxia from a right hemisphere lesion in a right hander is rare but has been reported, suggesting that hand preference is not entirely determined by the laterality of the movement representations and may he multifactorial. Whereas the laterality of the movement formula may be the most important factor, there are other factors including deftness (i.e., speed, precision), strength, and even environmental factors. Supplementary Motor Area Lesions. Muscles move joints, and motor nerves from the spinal cord activate these muscles. The spinal motor nerves are acrivated by corticospinal neurons and the corticospinal neurons are activated by the premotor areas. The premotor areas must instruct the motor area on which neurons to fire and in what order these should he tired. For each specific skilled movement there is a set of spatial loci that must be traversed in a specific temporal pattern. We proposed that movement formulas represented in the inferior parietal lobe are stored in a three-dimensional supramodal code (Heilman and Rothi 2003). For the corticospinal neurons to properly activate the motor nerves, the stored spatial temporal knowledge has to be transformed into a motor program. The medial premotor cortex or SMA appears to play an important role in mediating skilled movements. Whereas electrical stimulation of the primary motor cortex induces simple movements, SMA stimulation induces complex movements that may include the entire forelimb. The SMA receives projections from parietal neurons and projects to motor neurons. SMA neurons discharge before neurons in the primary motor cortex. Studies of cctebtal blood flow, an indicator of cerebral metabolism and synaptic activity, have revealed that single repetitive movement increases activation of the contralateral primary motor cortex, but complex movements increase flow in contralateral motor cortex and bilaterally in the SMA. When subjects remain still and think about making complex movements, blood flow is increased to the SMA but not rhe primary motor cortex. Watson et al. (1986)
INTENTIONAL MOTOR DISORDERS AND '1 UK APRAX1AS
reported several patients with left-sided medial frontal lesions that included the SMA who demonstrated an IMA when tested with cither arm. Unlike patients with parietal lesions, these patients could both comprehend questions or pantomimes and discriminate between correctly and incorrectly performed pantomimes. Apraxia has also been reported to be associated with lesions of the convexity premotor cortex. The convexity premotor cortex may be important in coordinating the synchronous actions of multiple joints. Figure 10.1 provides a model for the action processing system we have described thus far. In this figure the label "praxicon" is the theoretical store of the temporospatial representations of learned skilled movements. When performing a skilled act, these representations are transformed into innervatory patterns by SMA and convexity premotor cortex. By the term innervatory patterns we mean the program that activates the motor neurons such that the extremity moves in the correct spatial trajectory with the correct timing of each movement.
Conduction Apraxia A patient was reported who, unlike patients with IMA was more impaired when imitating than when pantomiming to command (Ochipa et al. 1994). Because this patient
127
was similar to the conduction aphasic who repeats poorly, the researchers termed this disorder conduction apraxia. Testing Testing for conduction apraxia is the same as testing for IMA. Whereas most patients with IMA will improve with imitation, patients with conduction apraxia appear to perform worse with imitation than they do to command. Patbnphysio logy The patient with conduction apraxia in the study by Ochipa et al. (1994) could comprehend the examiner's pantomimes and gestures. Wc therefore believe that the patient's visual system could access the movement representations or what we have termed praxicons, and these movement representations could activate semantics. It is possible that decoding a seen gesture requires accessing different movement representations than programming an action. Therefore there may be two different stores of movement representations, an input praxicon and an output praxicon. In the verbal domain a disconnection of the hypothetical input and output lexicons induces conduction aphasia, and in the praxis domain a disconnection between the input and output praxicons could induce c o n d u c t ion a p r a x i a .
FIGURE 10.1 Diagrammatical model of the praxis system. Degradation of action semantics (A) produces conceptual apraxia. Lesions that prevent afferent stimuli from activating movement representations (B, C, D) induce dissociation apraxia. Degradation of the movement representations (F.) causes ideomotor apraxia with impaired gesture discrimination and comprehension. Dysfunction of the premotor cortex (F) where the movement representations are converted to motor programs or innervatory patterns induces an ideomotor apraxia with preserved discrimination and comprehension of transitive gestures. Injury to the corpus eallosum (G) produces an ideomotor apraxia of the nonpreferred limb, and injury to the motor cortex (H) induces a loss of independent finger movement and precision called limb-kinetic apraxia. SMA = supplementary motor area.
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Wheteas the lesions that induce conduction aphasia are usually in the supramarginal gyrus, the arcuate fasciculus, ot Wernicke's atea, the lesions that induce conduction apraxia arc unknown.
Dissociation Apraxia Heilman (1973) described three patients who, when asked to pantomime to command, looked at their hand but would not perform any recognizable actions. Unlike patients with ideomotot or conduction apraxias described earlier, these patients' imitation and use of objects were flawless. Other researchers not only reported patients similar to those reported by Heilman (1973) but also other patients who had a similat defect in other modalities. For example, when asked to pantomime in response to visual or tactile stimuli, they may have been unable to do so but could correctly pantomime to vetbal command. Testing The testing that is performed to assess for this disorder is the same as that used for IMA. Pathopb ysiology Callosai lesions may not only be associated with an IMA, but callosai disconnection may also cause dissociation apraxia. The subjects of Gazzaniga, Bogcn, and Sperry (1967) and others had dissociation apraxia of theit left hand. With their left hand they could not gesture normally to command but perfotmed well with imitation and actual tools. Whereas language in these patients was mediated by the left hemisphere, movement representations may have been bilaterally represented. Thetefore their callosai lesion induced a dissociation apraxia only of the left hand because the verbal command could not get access to the movement representations stored in the right hemisphere. Whereas the patient with callosai dissociation apraxia will not be able to correctly perform skilled purposive movements of the left arm to command, these patients can imitate normally and use actual tools with their left hand. They perform normally because these tasks do not need vetbal mediation and the movement representations stored in their right hemisphere can be activated by tactile or visual input. Right-handed patients who have both language and movement formulas represented in their left hemisphere may show a combination of dissociation and IMA with callosai lesions (Watson and Heilman 1983). When asked to pantomime with their left hand, they perform no recognizable movement (disassociation apraxia), but when imitating or using actual rools, they may demonstrate the spatial and temporal errors seen with IMA. Left banders may demonstrate an IMA without aphasia from a right hemisphere lesion. These left handers are
apraxic because their movement tepresentations are stored in their right hemisphere and their lesions destroyed these representations (Heilman 1973; Valenstein and Heilman 1979). These left handers were not aphasic because language was mediated by their left hemispheres (as is the case in most left handers). If these left banders had a callosai lesion, they may have demonstrated a dissociation apraxia of theit left arm and an IMA of their right arm. These patients reported by Heilman (1973) and those of othct studies probably have an intrahemispheric language-movement formula, visual-movement formula, or somesrhetic-movement formula dissociation. The locations of the lesions that cause these intrahemispheric dissociation apraxias are not known.
Ideational Apraxia Unfortunately, use of the term ideational apraxia has been confusing, with the term erroneously used to label a variety of disorders. For example, Heilman (197,3) used this term when he first desctibed dissociation apraxia. Patients with IMA usually improved when using actual tools and objects, but other researches have reported patients who made errors with the use of actual tools and objects, Heilman (1973) also termed this disturbance ideational apraxia. Although the inability to use actual tools and objects may be associated with a conceptual disorder, a severe production disotder may also impair object use. Lastly, the term has also been used to desctibe patients who make conceptual errors. These patients are discussed in the next section. The inability to catry out a series of acts or sequence of actions, an ideational plan that leads to a goal, has also been called ideational apraxia. In this chapter, we also define ideational apraxia as an inability to correctly sequence a scries of acts that lead to a goal. Testing Unfortunately there are no standatdized tests that assess fot ideational apraxia. To test for ideational apraxia, the patients should be tested for their ability to perform multistep sequential tasks, bor example, the examiner may place two slices of bread, mustard, a knife (not too sharp), several slices of ham, and a sandwich bag in front of the patient and ask the patient to prepare a sandwich for work. If the subject fails to perform each step in the correct order that subject may have ideational apraxia. Path ophysioiogy Ideational apraxia is most often associated with degenerative dementia but may also be associated with focal lesions of the left hemisphere.
INTENTIONAL MOTOR DISORDERS AND THE Al'RAXIAS
Conceptual Apraxia To perform a skilled act, we require two types of knowledge: conceptual knowledge and production knowledge. Whereas dysfunction of the praxis production system induces IMA, defects in the knowledge needed to successfully select and use the tools and objects we term conceptual apraxia. Therefore patients with IMA make production errors (e.g., spatial and temporal errors), and patients with conceptual apraxia make content and tool-selection errors. The patients with conceptual apraxia may not recall the type of actions associated with specific tools, utensils, or objects (tool-object action knowledge) and therefore make content errors (DcRenzi and Luccelli 1988; Ochipa, Rothi, and Heilman 1989). For example, when asked to demonstrate the use of a screwdriver either by pantomiming or using the tool, the patient with the loss of tool-object action knowledge may pantomime a hammering movement or use the screwdriver as if it were a hammer. Content errors (i.e., using a tool as if it were another tool) can also be induced by an object agnosia. However, Ochipa et al. (1989) reported a patient who could name tools (and therefore was not agnosic) that he used inappropriately. Patients with conceptual apraxia may be unable to recall which specific tool is associated with a specific object (tool-object association knowledge). For example, when shown a partially driven nail, they may select a screwdriver rather than a hammer from an array of tools. This conceptual defect may also be in the verbal domain such that when an actual tool is shown to a patient, the patient may be able to name it (e.g., hammer), but when this patient with conceptual apraxia is asked to name or point to a tool when its function is described, he or she cannot. The patient may also be unable to describe the functions of tools. Patients with conceptual apraxia may also have impaired mechanical knowledge. For example, if they are attempting to drive a nail into a piece of wood and there is no hammer available, they may select a screwdriver rather than a wrench or pliers (which are hard, heavy, and good for pounding) (Ochipa et al. 1992). Mechanical knowledge is also important for tool development and patients with conceptual apraxia may also be unable to correctly develop tools (Ochipa et al. 1992).
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another test of associative knowledge (tool-object), the patients may be shown an object such as a screw and then are asked to select the proper tool from a group of five tools. To test mechanical knowledge in patients with normal associative knowledge, one can show them an object such as a partially driven in nail and have them select from five tools the one that would work best for completing the task. The tools from which they may select could include a wrench, a knife, a hand saw, a screwdriver, and scissors. Unfortunately, tests of tool fabrication require special equipment. Pathophysiology Licpmann (1920) thought that conceptual knowledge was located in the caudal parietal lobe and DeRenzi and Luccelli (1988) placed it in the temporoparietal junction. The patient reported by Ochipa et al. (1989) was left handed and rendered conceptually apraxic by a lesion in the right hemisphere, suggesting that both production and conceptual knowledge have lateralized representations and that such representations are contralateral to the preferred hand. Further evidence that these conceptual representations are lateralized contralateral to the preferred hand comes from the observation of a patient who had a callosal disconnection and demonstrated conceptual apraxia of the nonpreferred (left) hand (Watson and Heilman 1983). More recently, it has been demonstrated that conceptual apraxia in people who prefer their right hand is most often associated with left hemisphere lesions (Heilman et al. 1997). Conceptual apraxia is perhaps most commonly seen m degenerative dementia of the Alzheimer type (Ochipa et al. 1992). Although both IMA and conceptual apraxia co-occur, Ochipa et al. also noted that the severity nl conceptual and IMA did not always correlate. The observation that patients with IMA may not demonstrate conceptual apraxia and patients with conceptual apraxia may not demonstrate IMA provides support for the postulate that the praxis production and praxis conceptual systems are independent. Although Heilman et al. (1997) demonstrated that lesions located in the hemisphere opposite the preferred hand induce conceptual apraxia, these investigators did not find a specific anatomic area that appeared critical, suggesting that conceptual representations might be widely distributed.
Testing Clinical Pathology In one test of associative knowledge (tool or object-action), patients may be shown tools such as a screwdriver or objects that tools work on, such as nails, and asked to demonstrate the action that is associated with this tool or object. Patients with conceptual apraxia may make content errors such that they demonstrate the actions of tools other than the one they wetc asked to pantomime. In
The different forms of limb apraxia discussed in this chapter are most commonly associated with strokes and degenerative dementia of the Alzheimer's and Pick's types. Aptaxia may be seen with many other diseases of the central nervous system including tumors and trauma. Certain forms of apraxia (i.e., limb kinetic and ideomotor)
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
may be the presenting symptom of basal ganglia disorders such as corticobasal degeneration.
CONCLUSION Although cognitive-motor disorders are a common, disabling, and enduring sequelae of brain damage, these may be the least recognized neuropsychological disorders associated with cerebral disease. The proper evaluation and diagnosis of these cognitive-motor disorders may not only aid in the diagnosis of the underlying neurological disease but knowledge of these disabilities may help the physician provide the patient and caregiver with information that may help optimize residual resources and thereby improve the patient's quality of life. When possible, the underlying disease should he treated. Although there are no proven specific pharmacologic treatments, cognitive rehabilitation may be of help to some of these patients.
REFERENCES Butter, C. M., Rapcsak, S. Z., Watson, R. T., & Heilman, K. M. 1988, "Changes in sensory inattention, direction hypokinesia, and release of the fixation reflex following a unilateral frontal lesion: A case report," Neuropsychology, vol. 26, pp. 533-545 Coslctt, H. B., Bowers, D.,Fitzparrick, E., et al. 1990, "Directional hypokinesia and hemispatial inattention in neglect," Brain, vol. 113, pp. 475-486 DeRenzi, E. & Lucchelli, F. 1988, "Ideational apraxia," Brain, vol. 113, pp. 1173-1188 Gazzaniga, M., Bogen, J., & Sperry, R. 1967, "Dyspraxia following diversion of the cerebral commissures," Arch Neurol, vol. 16, pp. 606-612 Goodglass, H. & Kaplan, E. 1963, "Disturbance of gesture and pantomime in aphasia," Brain, vol. 86, pp. 703-720
Heilman, K. M. 1973, "Ideational apraxia—A re-definition," Brain, vol. 96, pp. 861-864 Heilman, K. M., Mahcr, L. M., Greenwald, M. L., & Rothi, L. J. G. 1997, "Conceptual apraxia from lateralized lesions," Neurology, vol. 49, pp. 457-464 Heilman, K. M. Sc Rothi, L. J. G. 1985, "Apraxia," in Clinical Neuropsychology, eds K. M. Heilman 8c E. Valenstein, Oxford University Press, New York Heilman, K. M., Rothi, L. J. G., & Valenstein, E. 1982, "Two forms of ideomotor apraxia," Neurology, vol. 32, pp. 342-346 Liepmann, H. & Mass, O. 1907, "Fall von linksseitcr Agraphie und Apraxie bei rechsseitiger," Labmung Z Pbychol Neurol, vol. 10, pp. 214-227 I,una, A. R. 1965, "Two kinds of motor preservation in massive injury to the frontal lobes," Brain, vol. 88, pp. 1-10 Ochipa, C, Rothi, L. J. G., 8c Heilman, K. M. 1989, "Ideational apraxia: A deficit in tool selection and use," Ann Neurol, vol.25, pp. 190-193 Ochipa, C, Rothi, L. J. G., & Heilman, K. M. 1992, "Conceptual apraxia in Alzheimer's Disease." Brain, vol. 114, pp. 25932603 Ochipa, C, Rothi, L. J. G., 8c Heilman, K. M. 1994, "Conduction apraxia," }NNP, vol. 57, pp. 1241-1244 Poizner, H., Mack, L., Verfaellie, M., et al. 1990, "Three dimensional computer graphic analysis of apraxia," Brain, vol. 113, pp. 85-101 Raymer, A. M., Maher, L. M., Eoundas, A. L., et al. 1997, "The significance of body part as tool errors in limb apraxia," Brain & Cognition, vol. 34, pp. 287-292 Rothi, L. J. G., Mack. L., Verfaellie, M., et al. 1988, "Ideomotor apraxia: Error pattern analysis," Apbjsinlagy, vol. 2. pp. 381-387 Sandson, J. & Albert, M. C. 1987, "Preservation in behavioral neurology," Neurology, vol. 37, pp. 1736-1741 Watson, R. T., Fleet, W. $., Rothi, L. J. G., 8c Heilman, K. M. 1986, "Apraxia and the supplementary motor area," Arch Neurol, vol. 43, pp. 787 792 Watson, R. T. & Heilman, K. M. 1983, "Callosal apraxia," Brain, vol. 106, pp. 391-403 Watson, R. T., Valenstein, E., 8c Heilman, K. M, 1981, "Thalamic neglect: The possible role of the medical thalamus and nucleus reticularis thalami in behavior," Arch Neurol, vol. 38, pp. 501-507
Chapter 11 The Agnosias Todd E. Feinberg and Martha J. Farah
Visual Agnosia Apperceptive-Associative Distinction Apperceptive Visual Agnosia Associative Visual Agnosia Assessment of Visual Agnosia Auditory Agnosia Nonverbal Auditory Agnosia
131 131 132 133 136 136 136
The word agnosia is Greek for "not knowing" and refers to a class of neu to psycho logical disorders in which patients fail to recognize familiar objects despite seemingly adequate perception, memory, language, and general intellectual ability. The very idea that a patient could "not know" an object or face by sight, for example, yet retain other prerequisite abilities seems paradoxical to some and was once fiercely contested in the neurological literature. As recently as the 1950s, it was suggested that pure visual agnosia does not exist but is merely an effect of the combination of subtle perceptual problems and genctal intellectual impairment. As we have come to understand more about perception, however, the appearance of paradox has receded. We now know that perception involves many levels of internal representation, ranging from lower level sensory images to more abstract representations of object shapes, sounds, feels, and so on. When perception is viewed in this way, it can be seen how various interruptions in processing along this cascade of representations could interfere with recognition while preserving at least some perceptual abilities, as well as language, memory, and intellect. From this perspective, it also follows that there should be a range of agnosic disturbances, depending on the perceptual modality affected and the level of processing at which it is affected. In this chapter, we focus on the three best known types of agnosia: visual, auditory, and tactile agnosia. Within visual agnosia, we delineate subtypes of clinical and theoretical interest. We review the clinical features of each disorder, along with their anatomy and their theoretical implications for basic neuroscience.
VISUAL AGNOSIA Perhaps because the human brain has devoted more tissue to vision than to any of the other senses, visual agnosias
Pure Word Deafness Other Auditory Agnosias Assessment of Auditory Agnosia Tactile Agnosia Anatomic Considerations Assessment of Tactile Agnosia
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appear to be the most common form of agnosia, with the largest number of distinct subtypes. In any case, more is known about the visual agnosias than agnosias in other senses, and our review accordingly treats visual agnosia in greatest detail.
Appcrceptive-Associative Distinction Understanding of visual agnosia began in 1890, when Lissauer first suggested that disorders of visual recognition could be divided into two types: apperceptive agnosia and associative agnosia. According to Lissauer, apperceptive agnosics have a disorder of complex visual perceptual processes. They arc not blind because they can describe their visual experience; however, they do not have sufficient higher level visual perception to enable object recognition. In contrast to apperceptive agnosia, Lissauer suggested that perception could be normal in associative agnosia, and the problem could lie downstream in the process of associating a perceptual representation with more general knowledge. Associative visual agnosics set' ":i normal percept stripped of its meaning." The apperceptivcassociative dichotomy is useful insofar as it distinguishes between two broad but fairly distinct classes of patients: those with frank perceptual impairments and those without. However, the underlying theoretical assumption that perception is at fault only in agnosics in the apperceptive group is no longer held; many cases of so-called associative agnosia are believed to result from the loss of highct level visual processes. Within the broad classes of apperceptive and associative agnosia, many finer distinctions can be made. For example, disruption of different types of perceptual processes can result in different agnosias with pronounced perceptual impairment. Among the associative agnosias, recognition l.i l
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of different types of visual stimuli may be disproportionately impaired. Each major subtype of apperceptive and associative visual agnosia is reviewed here.
Apperceptive Visual Agnosia Apperceptive visual agnosia is sandwiched, clinically and theoretically, between cortical blindness and associative visual agnosia. These patients arc not cortically blind; they have conscious visual experience, yet their visual perceptual processes are grossly abnormal and are clearly the cause of the object-recognition impairment. It could be argued that given the definition offered—of agnosia as a disorder of object recognition not resulting from a more basic perceptual impairment—these patients should not even be considered agnosic at all. The difference between apperceptive visual agnosia and patients who fall outside the exclusionary criteria is the relatively preserved primary visual capacities of the apperceptive visual agnosic, including acuity, brightness discrimination, color vision, motion perception, and other elementary visual capacities (Farah and Feinberg 1997), It is in contrast to these capacities that their shape perception and hence object recognition seem disproportionately impaired. The dramatic impairment of shape perception is suggested by the performance of one typical apperceptive agnosic (whose agnosia was secondary to carbon monoxide poisoning) in a shape-matching task, shown in Figure 11.1A. The patient's attempts at copying simple geometric figures are shown in Figure 11.IB, Recognition of real objects may be somewhat better than recognition of geometric shapes, although performance is still very poor and depends on nonshapc cues, such as size, color, texture, and specularity. In several cases of apperceptive agnosia, motion facilitates shape perception. This is true whether the motion is of the whole object or whether a simple shape, such as a letter or geometric figure, is "drawn" in the air with a finger. In most cases of apperceptive agnosia, the brain damage is diffuse and posterior, with carbon monoxide poisoning a common cause. One way of interpreting apperceptive agnosia is in terms of a disorder of grouping processes that normally operate over the array of local features representing contour, color, depth, and so on at each point in the visual field. Outside of their field detects, apperceptive agnosics have surprisingly good perception of local visual properties. They fail when they must exttact more global structure from the image. Motion is helpful because it provides another cue to global structure in the form of correlated local motions. The perception of structure from motion may also have different neural substrates from the perception of structure from static contour (Marcar and Cowey 1992), and this may conttibutc to its sparing in apperceptive agnosia.
FIGURE 11.1 Evidence of impaired shape matching (A) and copying ability (B) in a patient with apperceptive agnosia. (Reprinted with permission from Benson, R. & Greenberg, J, P. 1969, "Visual form agnosia. A specific defect in visual discrimination," Arch Neurol, vol. 20, pp. 82-89.)
Related
Syndromes
Some authors have grouped other types of visually impaited patients with the ones cited here as cases of apperceptive agnosia. A description of these disorders follows.
THE AGNOSIAS SiniitltiiHtiguosiii is a term used to describe impaired perception of multi element or multipart visual displays. When shown a complex picture with multiple objects or people, simultanagnosics typically describe them in a piecemeal manner, sometimes omitting much of the material entirely and therefore failing to interpret the overall nature of the scene being depicted. In dorsal simultanagnosia, patients have an attentional limitation that prevents them from seeing more than one object at a time. Occasionally, their attention may be captured by just one part of an object, leading to misidentification of the object and the appearance of petception confined to relatively local image features. The similarity to apperceptive agnosia is limited, however. Once they can attend to an object, dotsal simultanagnosics recognize it quickly and accurately, and even their "local" errors encompass much more global shape information than that available to apperceptive agnosics. Their lesions are typically in the posterior parietal cortex bilaterally. In ventral simultanagnosia, patients can recognize whole objects but are limited in how many objects can be recognized in a given period. Their descriptions of complex scenes are slow and piecemeal, but unlike apperceptive agnosics, their perception of single shapes is not obviously impaired. This impairment is most apparent when reading because the individual letters of words are recognized in an abnormally slow and generally serial manner. Unlike dorsal simultanagnosics, their detection of multiple stimuli appears normal; the bottleneck is in recognition per se. Unlike apperceptive agnosics, they perceive individual shapes reasonably well. In fact, the perceptual disorder of these patients is mild compared with both dorsal simultanagnosics and apperceptive agnosics, and for this reason it may be more sensible to consider them to have a form of associative agnosia. Indeed, they are discussed later
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in this chapter in rhe context of associative agnosia, ["heir lesions are typically in rhe left inferior tcmporo-occipital cortex. A final category of impairment whose relation to apperceptive agnosia should be made clear is perceptual categorization deficit. It is equivalent to the impairment that Warrington termed apperceptive agnosia but is quite distinct from what we and most other writers mean by the term. The hallmark of perceptual categorization deficit is poor performance at recognizing or matching objects seen from unusual views or illuminated in unusual ways so as to produce confusing shadows, such as the pictures shown in Figure 11,2. This impairment has been interpreted as a breakdown in the mechanisms of object shape constancy, that is, the visual mechanisms that allow us to appreciate the equivalence of an object's three-dimensional shape across different views and under different lighting conditions. Two considerations suggest that we should be cautious before accepting this interpretation. First, the impairment has been demonstrated only with unusual views, in which major axes arc foreshortened or salient features occluded, whereas a rrue loss of shape constancy affects the matching of any views that differ from each other, whether or not they are unusual. Second, the impairmenr is often seen in patients who have no problems with everyday object recognition. Thus perceptual categorization deficit may represent a loss of a certain type of visual problem-solving ability, rather than loss of an essential component of object recognition.
Associative Visual Agnosia Associative visual agnosia refers to a visual object-recognition impairment due neither to a more basic perceptual deficit, as seen in apperceptive visual agnosia, nor to a
FIGURE 11.2 Unusual views of common objects pose particular problems for patients with "perceptual categorization deficit.
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interest, theoretically, for what they tell us about the organization of normal visual recognition processes. Prosopagnosia
FIGURE 11.3 Example of the preserved copying ability of associative agnosic patients. higher order disorder of language, communication, intellectual impairment, or other deficits (Weinberg et al. 1994). Unlike the patient with apperceptive agnosia, associative visual agnosics are able to make good copies of objects they cannot recognize. Figure 11.3 shows examples of such copies. The preservation of copying seems to demonstrate that perception is not at fault in associative agnosia, but this conclusion is probably not correct. By its very nature, copying requires piecemeal processing because lines can he drawn only one at a time, whereas normal object recognition requires seeing the whole object simultaneously. When tested directly, the ability of associative visual agnosics to apprehend the whole of an object is impaired. The errors of agnosics often reflect their reliance on local features (e.g., calling a fork "a comb" on the basis of the tines) or an impoverished overall view of the object (e.g., calling a salt shaker "a barrel"). The functional locus of damage in associative visual agnosia is therefore presumed to be high-level visual perceptual representations of object shape.
Dissociations
within Associative
Visual Agnosia
Associative visual agnosics vary in the scope of their recognition impairment, with some encountering difficulty primarily with faces, others with printed words, and others showing sparing of these categories of stimuli. The dissociations among visual stimulus categories are of
Prosopagnosics cannot recognize familiar people by their faces alone and must rely on other cues for recognition, such as voice, distinctive clothing, or hairstyle. The disorder can be so severe that even close friends and family members are not recognized. Although many prosopagnosics have some degree of difficulty recognizing objects other than faces, in some cases the deficit appears strikingly selective for faces. Some writers have suggested that prosopagnosia is simply a mild agnosia and that faces are simply the most difficult type of object to recognize. Evidence is accumulating against this position. Prosopagnosics have been found to be disproportionately impaired with faces, when the recognition difficulty for normal subjects has been taken into account relative to a variety of comparison stimuli, including sheep faces {McNeil and Warrington 1993), eyeglass frames (Farah, Klein, and Levinson 1995), and inverted faces {Farah et al. 1995). Further evidence that prosopagnosia represents damage to a distinct system for face recognition comes from agnosic patients who show relative preservation of face recognition (Feinberg er al. 1994). Pure Alexia The impairment of visual word recognition, in the context of intact auditory word recognition and writing ability, is known as pure alexia and may be found alone or in association with visual object agnosia. Although visualverbal disconnection plays a role in some cases, impairment of visual letter and word representations is invariably found. As with prosopagnosia, the opposite dissociation also exists, namely, spared word recognition with impaired object and face recognition. Neuropathology
of Associative
Visual Agnosia
A variety of lesion locations have been reported to be responsible for cases of associative visual agnosia. Almost invariably, the lesions are posrerior and inferior, affecting ventral temporal and occipital regions. Damage is frequently bilateral, although in some cases only the left or right hemisphere is affected. The precise location of damage appears to correlate with the scope of the agnosic impairment. In patients who are agnosic for objects, faces, and printed words, damage is bilateral. If the impairment mainly affects faces, damage may be bilateral or confined to the right hemisphere (De Renzi et al. 1994), as in Figure 11.4. When face recognition is spared, the damage is generally confined to the left hemisphere, with medial structures, including the parahippocampal, fusiform, and lingual gyri, generally involved, as shown in
THE AGNOSIAS
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FIGURE 11,4 Typical partem of brain damage in a case of associative agnosia with prosopagnosia. (Reprinted with permission from De Renzi, E., Perani, D., Carlesimo, G. A., et a). 1994, "Prosopagnosia can be associated with damage confined to the right hemisphere: An MRI and PET study and a review of the literature," Neuropsychologic, vol. 32, pp. 893-902.)
Figure 11.5 (Feinberg et al, 1994). When face recognition alone is impaired, or when face and object recognition are impaired but reading is spared, the lesions are generally cither in the right occipitotemporal region or bilateral. When reading alone is impaired, or when reading and object recognition are impaired but face recognition is spared, the lesions are generally on the left. Recently, several investigations have studied object recognition using functional magnetic resonance imaging (fMRI). Kanwisher et al. (1996) compared regional brain activity as measured by fMRI while subjects viewed photographs of either objects or faces. These investigators initially found an inferolateral area located at the occipitotemporal junction that was activated during the extraction of processing of an object's shape. Further investigations (Kourrzi and Kanwisher 2000} suggested that an area known as the lateral occipital complex (LOC), a region composed of the lateral and ventral occipital cortex that extends into the posterior temporal lobe, is activated during the processing of an object's shape. The activation of this territory during shape discrimination was independent of the image cues that defined the shape (lines, shading, texture, etc.). Similar fMRI results regarding the role of the LOC in object shape processing were reported by Mazer and Gallant (2000). Ear et al. (2001) investigated fMRI activation during a task that required subjects to recognize briefly presented
FIGURE 11.5 Typical pattern of brain damage in a case of associative agnosia sparing face recognition. (Reprinted with permission from Feinberg, T. E., Schindler, R. J., Ochoa, E., et al. 1994, "Associative visual agnosia and alexia without prosopagnosia," Cortex, vol. 30, pp. 395-412.)
photographs of masked objects. They found ventral temporal activation eatly in the process of object identification. Furthermore, the degree of activation in this region correlated with the degree of object identification. Finally, awareness of an object's identity correlated with more anterior activation, and full awareness of an object's identity was associated with activation as far anterior as anterior fusiform gyrus. The authors argue that these findings suggest there is a gradient t>t object identification that spreads from posterior to more anterior visual areas as explicit object identification unfolds. Related
Syndromes
As with apperceptive agnosia, the term associative agnosia has been applied to a number of distinct but related syndromes. Two that merit discussion here are semantic memory impairments and optic aphasia. In the fonnct, patients lose general knowledge about the world (termed semantic memory by cognitive psychologists), resulting in an inability to name, or otherwise indicate recognition of, visually presented objects {Farah and Grossman 1997).
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
The impairment may affect all types of stimuli, as when it occurs in Alzheimer's disease or in the selective loss of semantic memory known as semantic dementia, or it may disproportionately affect knowledge from specific categories, such as living things. Because the functional locus of damage is postperccptual, in semantic memory, these patients also perform poorly in entirely nonvisual tasks, such as answering verbal questions about objects. Optic aphasics encounter difficult)' when naming visually presented objects. They can convey their recognition of a visual stimulus by pantomime (e.g., a drinking motion when shown a cup) or sorting semantically related stimuli together and can name stimuli in modalities other than vision. Most authors currently distinguish between associative agnosia and optic aphasia, although patients with the latter have sometimes been called associative agnosics. The underlying impairment in optic aphasia is unclear. To the extent that optic aphasics are able to derive semantic understanding of visual stimuli, it seems strange that they should be unable to name them.
Assessment of Visual Agnosia The first step in the assessment of visual agnosia is to establish the preservation of adequate elementary visual abilities, including tests of visual acuity and visual fields. If these are not sufficiently preserved to allow successful object recognition, the patient fails to meet a key exclusionary criterion for agnosia. Computed tomographic (CT) or magnetic resonance imaging (MRI) scans should be obtained and compared with the known patterns of neuropathology for associative visual agnosia and, although they are often less clear, for apperceptive visual agnosia. Difficulty with naming (anomia) can be distinguished from difficulty with visual recognition by comparing visual and tactile naming, naming of verbally described objects, and sorting of objects or pictures by semantic category (e.g., putting kitchen items together, separate from sports equipment). Patients with semantic memory impairment also, like anomics, fail to produce a name for touched or described objects and fail to sort. A purely anomic patient may be able to indicate the identity of a visually presented object by circumlocution and pantomime, even if the name escapes him or her. Patients with optic aphasia can be identified by assessing naming of objects through techniques other than vision and by assessing visual recognition nonverbally. These patients are generally able to name objects by touch or description (in contrast to patients with anomia and semantic memory impairment), as well as to circumlocute and pantomime an identification response to visually presented objects and sort semantically related objects (all in contrast to visual agnosics). Error types are also useful diagnostically. Visual agnosics generally misidentify an object as one that is visually similar (e.g., snake for hose, a "visual error"),
whereas patients with semantic memory impairment or optic aphasia make more "semantic errors" (e.g., lettuce for cucumber). Perseverative errors often predominate in optic aphasia. The distinction between the apperceptive and associative agnosias can be made by gauging the patient's perception of relatively simple shapes with tasks such as matching and copying. Associative agnosics perform these tasks accurately, whereas apperceptive agnosics do poorly on them.
AUDITORY AGNOSIA Like visual agnosia, auditory agnosia is not one disorder but a group of disorders, characterized by a failure to recognize verbal or nonverbal sounds. In this section, we focus on a few specific conditions that may exist in relatively pure form, with the understanding that most clinical cases have a unique profile of deficits representing a mixture of these characteristics. The auditory agnosias can be thought of as a spectrum of disorders, bounded by cortical deafness on one end and disorders of language and thought at the other. A patient who is cortically deaf fails to meet one of the primary exclusionary criteria for auditory agnosia, namely, elementary perceptual processes that are adequate for sound recognition. Such patients commonly demonstrate a host of auditory perceptual deficits, including abnormal puretone audiology, sound localization, and temporal auditory analysis. Cortical deafness has generally been described in patients with cerebrovascular disease resulting in bilateral infarcts of the temporal lobes destroying Heschl's gyri. The classic clinical presentation is of a patient with a preexisting unilateral lesion of one temporal lobe who suddenly develops deafness because of a second lesion in the opposite hemisphere. In the process of recovery from cortical deafness, the patient may pass through one or another of the auditory agnosic disorders described here.
Nonverbal Auditory Agnosia The auditory agnosia that seems most analogous to visual associative agnosia is nonverbal auditory agnosia, also known as auditory sound agnosia or environmental sound agnosia. The patient with this condition fails to recognize common objects and events by their sounds, such as a dog barking, keys jingling, or a door slamming. Although the patients are not cortically deaf, most reported cases initially present with the clinical picture of cortical deafness. They then recover to the point that standard audiometry is near normal or normal, but auditory recognition remains impaired. Just as visual agnosics' errors tend to be visual, auditory agnosics are often acoustically based. For instance, one patient misidentified a telephone ring as
THE AGNOSIAS
"sound of railroad crossing," a car honk as "hoot," and thunder as "fireworks." Just as visual agnosias may affect the recognition of some classes of visual stimuli more than others (e.g., words and faces), so auditory agnosia may affect recognition of certain classes of sounds more than others. The impairment of environmental sound recognition described here is usually found in conjunction with impaired recognition of speech sounds, although selective nonverbal auditory agnosias have been reported. "When the recognition deficit is largely restricted to nonverbal sounds, there is a tendency for right hemisphere lesions to predominate (Bauer and Zawacki 1997). Engelien et al. (1995} and Engclien, Stern, and Silbersweig (2001) performed a positron emission tomography (PET) study of a patient with bilateral perisylvian strokes and auditory agnosia. During one stage in recovery, the patient remained word deaf but made a partial recovery in his ability to make semantic judgments on meaningful nonverbal auditory stimuli. During this period, the investigators compared this subject's PET activation during passive listening of environmental sounds to PET activation during active semantic categorization of meaningful nonverbal sounds. The authors found that the patient's recovery of auditory nonverbal recognition was associated with "bilateral activation of a distributed network comprising prefrontal, middle temporal, and inferior parietal cortices." The authors suggest that in normal subjects during this auditory recognition task, this pattern of activation occurs exclusively in the left hemisphere. Auditory agnosias also exist for spoken words (analogous to pure alexia), for voices (analogous to prosopagnosia), and for music. It is to these more domain-specific forms of agnosia that we now turn.
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patient with pure word deafness has impaired word repetition. A variety of auditory perceptual processing deficits may be found in pure word deafness. For example, a generalized disturbance in the temporal resolution of the auditory stimuli, abnormal click-fusion thresholds, difficulties with phonemic discrimination, and abnormalities on dichotic listening tasks showing prominent right ear suppression have been reported (Bauer and Zawacki 1997). In reality, all cases of so-called "pure word deafness" that were adequately studied show other perceptual or agnosic disturbances. In spite of this, the term is still useful because cases do occur in which the primary deficit in word agnosia is the outstanding impairment and occurs out of proportion to whatever other cortical auditory defects may be present, As is the case with cortical deafness, pure word deafness most commonly occurs as a result of bilateral temporal cortical-subcortical infarcts. It may occur as a stage of recovery in a new onset Wernicke's aphasia or in a patient with a recovered Wernicke's aphasia with a new right temporal lobe infarction. It follows therefore that the lesions reported in pure word deafness are of two varieties. One circumstance is that of bilateral lesions located in the anterior or middle portions of the first temporal gyri, often with some sparing of Hcschl's gyri (area 41). A second localization is a single lesion involving Heschl's gyrus of the dominant hemisphere, as well as the subjacent white matter. In the latter case, the white matter lesion is presumed to destroy the auditory projection from the ipsilatcral medial geniculate nucleus, as well as the callosal fibers from the opposite superior temporal region. In both cases, the lesions arc presumed to isolate the Wernicke's areas from auditory input, resulting in a patient who is neither deaf nor aphasic but in whom auditory input cannot reach language areas necessary for auditory comprehension.
Pure Word Deafness Pure word deafness (also known as auditory agnosia for speech or verbal auditory agnosia) is characterized by a disturbance in comprehension of spoken language not explainable by the more generalized auditory processing defects seen in cortical deafness or the broader linguistic impairments typical of Wernicke's aphasia or transcortical sensory aphasia. Pure word deafness is distinguished from cortical deafness by the patient's relative preservation of prrmary sensory processing, as judged by pure-tone audiometry and other psycho acoustic measures. The patient's relatively preserved recognition of nonverbal environmental sounds, such as the ringing of a telephone or the whistling of a bird, separates the disorder from generalized auditory agnosia. It is further distinguished from Wernicke's aphasia by the relative preservation of reading, writing, and normal spontaneous speech. Unlike the patient with transcortical sensory aphasia, the
Other Auditory Agnosias Auditory amusia and sensory amusia are terms used to describe the condition in which a patient has lost the ability to recognize a range of features of heard music, such as distinguishing a particular singing voice or recognizing previously learned melodies. Due to the multifactorial nature of music appreciation and the effect of premorbid musical ability and training, it is difficult to make clear-cut clinicopathological correlations. It appears that both hemispheres normally contribute to music cognition. On the basis of two cases of auditory amusia, Peretz et al. (1994) suggested that bilateral lesions of auditory association cortices that spare Heschl's gyri are the critical lesions sufficient to impair melody, voice, and speech prosody discrimination or recognition.
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Pbonagnosia refers to a condition comparable to prosopagnosia, in which patients lose the ability to recognize familiar voices. This specific disorder in recognition of familiar voices has been linked to pathology to the right parieral lobe.
Assessment of Auditory Agnosia The first step in the detection and diagnosis of auditory agnosia is to assess primary auditory perception. This can range from the simple detection of softly spoken words or finger snaps at the bedside through a complete audiologic evaluation, including pure-tone audiometry and speech detection thresholds. Brainstem auditory evoked responses should also be obtained. The examiner must also rule out aphasia as the cause of the patient's auditory recognition disturbance. Thus in addition to assessment of verbal repetition and comprehension, a full assessment should be made of reading silently for comprehension, the ability to follow written commands, and visual naming, as well as a close observation of spontaneous speech for the presence of aphasia. Finally, the subtype of auditory agnosia can be distinguished by the relative disturbance in verbal versus nonverbal material, spoken speech, and melody appreciation. Melody appreciation can be assessed using various subtests of the Seashore Test of Musical Talent. CT scan or MRI should be helpful in distinguishing focal brain pathology as a cause of an agnosic disturbance from impairment resulting from more generalized dementias.
TACTILE AGNOSIA Tactile agnosia refers to a disorder of object recognition via the tactile modality that cannot be attributed to a more basic somatosensory impairment, language dysfunction, hemispatial neglect, or generalized intellectual impairment. The existence of a pure tactile agnosia has been disputed {Caselli 1997). One likely reason is that tactile agnosia is often subtle and escapes clinical detection. The lack of precise quantitative testing of somatosensory function for most clinical cases has also added to the difficulty of documenting a dissociation between tactile agnosia and more basic somatosensory disorders. Another complicating factor is that we normally recognize objects through vision and occasionally through sound, only rarely using purely tactual information (e.g., searching for keys or lipstick at the bottom of a handbag), and therefore it is not obvious what normal performance is. As with vision and hearing, tactile perception can break down at a number of stages. Caselli (1997) divides somesthetic functions into basic, intermediate, and complex types. Basic somesthetic functions include light touch,
vibration, position sense, superficial pain and temperature, and two-point discrimination. Intermediate somesthetic functions include weight and texture discrimination and the type of simple form discrimination that would generally fall under the category of astereognosis. Complex somesthetic functions are those that are disturbed in the pure forms of tactile agnosia. In detailed somesthetic and psychologic testing of a tactile agnosic, Reed and colleagues (Reed and Caselli 1994; Reed, Caselli, and Farah 1996) found that the simple and intermediate functions mentioned earlier were intact. They also found that tactual memories were intact (assessed by questions such as "Which is smoother, an orange skin or a golf ball?") but that the integration of complex tactile form information was impaired. Figure 11.6 shows a parienr's drawing of an object that she was unable to recognize. The two holes of the cassette were repeatedly touched in the course of her attempt to identify the object, and she was apparently unable to integrate the informarion from the separate touches into an accurate representation of the overall shape of the object. It is important to note that her spatial integration ability for separately encoded features of a visual stimulus was normal. Tactile agnosia is typically a unilateral disorder, which enables the examiner to use the normal hand as a control.
Anatomical Considerations Figure 11.7 shows the anatomy of somatosensory cortex in the human brain. The first somatosensory area (SI) receives the primary thalamic projections for cortical
THF. AGNOSIAS
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Assessment of Tactile Agnosia As with visual or auditory agnosia, basic perceptual functions must be assessed and found adequate for object recognition. These include light touch, vibration, position sense, superficial pain and temperature, and two-point discrimination, as well as weight and texture discrimination and simple form discrimination, such as distinguishing flat from curved surfaces and edges. Language and other cognitive functions required for object identification through any modality must also be examined. Because the ipsilesional hand is available as a control, norma! naming of palpated objects with that hand provides good evidence that higher order linguistic and cognitive factors are not the cause of the tactile agnosia. MRI or CT scans should be evaluated relative to the known anatomy of this disorder.
REFERENCES
FIGURE 11.7 Areas of the human brain involved in somatosensory perception and recognition, (Reprinted with permission from Caselli, R. J. 1993, "Ventrolateral and dorsomedial somatosensory association cortex infarction produce distinct sonicsthetic syndromes," Neurology, vol. 43, pp. 762-771.)
somatosensory functioning. It includes Brodmann's areas 3a, 3b, 1, and 2. Neurons in these regions are responsible for initial cortical sensory processing. Lesions in the region of SI produce impairment in basic and intermediate sense modalities, Caselli (1997) suggested that pure tactile agnosia results from lesions located in ventrolateral association cortices, in a region corresponding to the second somatosensory area (SII), located largely within the parietal operculum. He felt that the posterior insula may play a role in higher order tactile object identification. He also found that lesions in dorsomedial association cortex (the supplementary sensory area) produced a profound disturbance in basic somatosensory processing resembling that of patients with SI lesions, and these patients were additionally found to have severe contralateral limb apraxia. Furthermore, with time, these patients improved considerably and a chronic tactile agnosia occurred only in patients with ventrolateral damage. The role of the SII in higher order tactile rccogntion has found additional support from the fMRI study of Reed et al. (1999) who found selective activation of SII during tactile identification of common real objects.
Bar, M., Tootell, R. B. H., Schacter, D. L., et al. 2001, "Cortical mechanisms specific to explicit visual object recognition," Neuron, vol. 29, pp. 529-535 Bauer, R. M. & Zawacki, T. 1997, "Auditory agnosia and amusia," in Behavioral Neurology and Neuropsychology, eds T. E. Fein berg & M. J. Fa rah, McGraw-Hill, New York Caselli, R. J. 1993, "Ventrolateral and dorsomedial somatosensory association cortex infarcrion produce distinct somesthetic syndromes," Neurology, vol. 43, pp. 762-771 Caselli, R. J. 1997, "Tactile agnosia and disorders of tactile perception," in Behavioral Neurology and Neuropsychology, eds T. E. Fein berg & M. J. Farah, McGraw-Hill, New York De Renzi, E., Perani, D., Carlesimo, G. A., et al. 1994, "Prosopagnosia can be associated with damage confined to the right hemisphere: An MRI and 1'1'T study and a review of the literature," Neuropsychologia, vol. 32, pp. 893-902 Engelien, A., Silbersweig, D., Stern, E., et al. 1995, "The functional anatomy of recovery from auditory agnosia. A PET study of sound categorization in a neurological patient and normal controls," Brain, vol. 118, pp. 1395-1409 Engelien, A., Stern, E., 8c Silbersweig, D. 2001, "Functional neuroimaging of human central auditory processing in normal subjects and patients with neurological and neuropsychiatry disorders,"/ Clin Exp Neuropsychol, vol. 23, pp. 94-120 Farah, M. J. &C Feinberg, T. E. 1997, "Visual object agnosia," in Behavioral Neurology and Neuropsychology, eds T. E. Feinberg & M. J. Farah, McGraw-Hill, New York Farah, M. J. & Grossman, M. 1997, "Semantic memory impairments," in Behavioral Neurology and Neuropsychology, eds T. E. Feinberg & M. j. Farah, McGraw-Hill, New York Farah, M, J„ Wilson, K. D., Drain, H. M., & Tanaka, J. R. 1995, "The inverted inversion effect in prosopagnosia: Evidence for mandatory, face specific perceptual mechanisms," Vision Res, vol. 35, pp. 2089-2093 Feinberg, T. E., Schindler, R. J., Ochoa, E., et al. 1994, "Associative visual agnosia and alexia without prosopagnosia," Cortex, vol. 30, pp. 395-412 Kanwisher, N., Chun, M. M., McDermott, J., &c Ledden, P. J. 1996, "Functional imaging of human visual recognition," Cogu Brain Res, vol. 5, pp. 55-67
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Kourtzi, Z. 6c Kanwisher, N. 2000, "Cortical regions involved in perceiving object shape," / Neurosci, vol. 20, pp. 3310-3318 Marcar, V. L. & Cowey, A. 1992, "The effect of removing superior temporal cortical motion areas in the Macaque monkey. II. Motion discriminations using random dot displays," Eur J Neurosci, vol. 4, pp. 1228-1238 MnziT. J. A. & Gallant, J. L. 2000, "Object recognition: Seeing us seeing shapes," Curr Biol, vol. 10, pp. R668-R670 McNeil, J. E. & Warrington, E. K. 1993, "Prosopagnosia: A face-specific disorder," Q / Exp Psychol A, vol. 46A, pp. 1-10
lVnty. [., Kolinsky, R., Tramo, M., et al. 1994, "Functional dissociations following bilateral lesions of auditory cortex," Brain, vol. 117, pp. 1283-1301 Reed, C, L. &c Caselli, R. J. 1994, "The nature of tactile agnosia: A case study," Neuropsycbologia, vol. 32, pp. 527-539 Reed, C. L., Caselli, R. J., & Fa rah, M. J. 1996, "Tactile agnosia: Underlying impairment and implications for normal tactile object recognition," Brain, vol. 119, pp. 875-888 Reed, C. L., Shahom, S., Halgren, F,„ & Norman, R. 1999, "Tactile object recognition activates the secondary somatosensory area (SII): An fMRI study," Soc Neuroses Abstracts, vol. 25, p. 1895
Chapter 12 Language and Speech Disorders A. APHASIA Howard S. Kirshner Symptoms and Differential Diagnosis of Disordered Language Bedside Language Examination Differential Diagnosis of Aphasic Syndromes Broca's Aphasia Aphemia Wernicke's Aphasia Pure Word Deafness Global Aphasia Conduction Aphasia Anomic Aphasia Transcortical Aphasias
143 143 144 144 145 145 148 148 149 149 150
The study of language disorders involves the analysis of the most human of attributes, the ability to communicate through common symbols. Language has provided the foundation of human civilization and learning, and its study has been the province of philosophers and physicians. When language is disturbed by neurological disorders, analysis of the patterns of abnormality has practical usefulness in neurological diagnosis. Historically, language was the first higher cortical function to be correlated with specific sites of brain damage. It continues to serve as a model for the practical use of a cognitive function in the localization of brain lesions and for the understanding of human cortical processes in general. Aphasia is defined as a disorder of language that is acquired secondary to brain damage. This definition, adapted from Alexander and Benson (19.97), separates aphasia from several related disorders. First, aphasia is distinguished from congenital or developmental language disorders, called dysphasias. {Contrary to British usage, in the United States, the term dysphasia applies to developmental language disorders rather than partial or incomplete aphasia.} Second, aphasia is a disorder of language rather than speech. Speech is the articulation and phonation of language sounds; language is a complex system of communication symbols and rules for their use. Aphasia is distinguished from motor speech disorders, which include dysarthria, dysphonia (voice disorders), stuttering, and speech apraxia. Dysarthrias arc disorders of articulation of single sounds. Dysarthria may result from mechanical disturbance of the tongue or larynx or from neurological
Subcortical Aphasias Pure Alexia without Agraphia Alexia with Agraphia Aphasic Alexia Agraphia Language in Right Hemisphere Disorders Language in Dementing Diseases Investigation of the Aphasic Patient Clinical Tests Differential Diagnosis Recovery and Rehabilitation of Aphasia
150 LSI 153 153 154 154 155 156 156 158 i.sy
disorders, including dysfunction of the muscles, neuromuscular junction, cranial nerves, bulbar anterior horn cells, corticobulbar rracts, cerebellar connections, or basal ganglia. Apraxia of speech is a syndrome of misarticulation of phonemes, especially consonant sounds. Unlike dysarthria, in which certain phonemes are consistently distorted, apraxia of speech contains inconsistent distortions and substitutions of phonemes. The disorder is called an apraxia because there is no primary motor deficit in articulation of individual phonemes. Clinically, speech-a praxic patients produce inconsistent articulatory errors, usually worse on the initial phonemes of a word and with polysyllabic utterances. Apraxia of speech, so defined, is commonly involved in speech production difficulty in the aphasias. Third, aphasia is distinguished from disorders of thought. Thought involves the mental processing of images, memories, and perceptions, usually but not necessarily involving language symbols. Psychiatric disorders derange thought and alter the content of speech without affecting its linguistic structure. Schizophrenic patients, for example, may manifest bizarre and individualistic word choices, with loose associations and a loss of organization in discourse, together with vague or unclear references and communication failures (Docherty, DeRosa, and Andreasen 1996). Lk'int'iirary language and articulation, however, are intact. Abnormal language content in psychiatric disorders is therefore not considered aphasia. Language disorders associated with diffuse brain diseases, such as encephalopathies and dementias, do qualify as aphasias, but the involvement of other cognitive functions distinguishes them from aphasia secondary to focal brain lesions. Ill
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An understanding of language disorders requires an elementary review of linguistic components. Phonemes are the smallest meaning-carrying sounds; morphology is the use of appropriate word endings and connector words for tenses, possessives, and singular versus plural; semantics refers to word meanings; the lexicon is the internal dictionary; and syntax is the grammatical construction of phrases and sentences. Discourse refers to the use of these elements to create organized and logical expression of thoughts. Specific language disorders affect one or more of these elements. Language processes have a clear neuroanatomic basis. In simplest terms, the reception and processing of spoken language takes place in the auditory system, heginning with the cochlea and proceeding through a series of way stations to the auditory cortex, Heschl's gyrus, in each superior temporal gyrus. The decoding of sounds into linguistic information involves the posterior part of the left superior temporal gyrus, Wernicke's area or Brodmann's area 22, which gives access to a network of cortical associations to assign word meanings. For both repetition and spontaneous speech, auditory information is transmitted to Broca's area in the posterior inferior frontal gyrus. This area of cortex "programs" the neurons in the adjacent motor cortex, subserving the mouth and larynx, from which descending axons travel to the brainstem cranial nerve nuclei. The inferior parietal lobule, especially the supramarginal gyrus, may also be involved in phoneme processing in language comprehension and in phoneme production for repetition and speech (Hickok and Poeppel 2000). These anatomic relationships are shown in Figures 12A.1 and 12A.2. Reading requires the perception of visual language stimuli by the occipital cortex, followed by correlation with auditory language information, via the intermodal association cortex of the angular gyrus. Writing involves the activation of motor neurons projecting to the arm and hand.
Right
FIGURE 12A.2 Coronal plane diagram of the brain, indicating the inflow of auditory information from the cars to the primary auditory cortex in both superior temporal regions (xxx), and then to Wernicke's area [poo) in the left superior temporal gyrus. The motor outflow of speech descends from Broca's area [&) to the cranial nerve nuclei of the brainstem via the corticobulbar tract [dashed arrow). In actuality, Broca's area is anterior to Wernicke's area, and the two areas would not appear in the same coronal section. These pathways, and doubtless others, constitute the cortical circuitry for language comprehension and expression. In addition, other cortical centers involved in cognitive processes project into the primary language cortex, influencing the content of language. Finally, subcortical structures play increasingly recognized roles in language functions. The thalamus, a relay for the reticular activating system, appears to alert the language cortex, and lesions of the dominant thalamus often produce fluent aphasia. Nuclei of the basal ganglia involved in motor functions, especially the caudate nucleus and putamen, participate in expressive speech. It is no wonder, then, that
Postcentral Gyrus PARIETAL LOBE Supramarginal Gyrus .ngular Gyrus
OCCIPITAL LOBE
Superior Temporal Gyrus
- Wernicke's Area
Left
HGURK I 2A. I The lateral surface of the left hemisphere, showing a simplified gyral anatomy and the relationships between Wernicke's area and Broca's area. Not shown is the arcuate fasciculus, which connects the two cortical speech centers via the deep subcortical white matter.
APHASIA
language disotdcrs are seen in a wide variety of brain lesions and are important in practical neurological diagnosis and localization. In right-handed people, and in most left-handers, clinical syndromes of aphasia result from left hemisphere lesions. Rarely, aphasia may result from a right hemisphere lesion in a right-handed patient, a phenomenon called crossed aphasia (Bakar, Kirshncr, and Wert?. 1996). In left-handed persons, language disorders are usually similar to those of right-handed persons with similar lesions, but occasional cases present with atypical syndromes that suggest a right hemisphere capability for at least some language functions. For example, a patient with a large left frontal temporoparietal lesion may have preserved comprehension, suggesting right hemisphere language comprehension. For the same reason, recovery from aphasia may be better in some left-handed than right-handed patients with left hemisphere strokes.
SYMPTOMS AND DIFFERENTIAL DIAGNOSIS OF DISORDERED LANGUAGE Muteness, a total loss of speech, may represent severe aphasia (see Aphemia, later in this chapter). Muteness can also be a sign of dysarthria; frontal lobe dysfunction with akinetic mutism; severe extrapyramidal system dysfunction, as in Parkinson's disease; non-neurological disorders of the larynx and pharynx; or even psychogenic syndromes, such as catatonia. Caution must therefore he taken in diagnosing the mute patient as aphasic. A good rule of thumb is that if the patient can write or type and the language form and content are normal, the disorder is probably not aphasic in origin. If the patient cannot speak or write but makes apparent effort to vocalize, and if there is also evidence of deficient comprehension, aphasic muteness is likely. Associated signs of a left hemisphere injury, such as right hemiparesis, also aid in diagnosis. Finally, if the patient gradually begins to make sounds containing paraphasic errors, aphasia can be identified with confidence. Hesitant speech is a symptom not only of aphasia, but also of motor speech disorders, such as dysarthria or stuttering, and may be a manifestation of a psychogenic disorder. A second rule of thumb is that if one can transcribe the utterances of a hesitant speaker into normal language, the patient is not aphasic. Hesitancy occurs in many aphasia syndromes for varying reasons, including difficulty in speech initiation, imprecise articulation of phonemes, deficient syntax, or word-finding difficulty. Anomia, or the inability to produce a specific name, is generally a reliable indicator of a language disorder, although it may also reflect memory loss. Anomia is manifest in aphasic speech by word-finding pauses and circumlocutions or use of a phrase when a single word would suffice.
143
Paraphasic speech refers to the presence of errors in the patient's speech output. Paraphasic errors arc divided into literal or phonemic errors, involving substitution of an incorrect sound (e.g., shoon for spoon), and verbal or semantic errors, involving substitution of an incorrect word (e.g., fork for spoon). A related language symptom is perseveration, the inappropriate repetition of a previous response. Occasionally, aphasic utterances involve nonexistent word forms called neologisms. A pattern of paraphasic errors and neologisms that so contaminate speech that the meaning cannot be discerned is called jargon speech. Another cardinal symptom of aphasia is the failure to comprehend the speech of others. Most aphasic patients also have difficulty with comprehension and production of written language (reading and writing). Fluent, paraphasic speech usually makes an aphasic disorder obvious. The chief differential diagnosis here involves aphasia, psychosis, acute encephalopathy or delirium, and dementia. Aphasic patients are usually not confused or inappropriate in behavior; they do not appear agitated or misuse objects, with occasional exceptions in acute syndromes of Wernicke's or global aphasia. By contrast, most psychotic patients speak in an easily undetstood, grammatically appropriate manner, but their behavior and speech content are abnormal. Only rarely do schizophrenics speak in "clang association" or "word salad" speech. Sudden onset of fluent, paraphasic speech in a middle-aged or elderly patient should always be suspected of representing a left hemisphere lesion with aphasia. Patients with acute encephalopathy or delirium may manifest paraphasic speech and "higher" language disorders, such as inability to write, but the grammatical expression of language is less disturbed than is its content. These language symptoms, moreover, are less prominent than accompanying behavioral disturbances, such as agitation, hallucinations, drowsiness, or excitement, and cognitive difficulties, such as disorientation, memory loss, and delusional thinking. Chronic encephalopathies, or dementias, pose a more difficult diagnostic problem because involvement of the language cortex produces readily detectable language deficits, especially involving naming, reading, and writing. These language disorders (see Language in Dementing Diseases, later in this chapter) differ from aphasia secondary to focal lesions mainly by the involvement of other cognitive functions, such as memory and visuospatial processes.
BEDSIDE LANGUAGE EXAMINATION The first part of any bedside examination of language is the observation of the patient's speech and comprehension during the clinical interview. A wealth of information about language function can be obtained if the examiner pays deliberate attention to the patient's speech patterns and responses to questions. In particular, minor word-finding
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difficulty, occasional paraphasic errors, and higher-level deficits in discourse planning and in the pragmatics of communication, such as the use of humor and irony, can he detected principally during the informal interview. D. Frank Benson and Norman Gcschwind popularized a bedside language examination of six parts, and it has been updated by Alexander and Benson (1997) (Table 12A.1). This examination provides useful localizing information about lira in dysfunction and is well worth the few minutes it takes. The first part of the examination is a description of spontaneous speech. A speech sample may be elicited by asking the patient to describe the weather or the reason for coming to the doctor. If speech is sparse or absent, recitation of lists, such as counting or listing days of the week, may be helpful. The most important variable in spontaneous speech is fluency: Fluent speech flows rapidly and effortlessly; nonfluent speech is uttered in single words or short phrases, with frequent pauses and hesitations. Attention should first be paid to such elementary characteristics as initiation difficulty, articulation, phonation or voice volume, rate of speech, prosody or melodic intonation of speech, and phrase length. Second, the content of speech utterances should be analyzed in terms of the presence of word-finding pauses, circumlocutions, and errors such as literal and verbal paraphasias and neologisms. Naming, the second part of the bedside examination, is tested by asking the patient to name objects, object parrs, pictures, colors, or body parts to confrontation. A few items from each category should be tested because anomia can be specific to word classes. Proper names of persons are often affected severely. The examiner should ask questions to be sure that the patient recognizes the items or people that he or she cannot name. Auditory comprehension is tested first by asking the patient to follow a series of commands of one, two, and three steps. An example of a one-step command is "stick out your tongue"; a two-step command is "hold up your left thumb and close your eyes." Successful following of commands ensures adequate comprehension, at least at this
Tabic 12A.1:
Bedside language examination
1. Spontaneous speech a. Informal interview b. Structured task c. Automatic sequences 2. Naming 3. Auditory comprehension 4. Repetition 5. Reading a. Reading aloud h. Ri-iiJnii; comprehension 6. Writing a. Spontaneous sentences b. Writing to dictation c. Copying
simple level, but failure to follow commands does not automatically establish a loss of comprehension. The patient must hear rhc command, understand the language the examiner speaks, and possess the motor ability to execute it, including absence of apraxia. Apraxia (sec Chapter 10 for full discussion) is defined operationally as the inability to carry out a motor command despite normal comprehension and normal ability to carry out the motor act in another context, such as by imitation or with use of a real object. Because apraxia is difficult to exclude with confidence, it is advisable to test comprehension by tasks that do not require a motor act, such as yes-no questions, or by commands that require only a pointing response. The responses to nonsense questions (e.g., "Do you vomit every day?") quickly establish whether the patient comprehends. Nonsense questions often produce surprising results, given the tendency of some aphasics to cover up comprehension difficulty with social chatter. Repetition of words and phrases should be deliberately tested. Dysarthric patients have difficulty with rapid sequences of consonants, such as "Methodist Episcopal," whereas aphasics have special difficulty with grammatically complex sentences. The phrase "no ifs, ands, or huts" is especially challenging for aphasics. Often, aphasics can repeat familiar or "high-probability" phrases much better than unfamiliar ones. Reading should be tested both aloud and for comprehension. The examiner should carry a few printed commands to facilitate a rapid comparison of auditory to reading comprehension. Of course, the examiner must have some idea of the patient's premorbid reading ability. Writing, the element of the bedside examination most often omitted, not only provides a further sample of expressive language but also allows an analysis of spelling, which is not possible with spoken language. A writing specimen may be the most sensitive indicator of mild aphasia, and it provides a permanent record for future comparison. Spontaneous writing, such as a sentence describing why the patient has come for examination, is especially sensitive for the detection of language difficulty. When this fails, writing to dictation and copying should be tested as well. Finally, the neurologist combines the results of the bedside language examination with those of the rest of the mental status examination and of the neurological examination in general. These "associated signs" help classify the type of aphasia and localize the responsible brain lesion.
DIFFERENTIAL DIAGNOSIS OF APHASIC SYNDROMES Broca's Aphasia In 1861, the French physician Paul Broca described two patients, establishing the aphasic syndrome that now bears
APHASIA his name. The speech pattern is nonfluent; on hedsidc examination, the patient speaks hesitantly, often producing the principal, meaning-containing nouns and verbs but omitting small grammatical words and morphemes. This pattern is called agrammatism or telegraphic speech. An example is "wife come hospital." Patients with acute Broca's aphasia may be mute or may produce only single words, often with dysarthria and apraxia of speech. They make many phonemic errors, inconsistent from utterance to utterance, with substitution of phonemes usually differing only slightly from the correct target (e.g., p for b). Naming is deficient, but the patient ofren manifests a "tip of the tongue" phenomenon, getting out the first letter or phoneme of the correct name. Paraphasic errors in naming arc more often of the literal type than the verbal type. Auditory comprehension seems intact, but detailed testing usually reveals some deficiency, particularly in the comprehension of complex syntax. For example, sentences with embedded clauses involving prepositional relationships cause difficulty for Broca's aphasics in comprehension and in expression. A recent positron emission tomography (PET) study in normal subjects (Caplan, Alpert, and Waters 1998) showed activation of the Broca area in the frontal cortex during tests of syntactic comprehension. Repetition is hesitant in these patients, resembling their spontaneous speech. Reading is often impaired despite relatively preserved auditory comprehension. Benson termed this reading difficulty of Broca's aphasics the "third alexia," in distinction to the two classic types of alexia (see Aphasic Alexia, later in this chapter). Patients with Broca's aphasia may have difficulty with syntax in reading, jusr as in auditory comprehension and speech. Writing is virtually always deficient in Broca's aphasics. Most patients have a right hemiparesis, necessitating use of the nondominant, left hand for writing, but this left-handed writing is far more abnormal than the awkward renditions of a normal, righthanded patient. Many patients can scrawl only a few letters. Associated neurological deficits of Broca's aphasia include right hemiparesis, hemisensory loss, and apraxia of the oral apparatus and the nonparalyzed left limbs. Apraxia in response to motor commands is important to recognize because it may be mistaken fot comprehension disturbance. Comprehension should be tested by responses to yes-no questions or commands to point to an object. The common features of Broca's aphasia arc listed in Table 12A.2. An important clinical feature of Broca's aphasia is its frequent association with depression (Robinson 1997). Patients with Broca's aphasia are typically aware of and frustrated by their deficits. At times they become withdrawn and refuse help or therapy. Usually, the depression lifts as the deficit recovers, although it may be a limiting factor in rehabilitation. The lesions responsible for Broca's aphasia usually include the traditional Broca's area in the posterior part of the inferior frontal gyrus, along with damage to the adjacent cortex and subcortical white matter. Most patients with
Tabic 12A.2:
145
Bedside features of Broca's aphasia
feature
Syndrome
Spontaneous speech
Nonfluent, mute or telegraphic, usually dysarthria Impaired Intact (mild difficulty with complex grammatical phrases) Impaired Often impaired ("third alexia") Impaired (dysmorphic, dysgrammatical) Right hemiparesis Right hemisensory loss iApraxia of left limbs
Naming Comprehension Repetition Reading Writing Associated signs
lasting Broca's aphasia, including Broca's original cases, have much larger left frontoparietal lesions, including most of the territory of the upper division of the left middle cerebral artery. Such patients typically evolve from global to Broca's aphasia over weeks to months. Patients who manifest Broca's aphasia immediately after their strokes, bycontrast, have smaller lesions of the inferior frontal region, and their deficits generally resolve quickly. In computed tomography (CT) scan analyses at the Boston Veterans Administration Medical Center, lesions restricted to the lower precentral gyrus produced only dysarthria and mild expressive disturbance. Lesions involving the traditional Broca's area (Brodmann's areas 44 and 45) resulted in difficulty initiating speech, and lesions combining Broca's area, the lower precentral gyrus, and subcortical white matter yielded the full syndrome of Broca's aphasia. In studies by the same group, damage to two subcortical white matter sites—-the rostral subcallosal fasciculus deep to Broca's area and the periventricular white matter adjacent to the body of the left lateral ventricle—was required to cause permanent nonfluency. Figute 12A.3 shows a magnetic resonance imaging (MR1) scan from a case of Broca's aphasia.
Aphcmia A rare variant of Broca's aphasia is aphemia, a nonfluent syndrome in which the patient is initially mute and then able to speak with phoneme substitutions and pauses. All other language functions are intact, including writing. This rare and usually transitory syndrome results from small lesions either of Broca's area or its subcortical white matter or of the inferior precentral gyrus. Because written expression and auditory comprehension are normal, aphemia is not a true language disorder; aphemia may be equivalent to pure apraxia of speech.
Wernicke's Aphasia Wernicke's aphasia may be considered a syndrome opposite to Broca's aphasia, in that expressive speech is
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
FIGURE 12A.3 Magnetic resonance imaging scan from a patient with Broca's aphasia. In this patient, the cortical Broca's area, subcortical white matter, and the insula were all involved in the infarction. The patient made a good recovery.
fluent but comprehension is impaired. The speech pattern is effortless and sometimes even excessively fluent (lognrrhea). A speaker of a foreign language would notice nothing amiss, but a listenet who shares the patient's language detects speech empty of meaning, containing verbal paraphasias, neologisms, and jargon productions. Neurolinguists refer to this pattern as paragrammatism. In milder cases, the intended meaning of an utterance may be discerned, but the sentence goes awry with paraphasic substitutions. Naming in Wernicke's aphasia is deficient, often with bizarre, paraphasic substitutions for the correct name. Auditory comprehension is impaired, sometimes even for simple nonsense questions. Auditory perception of phonemes is deficient in Wernicke's aphasia, but deficient semantics is the major cause of the comprehension disturbance; disturbed access both to semantics and to the internal lexicon is central to the deficit of Wernicke's aphasia. Repetition is impaired; whispering a phrase in the patient's ear, as in a hearing test, may help cue the patient to attempt repetition. Reading comprehension is usually affected similarly to auditory comprehension, but some patients show greater deficit in one modality. The discovery of spared reading ability in Wernicke's aphasics is important in allowing these patients to communicate. In addition, neurolinguistic theories of reading must include access of visual language images to semantic interpretation, even in the absence of auditory comprehension. Writing is also impaired, but in a manner quite different from that of Broca's aphasia. The patient usually has no hemiparesis and can grasp the pen and write easily. Written productions are even more abnormal than oral ones, however, in that spelling errors are also evident. Writing samples are
especially useful in the detection of mild Wernicke's aphasia. Associated signs are limited in Wernicke's aphasia; most patients have no elementary motor or sensory deficits, although a partial or complete right homonymous hemianopia may be present. The characteristic bedside examination findings in Wernicke's aphasia are summarized in Table 12A.3. The psychiatric manifestations of Wernicke's aphasia are quite different from those of Broca's aphasia. Depression is less common; many Wernicke's aphasics seem unaware of or unconcerned about their communicative deficits. With time, some patients become angry or paranoid about the inability of family members and medical staff to understand them. This behavior, like depression, may hinder rehabilitative efforts. The lesions of patients with Wernicke's aphasia are usually in the posterior portion of the superior temporal
Table 12A.3: Feature Spontaneous speech
Bedside features of Wernicke's aphasia Syndrome
Fluent, with paraphasic errors Usually not dysarthric Sometimes logorrhcic Naming Impaired (often bi/.arre paraphasic misnaming) Comprehension Impaired Repetition Impaired Reading Impaired for comprehension, reading aloud Wntinn Well-formed, paragraphic Associated signs ±Right hemianopia Motor, sensory signs usually absent
APHASIA
gyrus, sometimes extending into the inferior parietal lobule. Figure 12A.4 shows a typical example. The exact confines of Wernicke's area have been much debated. Damage to Wernicke's area (Brodmann's area 22) has been reported to correlate most closely with persistenr loss of comprehension of single words, although others (Kertesz, Lau, and Polk 1993) have found only larger temporoparietal lesions in patients with lasting Wernicke's aphasia. In the acute phase, the ability to match a spoken word to a picture is quantitatively related to decreased perfusion of Wernicke's area on perfusion-weighted MR1 scans, indicating less
147
variability during the acute phase than after recovery has taken place (Hillis et al. 2001). Electrical stimulation of Wernicke's area produces consistent interruption of auditory comprehension, supporting the importance of this region for decoding of auditory language. A receptive speech area in the left inferior temporal gyrus has also been suggested by electrical stimulation studies and by a few descriptions of patients with seizures involving this area (Kirshner et al. 1995), but aphasia has not been recognized with destructive lesions of this area. Extension of the lesion into the inferior parietal region may predict greater
FIGURE 12A.4 Axial and coronal magnetic resonance imaging slices (A and B), and an axial positron emission tomographic (PET) scan view (C) of an elderly woman with Wernicke's aphasia. There is a large left superior temporal lobe lesion. The onset of the deficit was not clear, and the PET scan was useful in showing that the lesion had reduced metabolism, favoring a stroke over a tumor. Continued
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
FIGURE 12A.4, cont'd.
involvement of reading comprehension. In terms of vascular anatomy, Wernicke's area lies within the territory of the inferior division of the left middle cerebral artery.
Wernicke's aphasia with greater impairment of auditory comprehension than of reading.
Global Aphasia Pure Word Deafness Pure word deafness is a rare but striking syndrome of isolated loss of auditory comprehension and repetition, without any abnormality of speech, naming, reading, or writing. Hearing for pure tones and for nonverbal noises, such as animal cries, is intact. Most cases have mild aphasic deficits, especially paraphasia speech. Classically, the anatomic substrate is a bilateral lesion, isolating Wernicke's area from input from both Heschl's gyri. Pure word deafness is thus an example of a "disconnection syndrome," in which the deficit results from loss of white matter connections rather than of gray matter language centers. Some cases of pure word deafness, however, have unilateral left temporal lesions. These cases closely resemble
Global aphasia may be thought of as a summation of the deficits of Broca's aphasia and Wernicke's aphasia. Speech is nonfluent or mute, but comprehension is also poor, as are naming, repetition, reading, and writing. Most patients have dense right hemiparesis, hemisensory loss, and often hemianopia, although few patients have little hemiparesis. Milder aphasic syndromes in which all modalities of language are affected are often called mixed aphasias. The lesions of patients with global aphasia are usually latge, involving both the inferior frontal and superior temporal regions, and often much of the parietal lobe in between. This lesion represents most of the territory of the left middle cerebral artery. Patients in whom the superior temporal gyrus is spared tend to recover their auditory
APHASIA Table 12A.4:
Bedside features of global aphasia
henture
Syndrome
Spontaneous speech Naming Comprehension Repetition Reading Writing Associated signs
Mute or n on fluent Impaired Impaired Impaired Impaired Impaired Right hemiparesis Right hemisensory Right hemianopia
comprehension and to evolve toward the syndrome of Broca's aphasia. Recovery in global aphasia may be prolonged; global aphasics may recover more during the second month than in the first 6 months after a stroke. Characteristics of global aphasia are presented in Table 12A.4.
Conduction Aphasia Conduction aphasia is an uncommon but theoretically important syndrome that can be remembered by its striking deficit of repetition. Most patients have relatively normal spontaneous speech, although some make literal paraphasic errors and hesitate frequently for self-correction. Naming may be impaired, but auditory comprehension is preserved. Repetition may be disturbed to seemingly ridiculous extremes, such that a patient who can express himself or herself at a sentence level and comprehend conversation may be unable to repeat even single words. One such patient could not repeat the word "boy" but said "I like girls better," Reading and writing are somewhat variable, but reading aloud may share some of the same difficulty as repeating. Associated deficits include hemianopia in some patients; right-sided sensory loss may be present, but rightsided hemiparesis is usually mild or absent. Some patients have limb apraxia, creating a misiinpressioti that comprehension is impaired. Bedside examination findings in conduction aphasia are summarized in Table 12A.5. The lesions of conduction aphasia are usually in either the superior temporal or inferior parietal regions. Benson et al. suggested that patients with limb apraxia have parietal lesions, whereas those without apraxia have temporal lesions. Conduction aphasia may represent a stage of recovery in patients with Wernicke's aphasia in whom the damage to the superior temporal gyrus is not complete. Conduction aphasia has been advanced as a classic disconnection syndrome. Wernicke originally postulated that a lesion disconnecting Wernicke's and Broca's areas would produce this syndrome; Geschwind later pointed to the arcuate fasciculus, a white matter tract traveling from the deep temporal lobe, around the sylvian fissure to the frontal lobe, as the site of disconnection. Anatomic
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involvement of the arcuate fasciculus is present in most, if not all, cases of conduction aphasia, but there is usually also cortical involvement of the supramarginal gyrus or temporal lobe. The supramarginal gyrus appears to be involved in auditory immediate memory and in phoneme perception related to word meaning, as well as phoneme generation (Hickok and Poeppel, 2000). Lesions in this area are associated with conduction aphasia and phonemic paraphasic errors. Others have pointed out that lesions of the arcuate fasciculus do not always produce conduction aphasia. Another theory of conduction aphasia has involved a defect in auditory verbal short-term memory.
Anomic Aphasia Anomic aphasia refers to aphasic syndromes in which naming, or access to the internal lexicon, is the principal deficit. Spontaneous speech is normal except for the pauses and circumlocutions produced by the inability to name. Comprehension, repetition, reading, and writing are intact, except for the same word-finding difficulty in written productions. Anomic aphasia is common but less specific in localization than other aphasic syndromes. Isolated, severe anomia may indicate focal left hemisphere pathology. Alexander and Benson (1997) refer to the angular gyrus as the site of lesions producing anomic aphasia, but lesions there usually produce other deficits as well, including alexia and the four elements of Gerstmann's syndrome: agraphia, right-left disorientation, acalculia, and finger agnosia, or inability to identify fingers. Isolated lesions of the temporal lobe can produce pure anomia, and PET studies of naming in normal subjects have also shown consistent activation of the superior temporal lobe. Inability to produce nouns is characteristic of temporal lobe lesions, whereas inability to produce verbs occurs more with frontal lesions (Damasio 1992). Even specific classes of nouns may be selectively affected in some cases of anomic aphasia. Anomia is also seen with mass lesions elsewhere in the brain and in diffuse
Table 12A.5:
Bedside features of conduction aphasia
Feature
Syndrome
Spontaneous speech
Fluent, some hesitancy, literal paraphasic errors May be moderately impaired Intact Severely impaired ilnability to read aloud; some reading eomprehension Variable deficits ±Apraxia of left limbs ± Right hemiparesis, usually mild ± Right hemisensory loss ± Right hemianopia
Naming Comprehension Repetition Reading Writing Associated signs
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Tabic 12A.6:
Bedside features of amimic aphasia
i'dititri-
Syndrome
Spontaneous speech
Fluent, some word-finding pauses, circumlocution Impaired Intact Intact Intact Intact, except for anomia Variable or none
Naming Comprehension Repetition Reading Writing Associated signs
degenerative disorders, such as Alzheimer's disease (AD), Anomic aphasia is also a common stage in the recovery of many aphasic syndromes. Anomic aphasia thus serves as an indicator of left hemisphere or diffuse brain disease, but it has only limited localizing value. The typical features of anomic aphasia are presented in Table 12A.6.
Transcortical Aphasias The transcortical aphasias arc syndromes in which repetition is normal, presumably because the causative lesions do not disrupt the perisylvian language circuit from Wernicke's area through the arcuate fasciculus to Broca's area. Instead, these lesions disrupt connections from other cortical centers into the language circuit (hence the name transcortical). The transcortical syndromes are easiest to think of as analogues of the syndromes of global, Broca's, and Wernicke's aphasias, with intact repetition. Thus mixed transcortical aphasia, or the syndrome of the isolation of the speech area, is a global aphasia in which the patient repeats, often echolalically, but has no prepositional speech or comprehension. This syndrome is rare, occurring predominantly in large, watershed infarctions of the left hemisphere or both hemispheres that spare the perisylvian cortex or in advanced dementias. Transcortical motor aphasia is an analogue of Broca's aphasia in which speech is hesitant or telegraphic, comprehension is relatively spared, bur repetition is fluent. This syndrome occurs with lesions in the frontal lobe, anterior to Broca's area, and hence within the territory of the anterior cerebral artery. Disruption of the supplementary motor area or disconnection of this area from Broca's area by subcortical frontal white matter lesions may produce the syndrome. The occurrence of transcortical motor aphasia in an arterial territory other than the middle cerebral artery separates this syndrome from the many middle cerebral artery syndromes discussed previously. The third transcortical syndrome, transcortical sensory aphasia, is an analogue of Wernicke's aphasia in which fluent paraphasic speech, paraphasic naming, impaired auditory and reading comprehension, and abnormal writing coexist with normal repetition. This syndrome is relatively uncommon, occurring in strokes of the left temporo-occipital area and in dementias. Bedside
examination findings in the transcortical aphasias are summarized in Table 12A.7.
Subcortical Aphasias A current area of interest in aphasia research involves the "subcortical" aphasias. Although all the syndromes discussed so far are defined by behavioral characteristics that can be diagnosed on the bedside examination, the subcortical aphasias are defined by lesion localization in the basal ganglia or deep cerebral white matter. As knowledge about subcortical aphasia has accumulated, two major groups of aphasic symptomatology have been described: aphasia with thalamic lesions and aphasia with lesions of the subcortical white matter and basal ganglia. Left thalamic hemorrhages often produce a Wernickclike fluent aphasia, with better comprehension than cortical Wernicke's aphasia. A fluctuating or "dichotomous" state has been described, alternating between an alert state with nearly normal language and a drowsy state in which the patient mumbles paraphasically and comprehends poorly. Luria has called this a quasi-aphasic abnormality of vigilance, in that the thalamus plays a role in alerting the language cortex. Thalamic aphasia can occur even with a right thalamic lesion in a left-handed patient, indicating that hemispheric language dominance extends to the thalamic level. Whereas some skeptics have attributed thalamic aphasia to pressure on adjacent structures and secondary effects on the cortex, cases of thalamic aphasia have been described with small ischemic lesions, especially those involving the paramedian or anterior nuclei of the thalamus, in the territory of the tuberothalamic artery. Because these lesions produce little or no mass effect, such cases indicate that the thalamus and its connections play a definite role in language function. Lesions of the left basal ganglia and deep white matter also cause aphasia. As in thalamic aphasia, the first syndromes described were in basal ganglia hemorrhages, especially those involving the putamen, the most common site of hypertensive intracerebral hemorrhage. Here the aphasic syndromes are more variable but most commonly involve global or Wcrnickc-Iikc aphasia. As in thalamic lesions, ischemic strokes have provided better localizing information. The most common lesion is an infarct involving the anterior putamen, caudate nucleus, and anterior limb of the internal capsule. Patients with this lesion have an "anterior subcortical aphasia syndrome" involving dysarthria, decreased fluency, mildly impaired repetition, and mild comprehension disturbance (Mega and Alexander 1994). This syndrome most closely resembles Broca's aphasia, but with greater dysarthria and less language dysfunction. Figure 12A.5 shows an example of this syndrome. More restricted lesions of the anterior putamen, head of caudate, and periventricular white matter produce hesitancy or slow initiation of speech but little true
APHASIA
151
FIGURE 12A.S Magnetic resonance imaging (MRI) scan slices in the axial, coronal, and sagittal planes from a patient with subcortical aphasia. The lesion is an infarction involving the anterior caudate, putamen, and anterior limb of the left internal capsule. The patient presented with dysarthria and mild, nonfluent aphasia with anomia, with good comprehension. The advantage of MRI in permitting visualization of the lesion in all three planes is apparent. Continued
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FIGURE 12A.5, cont'd. language disturbance. More posterior lesions involving the putamen and deep temporal white matter, referred to as the temporal isthmus, are associated with fluent paraphasic speech and impaired comprehension resembling Wernicke's aphasia. Small lesions in the posterior limb of the internal capsule and adjacent putamen cause mainly dysarthria, but mild aphasic deficits may occasionally occur. Finally, larger subcortical lesions involving both the anterior and posterior lesion sites produce global aphasia. A wide variety of aphasia syndromes can thus be seen with subcortical lesion sites. Nadeau and Crosson (1997) discussed the anatomic model of the basal ganglia involvement in speech and language based on the known motot functions and fiber connections of these structures. Evidence from PET studies indicates that basal ganglia lesions affect language, both directly and indirectly, via decreased activation of cortical language areas. The "insula," a cortical structure that shares a deep location with the subcortical structures, may also be important to speech and language function. Dronkers (1996) reported that involvement of this area is closely associated with the presence of apraxia of speech in aphasic patients. In clinical terms, subcortical lesions do produce aphasia, although less commonly than cortical lesions, and the language characteristics of subcortical aphasias are often atypical. The presentation of a difficult-to-classify aphasic syndrome, in the presence of dysarthria and right hemiparesis, should lead to suspicion of a subcortical lesion.
Pure Alexia without Agraphia "Alexia," or the acquired inability to read, is a form of aphasia by the definition given at the beginning of this
chapter. The classic syndrome of alexia, pure alexia without agraphia, was described by the French neurologist Dejerine in 1892. This syndrome may be thought of as a linguistic blindfolding: Patients can write but cannot read their own writing. On bedside examination, speech, auditory comprehension, and repetition arc normal. Naming may be deficient, especially for colors. Patients initially cannot read at all; as they recover, they learn to read letter by letter, spelling out words laboriously. They cannot read words at a glance, as normal readers do. By contrast, they quickly understand words spelled orally to them, and they can spell normally. Some patients can match words to pictures, indicating that some subconscious awareness of the word is present, perhaps in the right hemisphere. Associated deficits include a right hemianopia or right upper quadrant defect in nearly all patients and, frequently, a deficit of short-term memory. There is usually no hemiparesis or sensory loss. The causative lesion in pure alexia is nearly always a stroke in the territory of the left posterior cerebral artery, with infarction of the medial occipital lobe, often the splenium of the corpus callosum, and often the medial temporal lobe. Dejerine postulated a disconnection between the intact right visual cortex and the left hemisphere language centers, particularly the angular gyrus. (Figure 12A.6 is an adaptation of Dejerine's original diagram.) Gcschwind later rediscovered this disconnection hypothesis. Although Damasio and Damasio found splenial involvement in only 2 of 16 cases, they postulated a disconnection within the deep white matter of the left occipital lobe. As in the disconnection hypothesis for conduction aphasia, the theory fails to explain all the behavioral phenomena, such as the sparing of single letters. A deficit in short-term memory for visual language elements
APHASIA Table 12A.9:
SPLENIUM
LEFT VISUAL CORTEX
FIGURE 12A.6 Horizontal brain diagram of pure alexia without agraphia, adapted from that of Dejerine, in 1892. Visual information from the left visual field reaches the right occipital cortex but 15 "disconnected" from the left hemisphere language centers by the lesion in the splenium of the corpus callosum.
or an inability to perceive multiple letters at o n c e (simultanagnosia) can also explain m a n y features of t h e s y n d r o m e . Typical findings of p u r e alexia w i t h o u t a g r a p h i a are presented in T a b l e 1 2 A . 8 .
Alexia with A g r a p h i a T h e second classic alexia s y n d r o m e , alexia with a g r a p h i a , described by Dejerine in 1 8 9 1 , m a y be t h o u g h t of as an acquired illiteracy, in which a previously e d u c a t e d patient is rendered unable to read or write. T h e oral language modalities ol speech, n a m i n g , auditory c o m p r e h e n s i o n , a n d repetition a r e largely intact, b u t m a n y cases manifest a fluent p a r a p h a s i c speech p a t t e r n with i m p a i r e d n a m i n g . Table 12A.8:
Bedside features of pure alexia without agraphia
Feature
Syndrome
Spontaneous speech Wunmt; Comprehension Repetition Reading Writing Associated signs
Intact ±Impaired, especially colors Intact Intact Impaited (some sparing of single letters) Intact Right hemianopia or superior quadrantanopia Short-term memory loss Motor, sensorx signs usually absent
153
Bedside features of alexia with agraphia
I Ciiturc
Syndrome
Spontaneous speech Naming Comprehension Repetition Reading Writing Associated signs
Fluent, often some paraphasia ilmpaired Intact, or less impaired than reading Intact Severely impaired Severely impaired Right hemianopia Motor, sensory signs often absent
T h i s s y n d r o m e t h u s o v e r l a p s W e r n i c k e ' s a p h a s i a , especially in cases in which reading is m o r e i m p a i r e d t h a n auditory c o m p r e h e n s i o n . Associated deficits include right h e m i a n o p i a and elements of G e r s t m a n n ' s s y n d r o m e : a g r a p h i a , acalculia, right-left disorientation, and finger a g n o s i a . T h e lesions a r e typically in t h e inferior parietal lobule, especially t h e a n g u l a r gyrus. Etiologies include strokes in t h e territory of t h e a n g u l a r b r a n c h of the left m i d d l e cerebral a r t e r y or m a s s lesions in the s a m e region. Characteristic features of t h e s y n d r o m e of alexia with a g r a p h i a are s u m m a r i z e d in T a b l e 1 2 A . 9 .
A p h a s i c Alexia In a d d i t i o n to t h e t w o classic alexia s y n d r o m e s , m a n y patients w i t h a p h a s i a h a v e associated r e a d i n g d i s t u r b a n c e . E x a m p l e s a l r e a d y cited a r e t h e " t h i r d a l e x i a " s y n d r o m e of Broca's a p h a s i a a n d the reading deficit of W e r n i c k e ' s a p h a s i a . N e u r o l i n g u i s t s a n d cognitive psychologists h a v e divided alexias a c c o r d i n g to b r e a k d o w n s in specific stages of the reading process. T h e linguistic concepts of surface structure versus the deep m e a n i n g s of w o r d s h a v e been i n s t r u m e n t a l in these n e w classifications. Four patterns of alexia (or dyslexia, in British usage) have been recognized: letter-by-letter, d e e p , p h o n o l o g i c a l , a n d surface dyslexia. Figure 1 2 A . 7 d i a g r a m s t h e steps in the reading process and t h e points of b r e a k d o w n in the four s y n d r o m e s . Letter-byletter dyslexia is equivalent to p u r e alexia w i t h o u t a g r a p h i a . Deep dyslexia is a severe r e a d i n g disorder in which patients recognize a n d read a l o u d only familiar w o r d s , especially c o n c r e t e imageable n o u n s a n d verbs. T h e y m a k e semantic or visual e r r o r s in r e a d i n g and fail completely in r e a d i n g n o n s e n s e syllables o r n o n w o r d s . W o r d r e a d i n g i s n o t affected by w o r d length or by regularity of spelling; o n e patient, for e x a m p l e , could read a m b u l a n c e but not a m . M o s t patients have severe a p h a s i a , w i t h extensive left frontoparietal d a m a g e . P h o n o l o g i c dyslexia is similar to d e e p dyslexia, with p o o r r e a d i n g of n o n w o r d s , but single n o u n s a n d verbs a r e r e a d in a nearly n o r m a l fashion, a n d semantic errors a r e r a r e . Patients a p p e a r t o read w o r d s w i t h o u t u n d e r s t a n d i n g . T h e fourth type, surface dyslexia, involves s p a r e d ability to read laboriously by g r a p h e m e - p h o n e m e c o n v e r s i o n but inability to recognize w o r d s at a glance. T h e s e patients can
1S4
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
read nonsense syllables but not words of irregular spelling, such as colonel or yacht. Their errors tend to be phonologic rather than semantic or visual (e.g., pronouncing rough and though alike). Agraphia Like reading, writing may be affected either in isolation (pure agraphia) or in association with aphasia (aphasic agraphia). In addition, writing can be impaired by motor disorders, by apraxia, and by visuospatial deficits. Isolated agraphia has been described with left frontal or parietal lesions. Agraphias can be analyzed the same way as the alexias (Figure I2A.S). Thus phonologic agraphia involves the inability to convert phonemes into graphemes or write pronounceable nonsense syllables, in the presence of ability to write familiar words. Deep dysgraphia is similar to phonologic agraphia, but the patient can read nouns and verbs better than articles, prepositions, adjectives, and adverbs. In lexical or surface dysgraphia, patients can write regularly spelled words and pronounceable nonsense words but not irregularly spelled words. These patients have intact phoneme-graph erne conversion but cannot write by a whole-word or "lexical" strategy.
LANGUAGE IN RIGHT HEMISPHERE DISORDERS Language and communication disorders are important even in parienrs with right hemisphere disease. First, left-handed patients may have right hemisphere language dominance and may develop aphasic syndromes from right hemisphere lesions. Second, right-handed patients occasionally become aphasic after right hemisphere strokes, a phenomenon called crossed aphasia (Bakar, Kirshner, and Wertz 1996), These patients presumably have crossed or mixed dominance. Third, even right-handed persons with typical left hemisphere dominance for language have subtly altered language function after right hemisphere damage. Such patients are not aphasic, in that the fundamental mechanisms of speech production, repetition, and comprehension are undisturbed. Affective aspects of language arc impaired, however, so the speech sounds flat and unemotional; the normal prosody, or emotional intonation, of speech is lost. Syndromes of loss of emotional aspecrs of speech are termed aprosodias Motor aprosodia involves loss of expressive emotion with preservation of emotional comprehension; sensory aprosodia involves loss of comprehension of affective language, also called affective agnosia. More than just emotion, stress and emphasis within a sentence are also affected by right hemisphere
APHASIA
155
Written words FIGURE 12A.8 Neurolinguistic model of writing and the agraphias. In deep agraphia, only the semantic (phonological-scmanticlexkal) route (route 1) is operative; in phonologic agraphia, route 2, the nonlexical phonologic route produces written words directly from spoken words; in surface agraphia, only route 3, the phone me-grapheme pathway, can be used to generate writing. dysfunction. More importantly, such vital aspects of human communication as metaphor, humor, sarcasm, irony, and related constituents of language that transcend the literal meaning of words are especially sensitive to right hemisphere disease. These deficits significantly impair patients in the pragmatics of communication. In other words, patients with right hemisphere damage understand what is said, but not how it is said. They may have difficulty following a complex story. Such higher level language deficits are related to the right hemisphere disorders of inattention and neglect, discussed in Chapters 4 and 38.
with early AD have anomic aphasia. In later stages, language functions become more obviously impaired. In terms of the components of language mentioned earlier in this chapter, the semantic aspects of language tend to deteriorate first, then syntax, and finally phonology. Reading and writing—the last-learned language functions— are among the first to decline. Auditory comprehension later becomes deficient, whereas repetition and articulation remain normal. The language profile may then resemble that of transcortical sensory or Wernicke's aphasia. In terminal stages, speech is reduced to the expression of simple biological want--; eventually, even muteness can develop. By this time, most patients are institutionalized or bedridden.
LANGUAGE IN DEMENTING DISEASES
The second pattern of language dissolution in dementia, considerably less common than the first, involves the gradual onset of a progressive aphasia, often without other cognitive deterioration. Auditory comprehension is involved early in the illness, and specific aphasic symptoms are evident, such as paraphasic or nonfluent speech, misnaming, and errors of repetition. These deficits worsen gradually, mimicking the course of a brain tumor or mass lesion rather than a typical dementia (Grossman et al. 1996; Mesulam 2001), The syndrome is generally referred to as primary progressive aphasia. CT scans may show focal atrophy in the left perisylvian region, whereas electroencephalographic (EEG) studies may show focal slowing. PET has shown prominent areas of decreased metabolism in the left temporal region and adjacent cortical areas. The pathology underlying primary progressive
Language impairment is commonly seen in patients with dementia. Despite considerable variability from patient to patient, two patterns of language dissolution can be described. The first, the common presentation of AD, involves early loss of memory and general cognitive deterioration. In these patients, mental status examination results are most remarkable for deficits in short-term memory, insight, and judgment, but language impairments can be found in naming and in discourse, with impoverished language content and loss of abstraction and metaphor. The mechanics of language—grammatical construction of sentences, receptive vocabulary, auditory comprehension, repetition, and oral reading—tend to remain preserved until later stages. By aphasia testing, patients
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aphasia varies (Kertesz et al. 2000). Some cases show the frontotemporal lobar atrophy of Pick's disease and localized spongiform degeneration. In Fnglnnd, this pattern of clinical syndrome and neuropathology is referred to as frontotemporal dementia, a term gaining popularity in the United States. In one study of 10 patients with primary progressive aphasia followed prospectively until they became nonfluent or mute, Kertesz and Munoz (2003) found that at autopsy all had evidence of frontotemporal dementia: corticobasal degeneration in 4, Pick body dementia in 3, and tau- and synuclein-negativc ubiquinated inclusions of the motor neuron disease in 3. Imaging studies have shown that primary progressive aphasia is often associated with atrophy in the left frontotemporal region, and other areas such as the fusiform and precentral gyri and intraparietal sulcus are activated, possibly as a compensatory neuronal strategy (Neary and Snowden 1996; Sonty et al. 2003). Familial cases of frontotemporal dementia have recently been linked to chromosome 17 (Heutink et al. 1997). Cases of isolated aphasia secondary to Creutzfeldt-Jakob disease and corticobasal degeneration have also been reported. Finally, a few patients with pathologically proven AD have presented with focal involvement of the language cortex, always with fluent aphasia.
INVESTIGATION OF THE APHASIC PATIENT Clinical Tests The bedside language examination is useful in forming a preliminary impression of the type of aphasia and the localization of the causative lesion. Follow-up examinations are also helpful; as in all neurological diagnoses, the evolution of a neurological deficit over time is the most important clue to the specific disease process. For example, an embolic stroke and a brain tumor might both produce Wernicke's aphasia, but strokes occur suddenly, with improvement thereafter, whereas tumors produce gradually worsening aphasia. In addition to the bedside examination, a large number of standardized aphasia test batteries have been published. The physician should think of these tests as more detailed extensions of the bedside examination. They have the advantage of quantitation and standardization, permitting comparison over time and, in some cases, even a diagnosis of the specific aphasia syndrome. Research on aphasia depends on these standardized tests. For neurologists, the most helpful battery is the Boston Diagnostic Aphasia Examination, or its Canadian adaptation, the Western Aphasia Battery. Both tests provide subtest information analogous to the bedside examination, and therefore meaningful to neurologists, as well as aphasia syndrome classification. The Porch Index of Communicative Ability quantitates performance in many specific
functions, allowing comparison over time. Other aphasia tests arc designed to evaluate specific language areas. For example, the Boston Naming Test evaluates a wide variety of naming stimuli, whereas the Token Test evaluates higher level comprehension deficits. Further information on neuropsychologic tests can be found in Chapter 38. Further diagnosis of the aphasic patient rests on the confirmation of a brain lesion by neuroimaging (Figure 12A.9). The CT brain scan (discussed in Chapter 37B) revolutionized the localization of aphasia by permitting "real-time" delineation of a focal lesion in a living patient; previously, the physician had to outlive the patient to obtain a clinicopathologic correlation at autopsy. MRI scanning provides better resolution of areas difficult to see on CT, such as the temporal cortex adjacent to the petrous bones, and more sensitive detection of tissue pathology, such as early changes of infarction. The anatomic distinction of cortical from subcortical aphasia is best made by MRI. Acute strokes are visualized early on diffusionweighted MRI. The EEG is helpful in aphasia in localizing seizure discharges, interictal spikes, and slowing seen after destructive lesions, such as traumatic contusions and infarctions. The EEG can provide evidence that aphasia is an ictal or postictal phenomenon and can furnish early clues to aphasia secondary to mass lesions or to herpes simplex encephalitis. In research applications, electrophysiologic resting via subdural grid and depth elect rod us. or stimulation mapping of epileptic foci in preparation for epilepsy surgery, have aided in the identification of cortical areas involved in language. Cerebral arteriography is useful in the diagnosis of aneurysms, arteriovenous malformations (AVMs), arterial occlusions, vasculitis, and venous outflow obstructions. In preparation for epilepsy surgery, the Wada test, or infusion of amobarbital through an arterial catheter, is useful in the determination of language dominance. Other related studies by language activation with functional MRI (fMRI) or PET are beginning to rival the Wada test for the study of language dominance (Ahou-Khalil and Schlaggar 2002). Single-photon emission CT (SPECT), PET, and fMRI (see Chapter 38} arc contributing greatly to the study of language. Patterns of brain activation in response to language stimuli have been recorded, mainly in normal persons, and these studies have largely confirmed the localizations based on pathology such as stroke over the past 140 years. In addition, these techniques can be used to map areas of the brain that activate during language functions after insults such as strokes, and the pattern of recovery can be studied. Some such studies have indicated right hemisphere activation in patients recovering from aphasia (Cappa et al. 1997}, hut others have found that only left hemisphere activation is associated with full recovery (Hciss et al. 1999}. Subcortical contributions to aphasia and language in degenerative conditions have been studied
APHASIA
1S7
B FIGURE 12A.9 (A) Coronal Tl-weighted magnetic resonance imaging scan of a patient with primary progressive aphasia. Note the marked atrophy of the left temporal lobe. (B) Axial fluorine-2-deoxyglucose positron emission tomographic scan showing extensive hypometabolisin in the left cerebral hemisphere, especially marked in the left temporal lobe.
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with PET. These techniques provide the best correlation between brain structure and function currently available and should help advance our understanding of language disorders and their recovery.
DIFFERENTIAL DIAGNOSIS Vascular lesions, especially ischemic strokes, are the most common causes of aphasia. Historically, most research studies in aphasia have used patients who have had a stroke because stroke is an "experiment" of nature in which one area of the brain is damaged while the rest remains theoretically intact. Strokes are characterized by the abrupt onset of a neurological deficit in a patient with vascular risk factors. The precise temporal profile is important: Most embolic strokes are sudden and maximal at onset, whereas thrombotic strokes typically wax and wane or increase in steps. The bedside aphasia examination is helpful in delineating the vascular territory affected. For example, the sudden onset of Wernicke's aphasia nearly always indicates an embolus to the inferior division of the left middle cerebral artery. Global aphasia may be caused by an embolus to the middle cerebral artery stem, thrombosis of the internal carotid artery, or even a hemorrhage into the deep basal ganglia. Whereas most aphasic syndromes involve the territory of the left middle cerebral artery, transcortical motor aphasia is specific to the anterior cerebral territory, and pure alexia without agraphia is specific to the posterior cerebral artery territory. The clinical features of the aphasia are thus of crucial importance to the vascular diagnosis. Hemorrhagic strokes are also an important cause of aphasia, most commonly the basal ganglionic hemorrhages associated with hypertension. The deficits tend to worsen gradually over minutes to hours, in contrast to the sudden ot stepwise onset of ischemic strokes. Headache, vomiting, and obtundation are more common with hemorrhages. Because hemorrhages compress cerebral tissue without necessarily destroying it, the ultimate recovery from aphasia is often better in hemorrhages than in ischemic strokes, although hemorrhages are more often fatal. Other etiologies of intracerebral hemorrhage include anticoagulant use, head injury, blood dyscrasias, thrombocytopenia, and bleeding into structural lesions, such as infarctions, tumors, AVMs, and aneurysms. Hemorrhages from AVMs mimic strokes, with abrupt onset of focal neurological deficit. Patients with ruptured aneurysms, on the other hand, present with severe headache and stiff neck or with coma; most patients have no focal deficits, but delayed deficits (e.g., aphasia) may develop secondary to vasospasm. Lobar hemorrhages may occur in elderly patients without hypertension. These hemorrhages occur near the cortical surface, sometimes extending into the subarachnoid space, and they may be recurrent. Pathological studies have shown amyloid deposition in small arterioles, or
amyloid angiopathy. A final vascular cause of aphasia is cerebral vasculitis (see Chapter 57G). Traumatic brain injury is a common cause of aphasia. Cerebral contusions, depressed skull fractures, and hematomas of the intracerebral, subdural, and epidural spaces all cause aphasia when they disrupt or compress left hemisphere language structures. Trauma tends to be less localized than ischemic stroke, and thus aphasia is often admixed with the general effects of the head injury, such as depressed consciousness, encephalopathy or delirium, amnesia, and other deficits. Head injuries in young people may be associated with severe deficits but excellent longterm recovery. Language deficits, especially those involving discourse organization, can be found in most cases of significant closed-head injury. Gunshot wounds produce focal aphasic syndromes, which rival stroke as a source of clinicoanatomic correlation. Subdural hematomas are infamous for mimicking other neurological syndromes. Aphasia is occasionally associated with subdural hematomas overlying the left hemisphere, but it may be mild and may be overlooked because of the patient's more severe complaints of headache, memory loss, and drowsiness. Tumors of the left hemisphere frequently present with aphasia. The onset of the aphasia is gradual, and other cognitive deficits may be associated because of edema and mass effect. Aphasia secondary to an enlarging tumor may thus be difficult to distinguish from a diffuse encephalopathy or early dementia. Any syndrome of abnormal language function should therefore be investigated for a focal dominant-hemisphere lesion. Infections of the nervous system may cause aphasia. Brain abscesses can mimic tumors in every respect, and those in the left hemisphere can present with progressive aphasia. Chronic infections, such as tuberculosis or syphilis, can result in focal abnormalities that run the entire gamut of central nervous system symptoms and signs. Herpes simplex encephalitis has a predilection for the temporal lobe and orbital frontal cortex, and aphasia can be an early symptom, along with headache, confusion, fever, and seizures. Aphasia is often a permanent sequela in survivors of herpes encephalitis. Acquired immunodeficiency syndrome (AIDS) is rapidly becoming a common cause of language disorders. Opportunistic infections can cause focal lesions anywhere in the brain, and the neurotropic human immunodeficiency virus agent itself produces a dementia (AIDS-dementia complex), in which language deficits play a part. Aphasia is frequently caused by the degenerative central nervous system diseases. Reference has already been made to the focal, progressive aphasia in patients with Pick's disease and spongiform degenerations as compared with the more diffuse cognitive deterioration characteristic of AD. Language dysfunction in AD may be more common in familial cases and may predict poor prognosis. Cognitive deterioration in patients with Parkinson's disease may also include language deterioration similar to that of AD,
APHASIA although Parkinson's disease tends to involve more fluctuation in orientation and greater tendency to active hallucinations and delusions, A striking abnormality of speech (i.e., initial stuttering followed by ttue aphasia and dementia) has been described in the dialysis dementia syndrome. This disorder may be associated with spongiform degeneration of the frontotcmporal cortex, similar to Creutzfeldt-Jakob disease. Paraphasic substitutions and nonsense speech are also occasionally encountered in acute encephalopathies, such as hyponatremia or lithium toxicity. A final cause of aphasia is seizures. Seizures can be associated with aphasia in children as part of the LandauKleffner syndrome or in adults as either an ictal or a postictal Todd's phenomenon. Epileptic aphasia is important to recognize, in that anticonvulsant drug therapy can prevent the episodes, and unnecessary investigation or treatment for a new lesion, such as a stroke, can be avoided. As mentioned earlier, localization of language areas in epileptic patients has contributed greatly to the knowledge of language organization in the brain. The work of Ojemann (1991) has shown that more than 1 5 % of young epileptic patients have no Broca's or no Wernicke's area. In addition, a new language area, the basal temporal language area, has been discovered through epilepsy stimulation studies and only later confirmed in patients with spontaneous seizures (Kirshner et al. 1995).
RECOVERY AND REHABILITATION OF APHASIA Patients with aphasia from acute disorders, such as stroke, generally show spontaneous improvement over days, weeks, and months. In general, the greatest recovery occurs during the first 3 months, but improvement may continue over a prolonged period, especially in young patients and in global aphasics. The aphasia type often changes during recovery: Global aphasia evolves into Broca's aphasia, and Wernicke's aphasia into conduction or anomic aphasia. Language recovery may be mediated by shifting of functions to the right hemisphere or to adjacent left hemisphere regions. As mentioned earlier, studies of language activation PET and SPECT scanning techniques are advancing our understanding of the neuroanatomy of language recovery (Heiss et al. 1999). In addition, study of patients in the very acute phase of aphasia, with techniques of diffusion- and perfusion-weighted MRI, has suggested less variability in the correlation of comprehension impairment with left temporal ischemia than has been suggested from testing of chronic aphasia, after recovery and compensation have commenced (Hillis et al. 2001). Speech therapy, provided by speech-language pathologists, attempts to facilitate language recovery by a variety of techniques and to help the patient compensate for lost functions (see Chapter 54), Repeated practice in
1S9
articulation and comprehension tasks has traditionally been used to stimulate improvement. Other techniques include melodic intonation therapy, which uses melody to involve the right hemisphere in speech production; visual action therapy, which uses gestural expression; and treatment of aphasic perseveration, which aims to reduce repetitive utterances. Two other therapeutic techniques are functional communication therapy, which takes advantage of extralinguistic communication, and cVIC or Lingraphica, a computer program originally developed for primate communication. Patients who cannot speak can learn to produce simple sentences via computer. Augmentative devices make language expression possible through use of printers or voice simulators. Speech therapy has remained controversial: Some studies have suggested that briefly trained volunteers can induce as much improvement as speechlanguage pathologists, but large randomized trials have clearly indicated that patients who undergo formal speech therapy recover better than untreated patients (Robey 1998). A new approach to language rehabilitation is the use of pharmacological agents to improve speech. Albert and colleagues first reported that the dopaminergic drug bromocriptine promotes spontaneous speech output in transcortical motor aphasia. Several other studies have supported the drug in nonfluenr aphasias, although one controlled study showed no benefit. Stimulant drugs are also heing tested in aphasia rehabilitation. As new information accumulates on the neurochemistry of cognitive functions, other pharmacologic therapies may he forthcoming.
REFERENCES Abou-Khalil, B. 8c Schlaggar, B. L. 2002, "Is it time to replace the Wada test?" Neurology, vol. 59, pp. 160-161 Albert, M. L., Bachman, D. L, Morgan, A., 8c Helm-Esta brooks, N. 1988, "Pharmacotherapy for aphasia," Neurology, vol. 38, pp. 877-879 Alexander, M. P. & Benson, D. F. 1997, "The aphasias and related disturbances," in Clinical Neurology, vol. 1, ed R. J. Joynt, Lippincott Co, Philadelphia Alexander, M. P., Benson, D. F., & Stuss, D. T. 1989, "Frontal lobes and language," Brain Lang, vol. 37, pp. 656-691 Bakar, M., Kirshner, H. S., & Wertz, R. T. 1996, "Crossed aphasia: Functional brain imaging with PF.T or SPECT," Arch Neurol, vol. 53, pp. 1026-1032 Cappa, S. F., Perani, D., Crassi, F., et al. 1997, "A PET follow-up study of recovery after stroke in acute aphasics," Brain Lang, vol. 56, pp. 55-67 Docherty, N. M., DcRosa, M., & Andreasen, N. C, 1996, "Communication disturbances in schizophrenia and mania," Arch Gen Psychiatry, vol. 53, pp. 358-364 Dronkers, N. F. 1996, "A new brain region for controlling speech articulation," Nature, vol. 384, pp. 159-161 Grossman, M., Mickanin, J., Onishi, K., et al. 1996, "Progressive nonfkient aphasia: Language, cognitive, and PET measures
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contrasted with probable Alzheimer's disease," J Cogn Neurosci, vol. 8, pp, 135-154 Heiss, W. D., Kessler, J., Thiol, A., et al. 1999, "Differential capacity of left and right hemispheric areas for compensation of poststroke aphasia," Ann Neurol, vol. 45, pp. 430-438 Heutink, P., Stevens, M., Rizzu, P., et al. 1997, "Hereditary frontotempora) dementia is linked to chromosome 17q2Tq22; a genetic and clinicopathological study of three Dutch families," Ann Neurol, vol. 4 1 , pp. 150-159 Hickok, G. & Pocppel. 2000, "Towards a functional neuroanatomy of speech perception," Trends Cogn Set, vol. 4, pp. 131-138 Hillis, A. E., Wiryk, R. J., Tuffiash, E., et al. 2001, "Hypoperfusion of Wernicke's area predicts severity of semantic deficit in acute stroke," Ann Neurol, vol. 50, pp. 561-566 Kertesz, A., Lau, W. K., & Polk, M. 1993, "The structural determinants of recovery in Wernicke's aphasia," Brain Lang, vol. 44, pp. 153-164 Kertesz, A., Martiiiez-Lage, P., Davidson, W., & Munoz, D. G. 2000, "Tin. corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia," Neurology, vol. 55, pp. 1368-1375 Kertesz, A. & Munoz, D. G. 2003, "Primary progressive aphasia and Pick complex," ] Neurol Sci, vol. 206, pp. 97-107 Kirshner, H. S., Hughes, T., Fakhoury, T., & Ahou-Khalil, B. 1995, "Aphasia secondary to partial status epilcpticus of the basal temporal language area," Neurology, vol. 45, pp. 1616-1618
Mega, M. S. 8c Alexander, M. P. 1994, "Subcortical aphasia: The core profile of capsulostriatal infarction," Neurology, vol. 44, pp. 1824-1829 Mesulam, M. M. 2 0 0 1 , "Primary progressive aphasia," Ann Neurol, vol. 49, pp. 425-432 Nadeau, S. E. 8c Crosson, B. 1997, "Subcortical aphasia," Brain Lang, vol. 58, pp. 355-402 Neary, D. & Snowden, J. 1996, "Frontotemporal dementia: Nosology, neuropsychology, and neuropathology," Brain Cogn, vol. 3 1 , pp. 176-187 Robey, R. R. 1998, "A meta-analysis of clinical outcomes in the treatment of aphasia," / Speech Lang Hearing Res, vol. 4 1 , pp. 172-187 Robinson, R. G. 1997, "Neuropsychiatric consequences of stroke," Annu Rev Med, vol. 48, pp. 217-229 Sonty, S. P., Mesulam, M. M., Thompson, C. K., et al. 2003, "Primary progressive aphasia; PPA and the language network," Ann Neurol, vol. 5 3 , pp. 35-49
REVIEWS Damasio, A. R. 1992, "Aphasia," IV Engl j Med, vol. 326, pp. 531-539 Kirshner, H. S. 1995, Handbook of Neurological Speech and Language Disorders, Marcel Dckker, New York Kirshner, H. S., Alexander, M., Lorch, M. P., tk Wertz, R. T. 1999, "Disorders of speech and language," Continuum, vol. 5, pp. 5-237
Chapter 12 Language and Speech Disorders B. DYSARTHRIA AND APRAXIA OF SPEECH Howard S. Kirshner Motor Speech Disorders Dysarthrias Apraxia of Speech Oral or Buccolingual Apraxia Aphcmia
161 1(51 163 163 163
M O T O R SPEECH DISORDERS M o t o r speech disorders are s y n d r o m e s of a b n o r m a l articulation, the m o t o r p r o d u c t i o n of speech, w i t h o u t abnormalities of language. A p a t i e n t with a m o t o r speech disorder should be able to p r o d u c e n o r m a l expressive language in writing and to c o m p r e h e n d b o t h s p o k e n a n d written language. If a listener transcribes into p r i n t or type the speech of a patient with a m o t o t speech d i s o r d e r , the text should read as n o r m a l l a n g u a g e . M o t o r speech disorders include d y s a r t h r i a s , disorders of speech articulation, a p r a x i a of speech, a m o t o r p r o g r a m m i n g disorder for speech, and five rarer s y n d r o m e s : a p h c m i a , foreign accent s y n d r o m e , a c q u i t e d stuttering, p r i m a r y progressive a n a r thria, and the opercular s y n d r o m e . In an analysis of speech and language disorders at t h e M a y o Clinic, Duffy ( 1 9 9 5 ) reported t h a t 4 6 . 3 % o f the patients had d y s a r t h r i a , 2 7 . 1 % h a d a p h a s i a , 4 . 6 % h a d a p r a x i a o f speech, 9 % h a d o t h e r speech disorders (such a s stuttcting), and 1 3 % h a d o t h e r cognitive or linguistic disorders.
DYSARTHRIAS Dysarthrias involve t h e a b n o r m a l a t t i c u l a t i o n of s o u n d s or p h o n e m e s because of a b n o r m a l activation of the o t o m a n dibular pharyngeal muscles, affecting the speed, strength, timing, range, or accuracy of speech (Duffy 1 9 9 5 ) . Dysarthria is generally neurogenic, related to dysfunction of the central nervous system, nerves, n e u r o m u s c u l a t junction, and muscle, with a c o n t r i b u t i o n of s e n s o t y deficits in some cases, but local structural p r o b l e m s of the palate, t o n g u e , ot larynx m a y also cause speech a b n o r malities. Dysarthria can affect n o t only articulation, b u t
The "Foreign Accent Syndrome" Acquired Stuttering Primary Progressive Anarthria Opercular Syndrome
163 163 164 164
also p h o n a t i o n , b r e a t h i n g , or p r o s o d y (emotional tone) of speech. Total loss of ability to articulate is called anarthria, w h e t e a s d y s a r t h r i a usually involves t h e distortion of
consonant sounds. Like the aphasias, dysatthtias can be analyzed in terms of the specific brain lesion sites associated with specificpatterns of speech impairment. Analysis of dysarthria at the bedside is useful for the localization of neurological lesions and the diagnosis of neurological disorders. An experienced examiner should be able to tecognize and categorize the majoi types of dysarthria, rather than referring to "dysarthria" as a single disorder. The examination of speech at the bedside should include repeating syllables, words, and sentences. Repeating consonant sounds (such as /p/, /p/, /p/) or shifting consonant sounds (/p/, /t/, Ik!) can help identify which consonants consistently cause trouble. The Mayo Clinic classification of dysarthria (Duffy 1995), widely used in the United States, includes six categories: (1) flaccid, (2) spastic and "unilateral upper motor neuron" (UMN), (3) ataxic, (4) hypokinetic, (5) hyperkinetic, and (6) mixed dysarthria. These types of dysarthria are summarized in Table 12B.1. Flaccid dysarthria is associated with disorders involving lower moror neuron weakness of the bulbar muscles, such as polymyositis, myasthenia gtavis, and bulbar poliomyeliris. The speech pattern is breathy and nasal, with indistinctly pronounced consonants. In the case of myasthenia gtavis, the patient may begin reading a paragraph with normal enunciation, but by the end of the paragraph, the atticulation is soft, breathy, and frequently interrupted by labored respirations. Spastic dysarthria occurs in patients with bilateral lesions of the motor cortex or corticobulbat tracts, such as bilateral strokes. The speech is harsh or "strain strangle" in vocal 161
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Table 12B.1:
Bedside features of transcortical aphasias
Type
Localization
Auditory signs
Diseases
Flaccid
Lower motor nei
Stroke, myasthenia gravis
Spastic
Bilateral upper motor neuron
Unilateral upper motor neuron Ataxic
Unilateral upper motor neuron (.i.Tcbi'llum
Hypokinetic
Extrapyramidal
] ty perk im-tic
Extrapyramidal
Spastic flaccid
Upper and
Breathy, nasal voice, imprecise consonants Strain strangle, harsh voice; slow rate; imprecise consonants Consonant imprecision, slow rate, harsh voice quality Irregular articulatory breakdowns, excessive and equal stress Rapid rate, reduced loudness, monopitch and monoloudness Prolonged phonemes, variable rate, inappropriate silences, voice stoppages Hypernasality; strain strangle, hatsh voice, slow rate, imprecise consonants
lower motor neuron
Bilateral strokes, tumors, primary lateral sclerosis Stroke, tumor Sttoke, degenerative disease Parkinson's disease Dystonic, Huntington's disease Amyotrophic lateral sclerosis, multiple strokes
Adapted with permission from Duffy, J, R. 1995, Motor Speech Disorders: Substrates, Differential Diagnosis, and Management, Mosby, St. Louis; and Kirshner, H. S. 2002, Behavioral Neurology: Practical Science of Mind and Brain , Butterworth-Hcinemann, Boston, quality, with reduced rate, low pitch, and consonant errors. Patients often have the features of "pseudobulbar palsy," including dysphagia, exaggerated jaw jerk and gag reflexes, and easy laughter and crying (emotional incontinence or pathological laughter and crying). Another variant is the "opercular syndrome" (see Opercular Syndrome, later in this chapter). A milder variant of spastic dysarthria, "unilateral UMN" dysarthria, is associated with unilateral UMN lesions (Duffy 1995). This type of dysarthria has similar features to spastic dysarthria, only in a less severe form. Unilateral UMN dysarthria is one of the most common types of dysarthria, occurring in patients with unilateral strokes. Ataxic dysarthria or "scanning speech," associated with cerebellar disorders, is characterized by one of two patterns: irregular breakdowns of speech with explosions of syllables interrupted by pauses or a slow cadence of speech with excessively equal stress on every syllable. The second pattern of ataxic dysarthria is referred to as scanning speech. A patient with ataxic dysarthria, attempting to repeat the phoneme /p/ as rapidly as possible, produces either an irregular rhythm, resembling popcorn popping, or a very slow rhythm. Causes of ataxic dysarthria include cerebellar strokes, tumors, multiple sclerosis, and cerebellar degenerations. Hypokinetic dysarthria, the typical speech pattern in Parkinson's disease, is notable for decreased and monotonous loudness and pitch, rapid rate, and occasional consonant errors. In a recent stud) of brain activation by positron emission tomography (PET) methodology (Liotti et al. 2003), premotor and supplementary motor area activation was seen in untreated patients with Parkinson's disease and hypokinetic dysarthria, but not in normal subjects. Following a voice treatment protocol,
these premotor and motor activations diminished, whereas right-sided basal ganglia activations increased. Hypokinetic dysarthria responds both to behavioral therapies and to pharmacologic treatment of Parkinson's disease. Hyperkinetic dysarthria, a pattern in some ways opposite to hypokinetic dysarthria, is characterized by marked variation in tate, loudness, and timing, with distortion of vowels, harsh voice quality, and occasional sudden stoppages of speech. This speech pattern is seen in hyperkinetic movement disorders such as Huntington's disease. The final category, mixed dysarthria, involves combinations of the other five types. One common mixed dysarthria is a spastic-flaccid dysarthria seen in amyotrophic lateral sclerosis (ALS). The patient with ALS has the harsh strain-strangle voice quality of spastic dysarthria, combined with the breathy and hypernasal quality of flaccid dysarthria. Multiple sclerosis may feature a spastic flaccid-ataxic or spastic-ataxic mixed dysarthria, in which slow rate or irregular breakdowns arc added to the other characteristics seen in spastic and flaccid dysarthria. Wilson's disease can involve hypokinetic, spastic, and ataxic features, The management of dysarthria includes speech therapy techniques to strengthen muscles, train more precise articulations, slow the rate of speech to increase intelligibility, or teach the patient to stress specific phonemes. Devices such as pacing boards to slow articulation, palatal lifts to reduce hypernasality, amplifiers to increase voice volume, communication boards for subjects to point to pictures, and augmentative communication devices and computer techniques can be used when the patient is unable to communicate in speech. Injections of collagen into the vocal folds and surgical procedures such as a pharyngeal
DYSARTHRIA AND AI'RAXIA OI : SPELCH
flap to reduce hypcrnasality or vocal fold transposition surgery to increase loudness may help the patient speak more intelligibly.
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Both oral apraxia and apraxia of speech can coexist with Broca's aphasia.
APHEMIA APRAXIA OF SPEECH Apraxia of speech is a disorder of the programming of articulation of sequences of phonemes, especially consonants. The motor speech system makes errors in selection of consonant phonemes, in the absence of any "weakness, slowness, or incoordination" of the muscles of speech articulation (Wert/., LaPointe, and Roscnbek 1991). The phrase "apraxia of speech" implies that the disorder is one of a skilled, sequential motor activity (as in other apraxias), rather than a primary motor disorder. Consonants are often substituted rather than distorted, as in dysarthria. Patients have special difficulty with polysyllabic words and consonant shifts, as well as in initiating articulation of a word. Errors arc inconsistent from one attempt to the next, in contrast to the consistent distortion of phonemes in dysarthria. The four cardinal features of apraxia of speech are (1) effortful, groping, or rrial-and-error" attempts at speech, with efforts at self-correction; (2) dysprosody; (3) inconsistencies in articulation errors; and (4) difficulty initiating utterances. Usually the patient has the most difficulty with the first phoneme of a polysyllabic utterance. The patient may make an error in attempting to produce a word on one trial, a different error the next time, and a normal utterance the third time. Apraxia of speech is rare in isolated form, but it frequently contributes to the speech and language deficit of Broca's aphasia. A patient with apraxia of speech, in addition to aphasia, will often write better than he or she can speak, and comprehension is relatively preserved. Dronkers (1996) presented evidence from computed tomographic (CT) and magnetic resonance imaging (MRI) scans indicating that although the anatomic lesions vary, patients with apraxia of speech virtually always have damage in the left hemisphere insula, whereas patients without apraxia of speech do not. Testing of patients for speech apraxia includes the repetition of sequences of phonemes (pa/ta/ka), as discussed previously (see Dysarthria). Repetition of a polysyllabic word (e.g., "catastrophe" or "television") is especiallylikely to elicit apraxic errors.
Oral or Buccolingual Apraxia Apraxia of speech is not the same as oral-buccolingual apraxia, or ideomotor apraxia for learned movements of the tongue, lips, and larynx. Oral apraxia can be elicited by asking a subject to lick his or her upper lip, smile, or stick out the tongue. Oral apraxia is discussed in Chapter 13.
Another differential diagnosis with both apraxia ol speech and dysarthria is the syndrome of aphemia, Broca first used the term aphemie to designate the syndrome later called "Broca's aphasia," but recently, the term has been reserved for a syndrome of near muteness, with normal comprehension, reading, and writing. Aphemia is clearly a motor speech disorder, rather than an aphasia, it written language and comprehension are indeed intact. Patients are often anarthric, with no speech whatever, and then effortful nonfluent speech emerges. Some patients have persisting dysarthria, with dysphonia and sometimes distortions of articulation that sound similar to foreign accents (see The "Foreign Accent Syndrome," later in this chapter). Alexander, Nacscr, and Palumbo (1990) associated pure anarthria with lesions of the face area of motor cortex. Functional imaging studies also suggest that articulation is mediated at the level of the primary motor face area (Riecker et al. 2000), and disruption of speech articulation can be produced by transcranial magnetic stimulation over the motor face area (Epstein et al. 1999). Controversy remains over whether aphemia is equivalent to apraxia of speech, as suggested by Alexander, Benson, and Stuss (1989). In general, aphemia is likely to involve lesions in the vicinity of the primary motor cortex and perhaps Broca's area, whereas apraxia of speech may be localized to the insula.
THE "FOREIGN ACCENT SYNDROME" The "foreign accent syndrome" is an acquired form of motor speech disorder, related to the dysarthrias, in which the patient acquires a dysflucncy resembling a foreign accent, usually after a unilateral stroke (Kurowski, Blumstcin, and Alexander 1996; Takayama et al. 1993). Lesions may involve the motor cortex of the left hemisphere. The disorder can also be mixed with aphasia.
ACQUIRED STUTTERING Another uncommon motor speech disorder following acquired brain lesions is a pattern resembling developmental stuttering, referred to as acquired or cortical stuttering. Acquired stuttering involves hesitancy in producing initial phonemes, with an associated dysrhythmia of speech. Acquired stuttering clearly overlaps with apraxia of speech but may lack the other features of apraxia of speech discussed earlier in this chapter. Acquired stuttering has been described most often in patients with left
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APPROACH TO COMMON NEUROLOGICAL PROBI.F.MS
hemisphere cortical strokes {Franco et al. 2 0 0 0 ; T u r g u t , Utku, a n d Balci 2 0 0 2 ) , but t h e s y n d r o m e h a s also been reported with subcortical lesions including infarctions of the pons, basal ganglia, a n d subcortical white m a t t e r (Ciabarra ct al. 2 0 0 0 ) . Recurrence of c h i l d h o o d stuttering has been reported in patients with P a r k i n s o n ' s disease, suggesting involvement of the d o p a m i n e r g i c system (Shahcd a n d Jankovic2001).
PRIMARY PROGRESSIVE A N A R T H R I A A few cases have been described of progressive m o t o r speech difficulty, usually leading to complete m u t e n e s s . These cases a r e closely related to the s y n d r o m e of p r i m a r y progressive a p h a s i a (sec C h a p t e r 12A). M o s t such patients have a progressive language disorder, but a few h a v e had either dysarthria or a p r a x i a of speech (Tyrrell ct al. 1 9 9 1 ; Kertesz et al. 1994; C h a p m a n ct al. 1997), These cases h a v e all had lobar degeneration of the frontal c o r t e x , s o m e with involvement also of t h e t e m p o r a l a n d parietal lobes. T h e clinical diagnoses of these patients have included frontot e m p o r a l dementia or cortical basal ganglionic degeneration. We studied a patient w h o s e final p a t h o l o g y w a s m o s t consistent with multiple system a t r o p h y .
OPERCULAR S Y N D R O M E T h e opercular s y n d r o m e , also called F o i x - C h a v a n y - M a r i e s y n d r o m e , W o r s t e r - D r o u g h t s y n d r o m e , o r cheiro-oral s y n d r o m e (sensory disturbance in o n e h a n d a n d t h e ipsilateral otal corner) (Bakar, Kirshner, and Nia?. 1998), is a severe form of p s e u d o b u l b a r palsy in which p a t i e n t s with bilateral lesions of the pcrisylvian cortex or subcortical connections become completely m u t e . These patients can follow c o m m a n d s involving the extremities but not of t h e cranial nerves; for e x a m p l e , they m a y be unable to open or close their eyes or m o u t h or smile voluntarily, yet they smile w h e n amused, y a w n s p o n t a n e o u s l y , a n d even utter cries in response to emotional stimuli. The ability to follow limb c o m m a n d s s h o w s t h a t t h e disorder is n o t an a p h a s i c disorder of c o m p r e h e n s i o n . T h e discrepancy between a u t o m a t i c activation of the cranial m u s c u l a t u r e and inability to perform the s a m e a c t i o n s voluntarily h a s been called an automatic-voluntary dissociation. T h e s y n d r o m e is usually seen in patients with multiple strokes, b u t rare cases of progressive disease, as in the s y n d r o m e of p r i m a r y progressive a n a r t h r i a , m a y occur.
REFERENCES Alexander, M, P., Benson, D. F., Sc Stuss, D. 1989, "Frontal lobes and language," Brain Long, vol. 37, pp. 656-691 Alexander, M. P., Naeser, M. A., & Pa (umbo, D. 1990, "Broca's area aphasias: Aphasia after lesions including the frontal operculum," Neurology, vol. 40, pp. 353-362 Bakar, M., Kirshner, H. S., & Niaz, F. 1998, "The opercular subopercular syndrome: Four cases with review of the literature," Behav Neurol, vol. 1 1 , pp, 97-103 Chapman, S. B., Rosenberg, R. N., Werner, M. F., & Shobe, A. 1997, "Autosomal dominant progressive syndrome of motor-speech loss without dementia," Neurology, vol. 49, pp. 1298-1306 Ciabarra, A. M., Elkind, M. S., Roberts, J. K., & Marshall, R. S. 2000, "Subcortical infarction resulting in acquired stuttering," J Neurol Neurosurg Psychiatry, vol. 69, pp. 546-549 Dronkers, N. F. 1996, "A new brain region for coordinating speech articulation," Nature, vol. 384, pp. 159-161 Duffy, J. R. 1995, Motor Speech Disorders: Substrates, Differential Diagnosis, and Management, Mosby, St. Louis Epstein, C. M., Mcador, K. j . , Loring, D. W., et al. 1999, "Localization and characterization of speech arrest during transcranial magnetic stimulation," Clin Neurophysioi, vol. I 10, pp. 1073-1079 Franco, E., Casado, J. L., Lopez Dominguez, J. M., et al. 2000, "Stuttering as the only manifestation of a cerebral infarct," Neurologia, vol. 15, pp. 414-416 Kertesz, A., Hudson, L., Mackenzie, i. R. A., &: Munoz, D. G. 1994, "The pathology and nosology of primary progressive aphasia," Neurology, vol. 44, pp. 2065-7202 Kurowski, K. M., Blumstein, S. E., & Alexander, M. 1996, "The foreign accent syndrome: A reconsideration," Brain Lang, vol. 54, pp. 1-25 Liotti, M., Ramig, L. O,, Vogel, D,, et al. 2003, "Hypophonia in Parkinson's disease. Neural correlates of voice treatment revealed by PET," Neurology, vol. 60, pp. 432-440 Riecker, A., Ackermann, H., Wildgruher, D., et al. 2000, "Articulatory/phonctic sequencing at the level of the anterior pcrisylvian cortex: A functional magnetic resonance imaging (fMRI) study," Brain Lang, vol. 75, pp. 259-276 Shahed, J. & Jankovic, J, 2001, "Re-cmcrgcncc of childhood stuttering in Parkinson's disease: A hypothesis," Mov Disord, vol. 16, pp. 114-118 Takayama, Y., Sugishita, M., Kido, T., et al. 1993, "A case of foreign accent syndrome without aphasia caused by a lesion of the left precentral gyrus," Neurology, vol. 4 3 , pp. 1361-1363 Turgut, N., Utku, U., & Balci, K. 2002, "A case of acquired stuttering resulting from left parietal infarction," Acta Neurol Scand, vol. 105, pp. 408-410 Tyrrell, P. J., Kartsounis, L. D., Frackowiak, R. S. J., et al. 1991, "Progressive loss of speech output and orofacial dyspraxia associated with frontal lobe hypometabolism," } Neurol Ncnrosurg Psychiatry, vol. 54, pp. 351-357 Wertz, R. T., LaPointe, L. I.., & Rosenbck, J. C. 1991, Apraxia of Speech in Adults: The Disorder and Its Management, Singular Publishing Group, San Diego
Chapter 13 Neurogenic Dysphagia Ronald F. Pfeiffer Normal Swallowing Neurophysiology of Swallowing Mechanical Dysphagia Neuromuscular Dysphagia Oculopharyngeal Muscular Dystrophy Myotonic Dystrophy Other Muscular Dystrophies Inflammatory Myopathics Mitochondrial Disorders Myasthenia Gravis
165 166 166 166 166 167 168 168 168 168
Swallowing is like a wristwarcb. It appears, at first glance, to be a simple, even mundane, mechanism but under the unassuming face is a process that is both tremendously complex and fascinating. When operating properly, it functions unobtrusively and is afforded scant attention. Malfunction can go completely unnoticed for a time, but when it finally becomes manifest, serious, and sometimes catastrophic, consequences can ensue. Impaired swallowing, or dysphagia, can originate from disturbances in the mouth, pharynx, or esophagus and can involve mechanical, musculoskeletal, or neurogenic mechanisms. Although mechanical dysphagia is an important topic, this chapter primarily focuses on neuromuscular and neurogenic causes of dysphagia because processes in these categories are what the neurologist is most likely to encounter. Dysphagia is actually a quite common problem in neurological patients and can occur in a broad array of neurological or neuromuscular conditions. It has been estimated that neurogenic dysphagia develops in approximately 400,000-800,000 people per year (Robbins 1999) and that dysphagia is present in roughly 5 0 % of inhabitants of long-term care units (Lin et al. 2002). Moreover, dysphagia can lead to superimposed problems such as inadequate nutrition, dehydration, recurrent upper respiratory tract infections, and frank aspiration with consequent pneumonia and even asphyxia. It thus constitutes a formidable and common problem confronting the neurologist in everyday practice.
NORMAL SWALLOWING Swallowing is a surprisingly complicated and intricate phenomenon, comprising a mixture of voluntary and reflex
Neurogenic Dysphagia Stroke Multiple Sclerosis Parkinson's Disease Other Basal Ganglia Disorders Brainstem Processes Cranial Neuropathies Evaluation of Dysphagia Conclusion
169 169 170 171 171 172 172 173 174
or automatic actions that arc engineered and carried out by a combination of 26 pairs of pharyngeal and laryngeal muscles (not counting muscles used for chewing) and 5 cranial nerves that in turn receive directions from centers within the central nervous system (Wuttge-Hanning and Hannig 1995). Reflex swallowing is coordinated and carried out at the brainstem level, where centers act directly on information received from sensory structures within the oropharynx and esophagus. Volitional swallowing is not surprisingly accompanied by additional activity that originates not only in motor and sensory cortices, but also in other cerebral structures (Hamdy et al. 1999; Zald and Pardo 1999). The process of swallowing can conveniently be broken down into three distinct stages or phases: oral, pharyngeal, and esophageal. These components have also been distilled into what have been termed the horizontal and vertical subsystems, reflecting the direction of bolus flow in each component (when the individual is upright when swallowing). The oral phase of swallowing comprises the horizontal subsystem and is largely volitional in character, whereas the pharyngeal and esophageal phases comprise the vertical subsystem and are primarily under reflex control. In the oral, or swallow preparatory, phase food is taken into the mouth and if needed is chewed; saliva is secreted to provide both lubrication and the initial "dose" of digestive enxymes, and the food bolus is formed and shaped by die tongue. The tongue then propels the bolus backward to the pharyngeal inlet where, in a piston-like action, it delivers the bolus into the pharynx. This in turn initiates the pharyngeal phase in which a cascade of intricate, extremely rapid, and exquisitely coordinated movements seal off the nasal passages and protect the trachea while the cricopharyngeal muscle, which functions as the upper esophageal sphincter (UES), relaxes and allows the bolus to enter the ifri
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pharynx. As an example of the intricacy of movements during this phase of swallowing, the UES, prompted in part by traction produced by elevation of the larynx, actually relaxes just before arrival of the food bolus, creating suction that assists in guiding the bolus into the pharynx. The bolus then enters the esophagus where peristaltic contractions usher it distally and, upon relaxation of the lower esophageal sphincter, into the stomach.
the nucleus ambiguus and the dorsal motor nucleus of the vagus, which directly control motor output to the pharyngeal musculature and proximal esophagus. It has thus become evident that a large network of structures participates in the act of swallowing, especially volitional swallowing. The presence of this network presumably accounts for the broad array of neurological disease processes that can produce dysphagia as a part of their clinical picture.
NEUROPHYSIOLOGY OF SWALLOWING MECHANICAL DYSPHAGIA Central control of swallowing has traditionally been ascribed to brainstem structures, with cortical supervision and modulation emanating from the inferior precentral gyrus. However, recent positron emission tomography (PET) (Zald and Pardo 1999) and transcranial magnetic stimulation (TMS) (Hamdy et al. 1996) studies of volitional swallowing reveal a considerably more complex picture in which a broad network of brain regions are active in the control and execution of swallowing. It is, perhaps, not surprising that the strongest activation in PET studies of volitional swallowing docs occur in the lateral motor cortex within the inferior precentral gyrus, wherein lie the cortical representations of tongue and face (Hamdy et al. 1999; Zald and Pardo 1999), There is disagreement among investigators, however, in that some have noted bilaterally symmetrical activation of the lateral motor cortex (Zald and Pardo 1999), whereas others have noted a distinctly asymmetrical activation, at least in a portion of subjects tested (Hamdy et al. 1999). Some additional, and perhaps somewhat surprising, brain areas arc also activated during volitional swallowing (Hamdy et al. 1999; Zald and Pardo 1999). The supplementary motor area may play a role in preparation for volitional swallowing and the anterior cingulate cortex may be involved with monitoring autonomic and vegetative functions. Another area of activation during volitional swallowing is the anterior insula, particularly on the right. It has been suggested that this activation may provide the substrate that allows gustatory and other intraoral sensations to modulate swallowing. PET studies also consistently demonstrate distinctly asymmetrical, left-sided activation of the cerebellum during swallowing. This activation may reflect cerebellar input concerning coordination, timing, and sequencing of swallowing. Activation of putamen has also been noted during volitional swallowing, but it has not been possible to differentiate this activation from that seen with tongue movement alone. Within the brainstem, swallowing appears to be regulated by central pattern generators that contain the programs directing the sequential movements of the various muscles involved with swallowing. These pattern generators reside in the medial reticular formation of the rostral medulla and the reticulum adjacent to the nucleus tractus soiitarius (Hunter et al. 1997). These centers then project to
Structural abnormalities, both within and adjacent to the mouth, pharynx, and esophagus, can interfere with swallowing on a strictly mechanical basis, despite fully intact and functioning nervous and musculoskeletal systems (Table 13.1). Within the mouth macroglossia., temporomandibular joint dislocation, certain congenital anomalies, and intraoral tumors can impede effective swallowing and produce mechanical dysphagia. Pharyngeal function can be compromised by processes such as retropharyngeal tumor or abscess, cervical anterior osteophyte formation, Zenker's diverticulum, or thyroid gland enlargement. An even broader array of structural lesions can interfere with esophageal function, including malignant or benign esophageal tumors, metastatic carcinoma, esophageal stricture from numerous causes, vascular abnormalities such as aortic aneurysm or aberrant origin of the subclavian artery, or even primary gastric abnormalities such as hiatal hernia. Gastroesophageal reflux can also produce dysphagia. Individuals with these problems, however, are more likely to wind up in the hands of a gastrocntcrologist rather than a neurologist.
NEUROMUSCULAR DYSPHAGIA A variety of neuromuscular disease processes of diverse etiology can involve the oropharyngeal and esophageal musculature and produce dysphagia as part of their broader neuromuscular clinical picture (Table 13.2). Certain muscular dystrophies, inflammatory myopathies, and mitochondrial myopathies all can display dysphagia, as can disease processes affecting the myoneural junction, such as myasthenia gravis.
Oculopharyngeal Muscular Dystrophy Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant disorder that is most frequently encountered in individuals with a French Canadian ethnic background. It is the consequence of a GCG trinucleotide repeat expansion in the poly{A)-binding protein nuclear 1 gene (also called poly |A]-binding protein 2, or PABP2,
NEUROGENIC DYSPHAGIA Table 13.1:
Mechanical dysphagia
Oral Amyloidosis Congenital abnormalities Intraoral tumors Lip injuries Burns Trauma Macroglossia Scleroderma Temporomandibular joint dysfunction Xerostomia Sjogren's syndrome Pharyngeal Cervical anterior osteophytes Infection Diphtheria Thyromegaly Retropharyngeal abscess Rctrophatyngeal tumor Zenker's diverticulum Esophageal Aberrant origin of right subclavian artery Caustic injury Esophageal carcinoma Esophageal diverticulum Esophageal infection Candida albicans Herpes simplex virus Cytomegalovirus Varicella-zoster virus Esophageal intramural pseudodiverticula Esophageal stricture Esophageal ulceration Esophageal webs or rings Gasttoesophageal reflux disease Hiatal hernia Metastatic carcinoma Posterior mediastinal mass Thoracic aortic aneurysm
gene) on chromosome 14 (Hill et al. 2001). OPMD is unique among the muscular dystrophies because of its appearance in older individuals, with symptoms typically first appearing between ages 40 and 60 years (Brais et al. 1999). It is characterized by slowly progressive ptosis, dysphagia, and proximal limb weakness. Because of the ptosis, patients with OPMD may assume an unusual posture characterized by raised eyebrows and extended neck. Dysphagia in OPMD is due to impaired function of the oropharyngeal musculature. Although ir evolves slowly over many years, OPMD can eventually result not only in difficulty or discomfort with swallowing, but also in weight loss, malnutrition, and aspiration (Christopher et al. 2001). No specific treatment for the muscular dystrophy itself is available, but cricopharyngeal myotomy affords dysphagia relief in more than 80% of treated individuals (Fradet et al.
Table 13.2:
167
Neuromuscular dysphagia
Oropharyngeal Inflammatory myopathies Detmatomyositis Inclusion body myositis Polymyositis Mitochondrial myopathics K earns- Say re syndrome Mitochonilriiil lk'nro^istrointi-stinal eiicephalomyopnthy Muscular dystrophies Due hen tie's Facioscapulohumeral Limb-girdle Myotonic Oculopharyngeal Neuromuscular junction disorders Botulism Lambert-Eaton syndrome Myasthenia gravis Tetanus Scleroderma Stiff-man syndrome Esophageal Amyloidosis Inrl.imiii.itory myopathics Derma tomy os itis Polymyositis Scleroderma
1997). More recently, botulinum toxin injections have been successfully used to treat dysphagia in OPMD (Restivo et al. 2000).
Myotonic Dystrophy Myotonic dystrophy is an autosomal dominant disorder whose phenotypic picture includes not only skeletal muscle, but also cardiac, ophthalmologic^!, and endocrinological involvement. Mutations at two distinct locations have now been associated with the clinical picture of myotonic dystrophy. Type 1 myotonic dystrophy is due to a CTG expansion in the DMPK gene on chromosome 19, whereas type 2 is the consequence of a CCTG repeat expansion in the ZNF9 gene on chromosome 3 (Ranum and Day 2002). Gastrointestinal (GI) symptoms develop in more than 5 0 % of individuals with the clinical phenotype of myotonic dystrophy and may be the most disabling component of the disorder in 2 5 % . GI symptoms may actually antedate the appearance of other neuromuscular features. Subjective dysphagia is one of the most prevalent GI features and has been repotted to be present in 3 7 - 5 6 % of patients (Fate-kin et al. 2001). Coughing when eating, suggestive of aspiration, may occur in 3 3 % . Objective measures paint a picture of even more pervasive impairment, demonstrating disturbances in swallowing in 7 0 - 8 0 % of persons with myotonic dystrophy (Errekin et al. 2001). In one study,
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7 5 % of patients asymptomatic for dysphagia were still noted to have abnormalities on objective testing. A variety of abnormalities in objective measures of swallowing have been documented in myotonic dystrophy. Abnormal cricopharyngeal muscle activity is present in 4 0 % of patients during electromyographic (EMG) testing (Ertekin ct al. 2001). Impaired esophageal peristalsis has also been noted in affected individuals studied with esophageal manometry. In vidcofluoroscopic testing, incomplete relaxation of the UES and esophageal hypotonia are the most frequently noted abnormalities. Both muscle weakness and myotonia are felt to play a role in the development of dysphagia in persons with myotonic dystrophy, and in at least one study, a correlation was noted between the size of the CTG repeat expansion and the number of radiologic abnormalities in myotonic patients.
Other Muscular Dystrophies Although less well characterised, dysphagia also occurs in other types of muscular dystrophy. Difficulty swallowing and choking while eating occur with increased frequency in children with Duchenne's muscular dystrophy. Dysphagia has also been documented in patients with limb-girdle dystrophy and facioscapulohumeral muscular dystrophy (Williget al. 1994).
Inflammatory Myopathies Dermatomyositis and polymyositis arc the most commonly occurring of the inflammatory myopathic disorders. Both are characterized by progressive, usually symmetrical, weakness affecting proximal muscles more prominently than distal. Fatigue and myalgia may also occur. Malignant disease is associated with the disorder in 1 0 - 1 5 % of patients with dermatomyositis and 5-10% of those with polymyositis. In individuals older than 65 years, more than 50% are found to have cancer. Although dysphagia can develop in both conditions, it more frequently is ptesent, and when present more severe, in dermatomyositis. Dysphagia is present in 2 0 - 5 5 % of individuals with dermatomyositis, but in only 18% with polymyositis (Parodi et al. 2002). It is the consequence of involvement of striated muscle in the pharynx and proximal esophagus. Involvement of pharyngeal and esophageal musculature in polymyositis and dermatomyositis is an indicator of poor prognosis and can be the source of significant morbidity (Marie et al. 1999). The resulting dysphagia can be severe enough to require enteral feeding. Acute total obstruction by the cricopharyngeal muscle has been reported in dermatomyositis, necessitating cricopharyngeal myotomy. Dysphagia in both conditions may respond to corticosteroids, and intravenous immune
globulin (IVIG) therapy has produced dramatic improvement in dysphagia in individuals who were unresponsive to steroids (Marie et al. 1999). Although dysphagia develops less often in inclusion body myositis, it can occur. In fact, in a group of individuals in whom inclusion body myositis mimicked and was confused with motor neuron disease, dysphagia was present in 4 4 % . A focal inflammatory myopathy involving the pharyngeal muscles and producing isolated pharyngeal dysphagia has also been described in elderly individuals older than 69 years. It has been suggested that this is a distinct clinical entity characterized by cricopharyngeal hypertrophy, although polymyositis localized to the pharyngeal musculature has also been reported.
Mitochondrial Disorders The mitochondrial disorders are a family of diseases that develop as a consequence of dysfunction in the mitochondrial respiratory chain. Most are the result of mutations in mitochondrial deoxyribonucleic acid (DNA) genes, but nuclear DNA mutations may be responsible in some. Mitochondrial disorders are by nature multisystemic, but myopathic and neurological features often predominate and symptoms may vaty widely, even between individuals within the same family. In addition to the classic constellation of symptoms that include progressive external ophthalmoplegia, retinitis pigmentosa, cardiac conduction defects, and ataxia, individuals with Kcarns-Sayre syndrome may also develop dysphagia (Katsanos et al. 2001, 2002; Kornblum et al. 2001). Severe abnormalities of pharyngeal and upper esophageal peristalsis have been documented in this disorder. Cricopharyngeal dysfunction is common, but impaired deglutitive coordination may also develop (Kornblum et al. 2001). Dysphagia has also been described in other mitochondrial disorders, but descriptions are only anecdotal and formal study has not been undertaken.
Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune disorder characterized by the production of autoantibodies directed against the postsynaptic i/| muscle nicotinic acetylcholine receptors at the neuromuscular junction, with destruction of the receptors and reduction in their number. The clinical consequence of this process is the development of fatigable muscle weakness that progressively increases with repetitive muscle action and improves with rest. MG occurs more often in women than men, and although symptoms can develop at any age, the reported mean age at onset in women is 2 8 - 3 5 years and in men 42—49 years (Kalb et al. 2002). Although myasthenic symptoms tcmain confined to the extraocular muscles in about 2 0 % of
NKUROCKMC DYSPHAGIA
patients, in most individuals more widespread muscle weakness becomes evident (Kalb et al. 2002; Wirtz et al. 2002). Involvement of bulbar musculature, with resultant dysphagia, is relatively common in MG. In approximately 6-30% of patients, bulbar involvement is evident from the beginning (Wirtz et al. 2002), but most patients eventually develop bulbar symptoms such as dysphagia and dysarthria as the disease progresses. Dysphagia in MG can be due to dysfunction at oral, pharyngeal, or even esophageal levels. Oral phase involvement can be due to fatigue and weakness of the tongue or masticatory muscles. In patients with MG who have bulbar symptoms, repetitive nerve stimulation studies of the hypoglossal nerve have demonstrated abnormalities (Lo et al. 2002), whereas studies using EMG of the masticatory muscles recorded while chewing have also revealed impaired performance (Weijnen et al. 2002). Pharyngeal dysfunction is also common in patients with MG who have dysphagia, as demonstrated with videofluoroscopy. Aspiration, often silent, may be present in 3 5 % or more of these individuals (Colron-Hudson ct al. 2002); in elderly patients, the frequency of aspiration may be considerably higher. Motor dysfunction involving the striated muscle of the proximal esophagus has also been documented in MG. In one study, 9 6 % of patients with MG demonstrated abnormalities, such as decreased amplitude and prolongation of the peristaltic wave, in this region on testing with esophageal manometry. Cricopharyngeal sphincter pressure was also noted to be reduced.
NEUROGENIC DYSPHAGIA A variety of disease processes originating in the central and peripheral nervous systems can also disrupt swallowing mechanisms and produce dysphagia. Processes affecting cerebral cortex, subcortical white matter, subcortical gray matter, brainstem, spinal cord, and peripheral nerves can elicit dysphagia as a component of their clinical picture (Table 13.3).
Stroke Cerebrovascular disease is an extremely common neurological problem and stroke is the third leading cause of death in the United States, It has been estimated that 500,000-750,000 strokes occur in the United States each year and that approximately 150,000 persons die following stroke annually. The mechanism of stroke is ischemic in 8 0 - 8 5 % of cases, and in the remaining 15-20%, it is hemorrhagic (Shah and Biller 1998). Approximately 2 5 % of ischemic strokes are due to small-vessel disease, 5 0 % to large-vessel disease, and 2 5 % to a cardioembolic source. Although stroke can occur at all ages, 7 5 % of strokes occur in individuals older than 75 years.
Table 13.3:
169
Neurogenic dysphagia
Oropharyngeal Arnold-Chiari malformation Basal ganglia disease Biotin responsive Corticobasal degeneration Dementia with Lewy bodies Huntington's disease Multiple system atrophy Ne u ro aca n t h oc y to s is P.)rkiiiM>n\ J : v ; u c
Progressive supranuclear palsy Wilson's disease Central pontine myelinolysis Cerebral palsy Drug related Cyclosporin Tardive dyskinesia Vincristine Infectious Brainstem encephalitis listeria Epstein-Barr virus Diphtheria Poliomyelitis Progressive multifocal leu ^encephalopathy Rabies Mass lesions Abscess Hemorrhage Metastatic tumor Primary tumor Motor neuron diseases Amyotrophic lateral sclerosis Multiple sclerosis Peripheral neuropathic processes Chareot-Marie-Tooth disease Guillain-Barre syndrome (Miller Fisher's variant) Spinocerebellar ataxias Stroke Syringobulbia Esophageal Achalasia Autonomic neuropathies Diabetes mellitus Familial dysautonomia Paraneoplastic syndromes Basal ganglia disorders Parkinson's disease Chagas' disease Esophageal motility disorders Scleroderma
Dysphagia develops in 4 5 - 5 1 % of individuals following stroke and its presence is associated with increased likelihood of severe disability or death (Lawrence et al. 2001; Mann, Hankey, and Cameron 2000). Aspiration is the most widely recognized complication of dysphagia following stroke, but undernourishment and even malnutrition occur with surprising frequency (Ullman and
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Reding 1996). Reported frequencies of nutritional deficits in patients with dysphagia following stroke range from 4 8 - 6 5 % . The presence of dysphagia following stroke has been noted as an independent risk factor for severe disability and death (Sharma et al. 2001). Although it is commonly perceived that the presence of dysphagia following stroke indicates a brainstem localization for the stroke, this is not necessarily so. Impaired swallowing has been documented in a significant proportion of strokes involving cortical and subcortical structures. The pharyngeal phase of swallowing is primarily impaired in brainstem infarction, whereas in hemispheric strokes, the most striking abnormality often is a delay in initiation of voluntary swallowing (Aydogdu et al. 2001). Dysphagia has been reported as the sole manifestation of infarction in both the medulla and the cerebrum (Celifarco er al. 1990). Approximately 5 0 - 5 5 % of patients with lesions in the posteroinferior cerebellar artery distribution, with consequent lateral medullary infarction (Wallenberg's syndrome:, develop dysphagia (Tcasell et al, 2002). The fact that unilateral medullary infarction can produce bilateral disruption of the brainstem swallowing centers suggests that they function as one integrated center (Vigderman et al. 1998). Infarction in the distribution of the anteroinferior cerebellar artery can also result in dysphagia. Following stroke within the cerebral hemispheres, dysphagia can develop by virtue of damage to either cortical or subcortical structures involved with volitional swallowing. Bilateral hemispheric damage is more likely to produce dysphagia, hut it can also occur in the setting of unilateral damage. Infarction of the frontoparietal operculum bilaterally may result in the anterior operculum (Maric-Foix-Chavany) syndrome, which is characterized by inability to perform voluntary movements of the face, jaw, tongue, and pharynx with fully preserved involuntary movements of the same muscles (Billith, Jorgler, and Baumhackl 2000). Impairment of volitional swallowing may be a component of this syndrome. Individuals with subcortical strokes have a higher incidence of dysphagia and aspiration than those with cortical damage. In one study, more than 8 5 % of individuals with unilateral subcortical strokes demonstrated videofluoroscopic evidence of delayed initiation of the pharyngeal stage of swallowing, and in 7 5 % , some radiographic aspiration was noted. Although tongue deviation is classically associated with medullary lesions damaging the hypoglossal nucleus, it has also been documented in almost 3 0 % of persons with hemispheric infarctions (Umapathi et al. 2000). When present in hemispheric stroke, tongue deviation is always associated with facial weakness and dysphagia is present in 4 3 % of affected patients. Aspiration is a potentially life-threatening complication of stroke. Studies have documented its occurrence in 3 0 - 5 5 % of stroke patients (Teasell et al. 2002). In one study, videofluoroscopic evidence of aspiration was
observed in 3 6 % of patients with unilateral cerebral stroke, 4 6 % with bilateral cerebral stroke, 6 0 % with unilateral brainstem stroke, and SO",, with bilateral brainstem lesions. Other studies have suggested that the incidence of aspiration in brainstem strokes may be considerably higher— more than 80%—and that subcortical strokes may result in aspiration in 7 5 % of cases (Horner et al. 1991). The risk of developing pneumonia is almost seven times greater in persons experiencing aspiration post-stroke compared with those who do not (Holas, Del'ippo, and Reding 1994). Individuals in whom aspiration occurs post-stroke do not always experience clinical symptoms such as coughing or choking during food or liquid ingestion. Furthermore, an absent gag reflex does not help differentiate those aspirating from those who are not. Therefore the employment of objective testing measures to detect the presence and predict the risk of aspiration has been advocated. Modified barium swallow (MBS) testing using vidcofluoroscopy is the gold standard to do this, but simple bedside techniques, such as a water swallowing test, have also been advocated as practical, though somewhat less sensitive, alternatives ( M a r i e t a l . 1997), Swallowing often improves spontaneously in the days and weeks following stroke. Tube feeding can temporarily provide adequate nutrition and buy time until swallowing improves sufficiently to allow oral feeding but does entail some risks itself, such as increasing the possibility of reflux wirh consequent aspiration. Various methods of behavioral swallow therapy can be useful in managing persistent poststroke dysphagia, but in a small percentage of individuals, placement of a percutaneous endoscopic gastrostomy (PEG) will be necessary. Dysphagia can also develop in the setting of various other cerebrovascular processes. Within the anterior circulation, dysphagia has been reported with carotid artery aneurysms, and within the posterior circulation, processes such as elongation and dilatation of the basilar artery, posterior inferior cerebellar artery aneurysm, intracranial vertebral artery dissections, and cavernous malformations within the medulla may produce dysphagia in addition to other symptoms.
Multiple Sclerosis Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that primarily, though not exclusively, affects young adults. The mean age at onset is approximately 30 years. In its most common guise, MS is characterized by exacerbations and remissions, although some individuals may follow a chronic progressive course right from the start. The etiology of MS is uncertain, but an autoimmune process is suspected. Dysphagia is a common, but often overlooked, problem in MS (Wiesncr et al. 2002). Survey studies have indicated the presence of dysphagia in 2 4 - 3 4 % of individuals with
NEUROGENIC DYSPHAGIA MS (Hartelius and Svcnsson 1994; Calcagno et al. 2002). The prevalence of dysphagia in MS rises with increasing disability, reaching 65% in the most severely affected (De Pauw et al. 2002). Individuals with scvcte brainstem involvement as parr of their MS are especially likely to experience dysphagia (Thomas and Wiles 1999). Objective studies demonstrate a somewhat higher frequency of dysphagia than their survey study counterparts. In fact, in such studies, approximately 5 0 % of individuals with ob]ective abnormalities were not aware of any difficulty swallowing (Thomas and Wiles 1999), Abnormalities in oral, pharyngeal, and even esophageal phases of swallowing have been documented. Rare instances of the anterior operculum syndrome, with buccolingual facial apraxia, have been reported in MS. Abnotmalities in the oral phase of swallowing are common in patients with MS who have mild disability, but additional pharyngeal phase abnormalities develop in those with more severe disability. Disturbances in both the sequencing of laryngeal events and the functioning of the pharyngeal constrictor muscles are typically present in persons experiencing dysphagia. Pharyngeal sensory impairment may also play a role in the development of dysphagia in some patients (Groher 1996).
Parkinson's Disease Parkinson's disease (I'D) is a neurodegenerative disorder m which symptoms typically emerge between the ages of 55 and 65 years. Although the most prominent neuropathology in PD involves the pigmented dopaminergic neurons in the substantia nigra, neuronal loss in other areas of the nervous system, including wirhin the enteric nervous system, has also been documented. Dysphagia was first documented in PD by James Patkinson himself in his original description of the illness in 1817 (Parkinson 1817). Recent survey studies have confirmed that dysphagia is indeed a common phenomenon in PD. Reported frequencies of dysphagia in these studies range from 3 0 - 8 2 % (Edwards et al. 1991; Clarke et al. 1998), with the broad range probably reflecting differences in the detail within the questionnaires. Objective testing indicates an even higher frequency of dysphagia in PD and has allowed its separation into two categories, oropharyngeal and esophageal (Pfeiffer 2003). Studies using MBS testing have demonstrated some abnormality in the oropharyngeal phase of swallowing in 7 5 - 9 7 % of persons with PD (Fuh et al. 1997; Leopold and Kagel 1997). Even individuals asymptomatic for dysphagia frequently display abnormalities on MBS testing. Within the oral phase, difficulty with bolus formation, delayed initiation of swallowing, repeated tongue pumping, and other abnormalities have been described (Nagaya et al. 1998), although pharyngeal dysmotility and impaired relaxation of the cricopharyngeal muscle constitute examples
171
of abnormalities noted in the pharyngeal phase (Byrne, Pfeiffer, and Quigley 1994; Ali et al. 1996; Pfeiffer 2003). Esophageal dysfunction can also trigger dysphagia in PD. Studies using esophageal manometry have demonstrated abnormalities in 6 1 - 7 3 % of patients with PD (Bassotti et al. 1998), and videofluoroscopic studies show a broader range with some abnormality reported in 5-86% of individuals (Stroudley and Walsh 1991; Edwards et al. 1994; Leopold and Kagel 1997). A wide variety of abnormalities of esophageal function have been described, including slowed esophageal transit, both segmental and diffuse esophageal spasm, ineffective or tertiary contractions, and even aperistalsis. Lower esophageal sphincter dysfunction may also be present in PD and can produce symptoms of reflux and dysphagia. Aspirarion has been noted to be present in 15-56% of patients with PD (Robbins, Logemann, and Kirshner 1986; Stroudley and Walsh 1991; Ali et al. 1996; Nagaya et al. 1998), and completely silent aspiration in 1 5 - 3 3 % {Robbins, Logemann, and Kirshner 1986). Even more striking is a study in which vallecular residue, believed to indicate an incteased risk of aspiration, was found to be present in 8 8 % of patients with PD who do not have clinical dysphagia. Dysphagia demonstrates an inconsistent response to L-dopa or dopamine agonist therapy (Pfeiffer 2003). Objective improvement in swallowing, documented by MBS testing, has been observed in 3 3 - 5 0 % of patients in some, but not all, studies (Fuh et al. 1997; Hunter et al. 1997). In patients with cricopharyngeal muscle dysfunction, both cricopharyngeal myotomy (Born et al. 1996) and botulinum toxin injections (Restivo, Palmcri, and Marchese-Ragona 2002} have been used successfully. Behavioral swallowing therapy approaches are of benefit to some individuals. On rare occasions, PEG placement may be necessary.
Other Basal Ganglia Disorders In the parkinsonism-plus syndromes, such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB), dysphagia is a common problem and, in contrast to PD, often develops relatively early in the course of the illness (Litvan, Sastry, and Sonies 1997; Muller et al. 2001). Although the median latency to the development of dysphagia in PD is more than 130 months, it is 67 months in MSA, 64 months in CBD, 43 months in DLB, and 42 months in PSP (Muller et al. 2001). In fact, the appearance of dysphagia within 1 year of symptom onset virtually eliminates PD as a diagnostic possibility, although it does not help distinguish between the various parkinsonism-plus syndromes (Muller et al. 2001). Dysphagia can be a prominent problem in patients with Wilson's disease and is frequently a component of the
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
clinical picture in neuroacanthocytosis (Rampoldi, Danek, and Monaco 2002). A unique basal ganglia process characterized by the presence of subacute encephalopathy, dysarthria, dysphagia, rigidity, dystonia, and eventual quadriparesis has been shown to improve promptly and dramatically to biotin administration (Ozand et al. 1998), Dysphagia is also a well-documented complication of botulinum toxin injections for cervical dystonia, presumably as a consequence of diffusion of the toxin {Cornelia et al. 1992). It should be noted, however, that 1 1 % of patients with cervical dystonia experience dysphagia as parr of the disease process itself and 2 2 % may display abnormalities on objective testing (Cornelia et al. 1992). Amyotrophic
Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. It is characterized by progressive loss of motor neurons in the cortex, brainstem, and spinal cord, which results in a clinical picture of progressive weakness that combines features of both upper motor neuron dysfunction, with spasticity and hyper-reflexia, and lower moror neuron dysfunction, with atrophy, fasciculations, and hyporeflexia (Borasio and Miller 2001). The mean age at symptom onset is 54-58 years (Borasio and Miller 2001). Although dysphagia eventually develops in most individuals with ALS, bulbar symptoms can be the presenting feature in approximately 2 5 % of patients. A sensation of solid food sticking in the esophagus may provide the initial clue to emerging dysphagia, but abnormalities in the oral phase of swallowing are most often evident in patients with early ALS (Kawai et al. 2003). Impaired function of lips and tongue, particularly its posterior portion, due to evolving muscle weakness typically appears first, followed next by involvement of jaw and suprahyoid musculature and finally by weakness of pharyngeal and laryngeal muscles (Hillel and Miller 1989). Lip weakness can result in spillage of food from the mouth, whereas tongue weakness leads to impaired food bolus formation and transfer (Groher 1996). Inadequate mastication due to the jaw muscle weakness adds to the difficulty with bolus formation, and the eventual development of pharyngeal and laryngeal weakness opens the door for aspiration. Neurophysiologic testing in patients with ALS who have dysphagia demonstrates delay in and eventual abolishment of triggering of the swallowing reflex for voluntarily initiated swallows, with relative preservation of spontaneous reflexive swallows until the terminal stages of the disease (Ertekin et al. 2000). Spasm of the UES, with hyper-reflexia and hypertonicity of the cricopharyngeal muscle, has been reported in patients with ALS who have bulbar dysfunction, presumably as a consequence of upper motor neuron involvement, and has been considered an important cause of aspiration (Ertekin et al. 2000). This has prompted the employment of
cricopharyngeal myotomy as a treatment measure in such patients, but this approach should be limited to those with objectively demonstrated UES spasm. Control of oral secretions can be a difficult problem for patients with ALS. Because ^-adrenergic stimulation increases production of protein and mucus-rich secretions, which may thicken saliva and make it especially difficult for patients to handle, administration of beta blockers has been proposed to reduce thickness of oral, nasal, and pulmonary secretions. Surgical procedures to reduce salivary production, such as tympanic neurectomy and submandibular gland resection, have also been employed but not extensively studied. Behavioral therapy approaches can be useful in treating mild to moderate dysphagia in ALS. Alterations in food consistency (such as thickening liquids), swallowing compensation techniques and voluntary airway protection maneuvers all provide benefit and can be taught by speech/ swallowing therapists (Groher 1996). Eventually, however, enteral feeding becomes necessary in many individuals with advanced ALS. Placement of a PEG can stabilize weight loss, relieve nutritional deficiency, and improve quality of life for individuals with advanced ALS and severe dysphagia (Borasio, Voltz, and Miller 2 0 0 1 ; Chio et al. 1999; Kasarskis et al. 1999).
Brainstem Processes Any process damaging the brainstem swallowing centers or lower cranial nerve nuclei can lead to dysphagia. Therefore in addition to stroke and MS, a number of other processes affecting brainstem function may display dysphagia as part of their clinical picture. Brainstem tumors, both primary and metastatic, may be responsible for dysphagia, as can central pontine myelinolysis, progressive multifocal leukocncephalopathy, and leukoencephalopathy due to cyclosporin toxicity. Brainstem encephalitis, produced by organisms such as Listeria and Epstein-Barr virus (FolletBouhamed er al. 1999) may also result in dysphagia.
Cranial Neuropathies Pathological processes involving the lower cranial nerves can produce dysphagia, usually as a part of a broader clinical picture. Dysphagia can be prominent in the Miller Fisher variant of acute inflammatory demye I mating polyneuropathy (Guillain-Barre syndrome). Response to plasmapheresis is expected in this situation. Dysphagia may also be present in herpes-zoster infection, where it has been attributed to cranial ganglionic involvement. Examples of other processes from which cranial nerve involvement can result in dysphagia include Charcot-Marie-Tooth disease and primary or metastatic tumors involving the skull base. Severe, but reversible, dysphagia with significantly
NEUROGENIC DYSPHAGIA prolonged esophageal transit time has been attributed to vincristine therapy (Wang et al. 2000).
EVALUATION OF DYSPHAGIA Various diagnostic tests, ranging from simple bedside analysis to sophisticated tadiologic and neurophysiology procedures, have been developed to evaluate dysphagia (Logemann 1996). Although most are actually performed by specialists other than neurologists, it is important for neurologists to have an awareness of them so they can be employed when clinical citcumstanccs arc appropriate (Table 13.4). Clinical examination is somewhat limited because of the inaccessibility of some structures involved with swallowing, but both history and examination results can provide useful clues to localization and diagnosis (Table 13.5). Difficulty initiating swallowing or the need for repeated attempts to succeed at swallowing suggests an oropharyngeal source for the dysphagia, whereas a sensation of food "hanging u p " in a retrosternal location implicates esophageal dysfunction. Individuals who report dysphagia for solid food hut not liquids are more likely to have a mechanical obstruction, whereas dysphagia for both solids and liquids equally is more typical for an esophageal motility disorder. Lip and rongue function can be easily assessed during routine neurological examination, and both palatal and gag reflexes can be evaluated. Cervical auscultation is not widely used to evaluate swallowing but may be useful to assess coordination between respiration and swallowing (Table 13.6 and Figure 13.1) (Logemann 1996). In the normal situation, swallowing occurs during exhalation, which reduces the risk of aspiration. Dys-coordinatcd swallowing in the midst of inhalation, conversely, increases the possibility that food might be drawn into the tespiratory tract. Timed swallowing tests, which require repetitive swallowing of specific amounts of water, have also been employed in the evaluation of dysphagia. Individuals
Table 13.4:
Diagnostic tests
Oropharyngeal Clinical examination Cervical auscultation Timed swallowing tests 3-ounce water swallow test Modified barium swallow test Pharyngeal videoendoscopy Pharyngeal manometry Videomanofluorometry Electromyographic recording Esophageal Endoscopy Esophageal manometry Videofluoroscopy
Table 13.5:
173
Dysphagia clues
l)it(ii:iill\ iniliatini; swallowing Repetitive swallowing Retrosternal "hanging up" sensation Difficulty with solids, hut not liquids Difficulty with both solids and liquids Regurgitation of undigested food Halitosis
Oropharyngeal dysfunction Oropharyngeal dysfunction l;.snplia,nfLil dysfunction
Mechanical obstruction Esophageal dysmotility Zenker's diverticulum Zenker's diverticulum
with swallowing impairment may display a number of abnormalities, including slower swallowing speed (!iigiTiii,il or hired irarv Kallmann's syndrome S Albinism S I'iimiluil S
Developmental Facial hypoplasia T Other Idiopathic S Bell's palsy T Raeder's paratrigeminal neuralgia T Smoking S, T Dentures T Pregnancy S, T Inhaled toxic chemicals S Hydrocephalus, obstructive S Aging S, T, Ds High-altitude sickness T Ciguatera fish poisoning Td
*Also asymptomatic relatives. Ds = discrimination decreased for smells; GH = gustatory hallucination; OH = olfactory hallucination; P = parosmia; S = smell decreased or absent; T = taste decreased or absent; Td = taste distorted; Ti = taste increased,
removal of the parts of t h e orbitofrontal cortex t h a t receive projections from medial dorsal t h a l a m i c nucleus p r o d u c e s a c o m p a r a b l e deficit. In patients with P D , there is no correlation between degree of olfactory i m p a i r m e n t and age, d u r a t i o n of disease, disease severity, cognitive impairment, a n d d o p a m i n e r g i c or cholinergic t r e a t m e n t . H y p o s m i a in a s y m p t o m a t i c relatives of patients with PD suggests subclinical d o p a m i n e dysfunction (Bcrendse et al. 2 0 0 1 ) . N o r m a l olfactory function in progressive s u p r a n u c l e a r palsy a n d benign essential t r e m o r s u p p o r t s the distinctness of these disorders from PD, O t h e r studies in PD d e m o n strate a b n o r m a l olfactory evoked potentials a n d Lewy bodies on pathologic e x a m i n a t i o n of t h e olfactory b u l b ,
particularly in t h e anterior olfactory nucleus. As with i d i o p a t h i c P D , familial PD is also associated with olfactory i m p a i r m e n t , and [his heritable detect occurs independent of the p a r k i n s o n i a n p h e n o t y p e ( M a r k o p o u l o u et al. 1997). Significant neurofibrillary tangle f o r m a t i o n a n d cell loss in t h e a n t e r i o r olfactory nuclei occur in Alzheimer's disease, a l o n g w i t h reduced choline acety[transferase activity in the olfactory tubercle. Olfactory i m p a i r m e n t is also present in o t h e r n e u r o d e g e n e r a t i v e c o n d i t i o n s , such as m o t o r n e u r o n disease, Lewy b o d y disease, H u n t i n g t o n ' s c h o r e a , g r a n u l o m a t o u s angiitis of t h e central n e r v o u s system, i d i o p a t h i c midline g r a n u l o m a , W o l f r a m ' s s y n d r o m e , a n d h y p o g o n a d o t r o p i c h y p o g o n a d i s m {Kallmann's s y n d r o m e ) .
DISTURBANCES OF TASTE AND SMELL
Table 20.2;
Causes of smell disturbance
Cause
Patients affected (%)
Nasal or paranasal sinus disease Idiopathic Post-upper respiratory tract infection Head trauma Miscellaneous Postexposure (environmental toxins, noxious vapors, metals)
15 22 26 I8 I5 2
Dental
2
M f d i L i i l i o n induced
2
Source: Adapted with permission from Deems, D. A., Doty, R. L., Settle, R. G., et al. 1991, "Smell and taste disorders: A study of 750 patients from the University of Pennsylvania Smell and Taste Center," Arch Otolaryngol Head Neck Surg, vol. 117, pp. 519-528. In patients with reduced or no sense of smell since birth, there is absence or hypoplasia of olfactory bulbs and tracts on MRI; thus congenital anosmia or hypoplasia may be an olfactory bulb-olfactory tract phenomenon rather than a cerebral process (Yousem et al. 1996a). Olfactory dysfunction, reported in almost 4 0 % of patients with multiple sclerosis, correlated with the number of demyelinating plaques on MRI involving areas of olfaction in the inferior frontal and temporal lobe regions (Doty et al. 1997), An increased sense of smell, hyperosmia, is uncommon and may occur with depression and exposure to toxic vapors. Parosmia, the distortion of normal smell, may reflect an intracranial disease, such as a temporal lobe seizure or a tumor, olfactory bulb injury from rrauma, depression, or a local nasopharyngeal condition, such as sinusitis. Approximately 7 5 % of patients with parosmia have associated hyposmia or anosmia. Olfactory hallucinations occur in association with Alzheimer's disease, depression, schizophrenia, alcohol withdrawal, and uncinare seizures. In seizures, the olfactory auras are characteristically unpleasant or foul and rarely, if ever, appear as isolated epileptic events. One study, however, showed the olfactory sensation was unpleasant in only 7 of 13 patients; tumor was the most common etiology (10/13 patients), most likely involving the amygdala, with mesial temporal sclerosis a rare cause (Acharya V, Acharya J, and I.udcrs 1998). Cigarette smoking, a variety of drugs (both prescribed and recreational), radiation therapy, and hemodialysis, as well as environmental and industrial toxins, cause disturbances of smell (sec Table 20,2). Abnormalities of taste and smell may be an early manifestation of temporal arteritis.
TASTE In humans, the gustatory system is responsible for the perception of sweet, salty, bitter, and sour. Disturbances of
261
taste arc far less common than disturbances of smell. Although patients with chemosensory disorders often have complaints that food no longer has any taste, most such patients have olfactory dysfunction with normal taste. Disorders of taste are characterized as absence of taste (ageusia), diminished sensitivity (hypogeusia), increased sensitivity to some or all taste qualities (hypcrgeusia), distortion of normal taste (dysgeusia or parageusia), and gustatory hallucinations.
Pathophysiology Gustatory receptor cells are clustered in taste buds, which are located in the papillae on the surface of the tongue and, to a lesser extent, at the back of the mouth and pharynx. Taste buds are innervated by sensory fibers of the chorda tympani and greater superficial petrosal bundles of the facial nerve, the glossopharyngeal nerve, and the superior laryngeal branch of the vagus nerve. Receptor cells have a limited life span and undergo constant replacement. Unlike the olfactory system, taste receptor cells lack axons; thus their replacement does not involve regenerative processes within the nervous system. Taste afferent fibers from the anterior two thirds of the tongue course through the lingual nerve, a branch of the trigeminal nerve, which they leave via the chorda tympani to join the facial nerve as the nervus intermedius with cell bodies in the geniculare ganglion. The posterior one third of the tongue, pharynx, and soft palate are subserved by taste fibers in the glossopharyngeal nerve; the cell bodies lie in the nodose ganglion. Gustatory nerve fibers from the facial, glossopharyngeal, and vagus nerves terminate in the brainstem in the ipsilareral nucleus of the solitary tract. The central pathway from this nucleus projects via the parvocellular division of the ventral posterior medial nucleus and then via the posterior limb of the internal capsule to the frontal operculum and the anterior insular cortex. Studies of cerebral blood flow in humans (Small et al. 1997) and single-unit activity in monkeys indicate a secondary gustatory area in caudal orbitofrontal cortex. Damage to these central pathways may explain why temporal lobectomies affect the ability to recognize tastes without affecting taste detection. There may be an alternative or accessory taste pathway through the trigeminal nerve. This is supported by abnormal electrogustometric detection thresholds in patients with trigeminal neuralgia and trigeminal sensory neuropathy, with a further moderate but significant threshold increase after surgical treatment. Gustatory responses depend on the adaptive state of the tongue. For example, if the tongue is exposed (i.e., adapted) to a variety of substances, water itself becomes capable of evoking tastes (the so-called water taste). This phenomenon has important clinical implications in conditions associated with changes in the rate of flow or composition of saliva.
262
APPROACH TO COMMON M-UROI.OGICAT. PRORI.F.MS
These can be affected by food or drug consumption; diseases affecting salivary secretions, such as cystic fibrosis, Sjogren's syndrome, Cushing's disease, or Addison's disease; destruction of salivary tissue by irradiation; or periodontal conditions that add gustatory stimulants to the fluid bathing the tongue. In all cases of dysgeusia or parageusia, it is important to rule our conditions affecting salivary fluids before considering less common causes ot altered taste perception.
Clinical Evaluation of Taste Patients presenting with a disturbance of taste should be asked about any associated disorder of smell; any preexisting medical conditions and their treatment, such as ear infection, ear surgery, Bell's palsy, significant head injury, or tracheal intubation; recent upper respiratory tract illness; dental procedures or prostheses; and a detailed drug history. In addition to a physical examination and testing of taste and smell, special attention should be paid to the oral cavity for evidence of infection, inflammation, degeneration, and masses, as well as atrophy and dryness of tongue, gums, dentition, and surrounding mucous membranes. Specific investigations are ordered to identify suspected causative considerations suggested by the clinical features. If no local cause is suggested, patients with taste abnormalities, particularly unilateral, should have audiologic evaluation and imaging studies to include the middle ear. The sense of taste can be tested with natural stimuli, such as aqueous solutions of sugar, sodium chloride, acetic acid, and quinine, or with electrical stimulation of the tongue (clectrogustometry). A cotton applicator is used to rub the aqueous solution gently on one quadrant of the protruded tongue. The patient should not talk but should identify the perceived taste by pointing to cards printed with the words sweet, salt, sour, and bitter. The mouth is rinsed with water between tests. Elecrrogtistometry is the evaluation of taste by applying graded electrical currents to the tongue to produce a sensation described as sour or metallic. In normal subjects, the two sides of the tongue have similar thresholds for electrical stimulation, rarely differing by more than 2 5 % . The technique has the advantages of simplicity, speed, and case of quantification and is capable of providing a reliable objective recording of the gustatory detection threshold.
Disease Entities Although the cause of most cases of hypogeusia is unknown, the two most common are nasal disorders and a prior respiratory tract infection. Disturbances of taste may result from local disorders involving the tongue, taste
buds, or both and from damage to neural pathways in the peripheral or central nervous system. Drugs, Physical Agents, and Aging Heavy smoking, particularly of pipe tobacco, and pharmaceutical agents, especially antirheumatic drugs, antiproliferative drugs, and drugs with sulfhydryl groups, such as penicillamine and captopril, are frequent causes of taste dysfunction (Table 20.3). Calcium-channel blockers, such as nifedipine and diltiazem, as well as antifungal agents, smokeless tobacco, anticonvulsants, and sumatriptan nasal spray may cause abnormalities of taste. Other local causes, in part related to drying of the mouth (xerostomia), include Sjogren's syndrome, radiation therapy, and pandysautonomia; these illustrate the important role saliva plays in taste perception. In the elderly, the taste threshold is more than twice as high as that of the general population, and drugs and disease states may further decrease taste (Schiffman 1997). Loss of taste may be the initial symptom of primary amyloidosis and is reported with variant Creutzfeldt-Jakob disease and ciguatera fish poisoning. Belt's Palsy (See Chapter 76) Although Bell's palsy is frequently associated with ipsllateral loss of taste over the anterior two thirds of the tongue, the patient usually does not recognize the loss. Loss of taste with facial palsy indicates involvement of the nervus intermedins portion of the facial nerve and localizes the lesion to the region between the pons and the point where the chorda tympani joins the facial nerve in the facial canal, distal to the geniculate ganglion. Recovery of taste within the first 14 days of onset of Bell's palsy is usually associated with complete recovery from paralysis. Impairment of taste for more than 2 weeks suggests a poor prognosis for the rapid return ol facial movement. Trauma The chorda tympani is particularly vulnerable to injury in its course through the middle ear on the medial superior surface of the tympanic membrane between the malleus and the incus. Isolated involvement of the chorda rympani is rare but can occur with middle ear lesions, such as cholesteatoma, otitis media, ear surgery (including tympanoplasty, stapedectomy, and mastoidectomy), and head trauma. Injury to preganglionic parasympathetic fibers within the chorda tympani, with loss of salivary secretion, may contribute to long-term impairment of taste even if taste fibers regenerate. Injury to the lingual nerve (a branch of the mandibular division of the trigeminal nerve) causes loss of both general somatic sensation, resulting in numbness, and special visceral sensation, with taste loss over the anterior two
DISTURBANCES OF TASTE AND SMELL Tabic 20.3:
263
Drugs affecting taste and smell
Classification
Drug
Amebic ides and anthelmintics Anesthetics, local
Metronidazole, niridazole Ben^ocaine, procaine hydrochloride (Novocain), and others, cocaine hydrochloride, tetracaine hydrochloride Clofibrate Phenindione Lamotrigine Chlorpheniramine maleate Amphotericin B, ampicillin, cefamandole, griseofulvin, ethambutol hydrochloride, lincomycin, protease inhibitors, sulfasalazine, sulfortes, streptomycin, terbinafine, tetracyclines, tyrothricin Doxorubicin and methotrexate, azathioprine, earmustine, vincristine sulfate Allopurinol, colchicine, gold, levamisole, o-penicillamine, phenylbutazone, 5-thiopyriodoxine Hexetidinc Catbimazole, methimazole, methylthiouracil, propylthiouracil, thiouraeil Sodium lauryl sulfate (toothpaste) Nifedipine, diltiazem Captopril, diazoxide, ethacrynic acid Glipizide, phenformin, and derivatives Baclofen, chlormezanone, L-dopn Codeine, hydromorphone hydrochloride, morphine Carbamazepine, lithium carbonate, phenytom, psilocyhin, trifluoperazine Amphetamines, phenmetrazinc thcoclatc and fenhutrazate hydrochloride (combined) Oxyfedrine, bamifylline hydrochloride Germine monoacctatc, hydroquinone, idoxuridinc, ironsorbitex, vitamin D, industrial chemicals (including insecticides), smokeless tobacco, sumatriptan nasal spray
Antilipemic Anti coagulants Anticonvulsants Antihistamines Antimicrobial agents
Antiproliferative, including immunosuppressive agents Antirheumatic, analgesic-antipyretic, anti-inflammatory agents Antiseptics Antithyroid agents Agents for dental hygiene Calcium-channel blockers Diuretics and antihypertensive agents Hypoglycemic drugs Muscle relaxants and drugs for treatment of Parkinson's disease Opiates Psycho pharmacologic, including antiepileptic, dtugs Sympathomimetic drugs Vasodilators Others
Source: Modified with permission from Schiffman, S. S. 1983, "Taste and smell in disease," N Engl J Med, vol. 308, p. 1275.
thirds of the tongue. This nerve may be injured as a result of jaw trauma and wounds, but most cases are iatrogenic due to laryngoscopy, difficult orotracheal intubation, and removal of wisdom teeth. Head Injury Taste disorders after head injury are rare and, when present, arc almost always due to disturbance of smell. They may be central or peripheral in origin. The frequency of ageusia after head injury is approximately 0 . 5 % , with approximately 6% of all patients with post-traumatic anosmia also having ageusia. Recovery from ageusia is much more likely than from anosmia and usually occurs in most over a period of a few weeks to a few months. Areas of brainstem damage that can cause taste disturbance include the tractus solitarius and its nucleus (ipsilateral ageusia) and the pontine tegmentum, involving both gustatory lemnisci (bilateral ageusia). Ipsilateral hypogeusia may follow pontine hemorrhage or infarcts involving the tegmentum. Ageusia may occur after bilateral thalamotomy. Unilateral thalamic or parietal lobe lesions
may cause contralateral impairment of taste sensation. Gustatory hallucinations occur much less frequently than olfactory hallucinations hut may occur with similar structural lesions and with psychosis. Dysgeusia is commonly experienced in association with dental problems, presence of dental prosthesis, poor oral hygiene, recent upper respiratory tracr infection, aging, depression, and psychotic conditions. Dysgeusia with facial numbness may occur with dissecting aneurysms of the carotid artery, possibly related to an alteration in blood supply to the seventh cranial nerve or branches of the chorda tympani, Other
Causes
Impaired raste may follow a focal disturbance of anatomic structures subserving taste, including jugular foramen tumors and more diffuse processes, such as idiopathic midline granuloma, high-altitude sickness, and diabetes mellitus. Hcmiagcusia can accompany vascular and demyelinating processes of the brainstem. Increased sensitivity to taste (hypergeusia) is uncommon and is reported in
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
association with cerebellar glioma, the m e c h a n i s m of which is unclear.
REFERENCES Acharya, V., Acharya, J., & Ludcrs, H. 1998, "Olfactory epileptic auras," Neurology, vol. 5 1 , pp. 56-61 Berendse, H. W., Booij, J., Francot, C. M, J. E., ct al. 2001, "Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell," Attn Neurol, vol. 50, pp. 34-41 Doty, R. L., Li, C, Mannon, L. J., & Yousem, D. M. 1997, "Olfactory dysfunction in multiple sclerosis," N Engl ) Med, vol. 336, pp. 1918-1919 Jones-Gotman, M., Zatorre, R, J., Ccndes, F., et al. 1997, "Contribution of medial versus lateral temporal-lobe structures to human odout identification," Brain, vol. 20, pp. 1845-1856 Levy, M., Henkin, R. I., Hutter, A., ct al. 1997, "Functional MRI of human olfaction," / Comput Assist Tomogr, vol. 2 1 , pp. 849-856
Levy, L. M\, Henkin, R. I., Lin, C. S., et al. 1998, "Increased brain activation in response to odors in patients with hyposmia after theophylline treatment demonstrated by fMRI," / Comput Assist Tomogr, vol, 22, pp. 760-770 Markopoulou, K., Larsen, K. W., Wszolek, E. K., et al. 1997, "Olfactory dysfunction in familial parkinsonism," Neurology, vol. 4 9 , pp. 1262-1267 Meredith, M. 2001, "Human vomeronasal organ function: a critical review of best and worst cases," Cbem Senses, vol. 26, pp. 433-445 Sehiffman, S. S. 1997, "Taste and smell losses in normal aging and disease," JAMA, vol. 278, pp. 1357-1362 Small, D. M., Jones-Gotman, M., Zatorre, R. J., ct al. 1997, "A role for the right anterior tempotal lobe in taste quality recognition,"/ Neurosci, vol. 17, pp. 5136-5142 Yousem, D. M., Geckle, R. J., Bilker, W. B., et al. 1996a, " M R evaluation of patients with congenital hyposmia or anosmia," AjR, vol. 166, pp. 439-443 Yousem, D. M., Geckle, R. J., Bilker, W. B., et al. 1996b, "Posttraumatic olfactory dysfunction: MR and clinical evaluation," AjNR, vol. 17, pp. 1171-1179
Chapter 21 Cranial and Facial Pain J. D. Bartleson, David F. Black, and Jerry W. Swanson History Types of Headaches Onset of Headaches Frequency and Periodicity of Episodic Headaches Peak and Duration of Headaches Time and Occurrence and Precipitating Factors Location and Evolution Quality and Seventy Premonitory Symptoms, Aura, and Accompanying Symptoms Aggravating Factors Mitigating Factors Family History of Headaches Prior Evaluation
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Headache is a common symptom with a high prevalence in most epidemiological studies of Western populations (Rasmussen and Lipton 2000). Headache is one of the 10 most common reasons for outpatient physician visits in the United States. Patients typically present with head and facial pain because the discomfort is severe, intetferes with work or other activities, or raises concerns about a serious underlying cause. The diagnosis of a painful cephalic condition depends on three elements: the history, neurological and general examinations, and appropriate investigations.
HISTORY The diagnostic advice offcted by the late Dr. A. L, Sahs is useful also for rhe patient with headache: "If you have 30 minutes to see a patient, spend 29 on history, one on the examination." The method of taking a histoty for headache or facial pain is usually straightforward. Nevertheless, several specific aspects need to be addressed. The scheme of questions listed in Table 21.1 can be useful tor nhnnning a pertinent history. The discussion that follows illustrates some responses and theit implications. It is usually helpful to begin by asking the patient to describe the pain or, alternatively, simply by asking what kind of help the patient seeks. This approach allows patients to relax and to say what they had planned to say previously. Usually, the patient continues to speak fot only a few minutes if not interrupted (Langcwitz et al. 2002). Once the patient has had an opportunity to speak,
Prior Medications ' Disability Patient Concerns Reason for Seeking Help Other Medical or Neurological Problems Examination Differential Diagnosis \eumiiiia«ing "IVsi-. Cerebrospinal Fluid Tests Electroencephalography General Medical Tests Special Examinations and Consultations Further Observation
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directed but open-ended questions (see Table 21.1) can be asked. The questions typically contain the word headache, although facial pain could easily be substituted, if appropriate.
Types of Headaches Many individuals, especially those with a long-standing problem, have more than one rype of headache. It is valuable to establish this information at the beginning of the interview so each type of pain can be carefully delineated. For instance, some patients have frequent or persistent headaches that are punctuated occasionally by migraine headaches. Other patienrs have clearly separated migraine and tension-type headaches (formerly called muscle contraction or tension headaches). A patient with a chronic headache disorder may also develop a new headache that is a manifestation of a new different condition.
Onset of Headaches A headache disorder of many years' duration, with little change, is almost always of benign origin. Migraine headaches often begin in childhood or early adulthood. A headache of recent onset obviously has many possible causes, including the new onset of either a benign or a more serious condirion. An increasingly severe headache raises rhe possibility of an expanding intracranial lesion. A new headache in an older patient suggests an intracranial lesion >s
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Tabic 21.1:
Questions for obtaining the history of headache
How many types of headaches occur? When and how did the headaches begin? If the headaches are episodic, what is their frequency and periodicity? How long does it take for the headaches to reach maximal intensity, and how long do they last? When do the headaches tend to occur, and what factors precipitate a headache? Where does the pain start, and how does it evolve? What is the quality and the severity of the pain? Is the pain pulsatile (throbbing)? Are there symptoms dun herald the onset or that accompany the headaches? Does anything aggravate the pain? What measures tend to reduce the pain? Is then- ;i family history of headaches? What prior evaluation has the patient undergone? What medications have been used to treat the headaches? What ideas does the patient have about the headaches? How disabling are the headaches? Why is the patient seeking help now? Are there other medical or neurological problems?
(e.g., subdural hematoma) or giant cell (temporal or cranial) arteritis. Headaches of instantaneous onset suggest an intracranial hemorrhage, usually in the subarachnoid space, but also may be caused by cerebral venous sinus thrombosis, spontaneous cerebrospinal fluid (CSF) leaks, pituitary apoplexy, and severe hypertension (Dodick 2002). Occasionally, mass lesions, such as third ventricular tumors and posterior fossa or cervicomedullary tumors, can produce intermittent acute headaches if there is interference with CSF circulation.
Peak and Duration of Headaches Migraine usually peaks within 1-2 hours of onset and usually lasts 6 to 36 hours. Cluster headache is typically maximal immediately if the patient awakens with the headache in progress or peaks within a few minutes if it begins during wakefulness. Cluster headaches characteristically last 45-120 minutes but occasionally last a few hours. Headaches similar to cluster headaches but lasting only about 15 minutes several times a day are typical of chronic or episodic paroxysmal hemicrania. "Ice-pick" head pains (idiopathic stabbing pain) are momentary, lasting only seconds. Tension-type headaches commonly build up over hours and may last days to years. These headaches may include some migraine features and were formerly called a mixed or tension-vascular headache but more appropriately fall under the rubric of chronic migraine. A new sudden, severe headache that is maximal at onset suggests intracranial hemorrhage, cerebral venous sinus thrombosis, or pituitary apoplexy. A chronic, continuous, unilateral headache of moderate severity with superimposed attacks of more intense pains that are associated with autonomic features suggests the diagnosis of hemicrania continua, an indomethacin-rcsponsive syndrome (Goadsby and Lipton 1997). Occipital neuralgia and trigeminal neuralgia manifest as brief shocklike pains, sometimes occurring in a crescendo pattern over a period of seconds to minutes. Occasionally, a duller pain in the same nerve distribution persists longer. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a rare syndrome manifested by paroxysms of retro-orbital pain lasting seconds but with 3-100 episodes per day and the associated autonomic symptoms for which it is named.
Frequency and Periodicity of Episodic Headaches Time and Occurrence and Precipitating Factors Migraine may be episodic or chronic. Chronic migraine (formerly referred to as transformed migraine) usually occurs in individuals with a history of episodic migraine headaches. Episodic migraine may become chronic with or without medication overuse. Episodic cluster headaches typically occur daily for several weeks or months and are followed by a long, headache-free interval, although chronic cluster headaches may occur daily for years. A related disorder, chronic paroxysmal hemicrania, occurs multiple times per day, often for years. A chronic daily headache without migrainous or autonomic features is likely to be a chronic tension-type headache. If there is no regular periodicity, it is useful to inquire about the longest and shortest periods of freedom between headaches. Asking the patient to monitor headache frequency, intensity, and medication use on a "headache calendar" often provides very helpful information.
Cluster headaches often awaken patients from a sound sleep and have a tendency to occur at the same time each day in a given person. Hypnic headaches typically affect elderly patients, regularly awakening the patient at a particular time of night. Unlike cluster headaches, they are typically diffuse and not associated with autonomic phenomena (Raskin 1997). Migraine can occur at any time during the day or night but usually begins in the morning, A headache of recent onset that disturbs sleep or is worse on waking may be caused by increased intracranial pressure. Tension-type headaches are typically present during much of the day and are often more severe late in the day. Obstructive sleep apnea may be accompanied by the chronic occurrence of headaches on awakening. Patients with chronic, recurrent headaches often can recognize factors that trigger an attack. Migraine headaches may be precipitated by bright light, menstruation,
CRANIAL AND FACIAL PAIN weather changes, caffeine withdrawal, sleeping longer or less than usual, and ingested substances, such as alcohol. Trauma, emotional or physical, may be an important causative factor in the pathogenesis of headache. If bending, lifting, coughing, or Valsalva's maneuver produces a headache, an intracranial lesion, especially involving the posterior fossa, must be considered; however, most exertional and cough headaches are benign. Intermittent headaches that are precipitated by assuming the upright position and promptly relieved by lying down are characteristic ot a CST leak. If no Iiisrorv exists of a lumbar puncture, head trauma, or neurosurgical procedure, a spontaneous leak may be the cause. Alcohol is often a potent precipitant of cluster headaches. Headache occurring during sexual activity, especially during or shortly after orgasm, may be of benign origin, especially if a headache has occurred on multiple occasions previously. A single headache in this circumstance, however, may be caused by a subarachnoid hemorrhage. Lancinating face pain triggered by facial or intraoral stimuli occurs with trigeminal neuralgia. Glossopharyngeal neuralgia is most commonly triggered by chewing, swallowing, and talking, although cutaneous trigger zones in and about the ear are occasionally present.
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the tonsillar fossa and the posterior tongue. Unilateral facial pain when chronic often does not have an underlying lesion. Occasionally, though, facial pain may be a symptom of nonmetastatic lung cancer (Eross et al. 2003).
Quality and Severity Although it is often difficult for the patient to describe the quality of the pain, this information may be useful. It may be helpful to ask the patient to grade the severity of pain on a scale of 1 to 10. Migraine often has a pulsating quality that may be superimposed on a more continuous pain. Cluster headache is characteristically severe, boring, and steady and is often described as similar to a "hot poker." SUNCT produces moderately severe pain in the orbital or temporal region and may be described as stabbing or pulsatile. Tension-type headaches are usually described as a feeling of fullness, tightness, or pressure, or as being like a cap, band, or vise. Headaches caused by meningeal irritation, whether related to infectious meningitis or to a hemorrhage, are typically severe. Trigeminal neuralgia is severe, brief, and stabbing, occurring up to several times per minute; a milder ache may occur between paroxysms of pain. Pain caused by glossopharyngeal neuralgia is similar in character to that of trigeminal neuralgia.
Location and Evolution Asking the patient to delineate the location of the pain with a finger is often helpful. Trigeminal neuralgia is confined to one or more branches of the trigeminal nerve. The patient may be able to localize one or more trigger points over the face or in the mouth and then outline the spread of the pain. Pain in the throat may be related to a local process or glossopharyngeal neuralgia. Pain in the lower portion of the face and neck can be produced sometimes by either a cluster or a migraine variant—a so-called lower half headache. Carotid dissection commonly presents with neck, face, and head pain ipsilateral to the dissection; this should be considered in any patient with pain of recent onset in these locations. Migraine is most often unilateral, commonly in the frontotemporal region, but it may be generalized or may evolve from a unilateral location to become generalized. Cluster headaches are virtually always unilateral during an attack and are typically centered in, behind, or about the eye. At different times (different clusters), some patients do experience cluster headaches that have switched sides from a prior cluster. A typical tension-type headache is generalized, although it may originate across the nuchal muscles only to spread and perhaps predominate in the frontal or occipital regions. When pain is localized to an eye, the intraoral region, or the ear, local processes involving these structures must be considered. Otalgia may be caused by a process involving
Premonitory Symptoms, Aura, and Accompanying Symptoms Leading questions may be necessary. Some patients have premonitory symptoms that precede a headache attack by hours. These can include psychological changes, such as depression, euphoria, and irritability, or more somatic symptoms, such as constipation, diarrhea, abnormal hunger, fluid retention, or increased urination. The term aura refers to focal cerebral symptoms associated with a migraine attack. These symptoms most commonly last 20-30 minutes and precede the headache. At other times, the aura may continue into the headache phase or arise during the headache phase. Visual symptoms are the most common kind of cerebral dysfunction and may consist of either positive or negative phenomena or a mixture of both. Other hemispheric symptoms, such as weakness, somatosensory disturbances (usually paresthesias), or language dysfunction, may precede the headache. Aura symptoms usually have a gradual onset and spread over minutes. If more than one symptom occurs (e.g., visual and somatosensory), the onsets are usually staggered and not simultaneous. The slow spread is a helpful feature to differentiate these from focal neurological symptoms caused by cerebral ischemia. Symptoms of brainstem origin, such as vertigo, dysarthria, ataxia, quadriparesis, diplopia, and loss of
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consciousness, accompany basilar migraine. Nausea, vomiting, photophobia, phonophobia, and osmophobia characteristically accompany migraine attacks. In addition, lacrimation, rhinorrhea, and nasal congestion accompany migraine headache in many patients and should not be confused with a headache of sinus origin (Cady and Schreiher 2002). Ipsilateral miosis and ptosis (oculosympathetic paresis or Horner's syndrome), lacrimation, conjunctival injection, and nasal stuffiness commonly accompany cluster headache. Sweating and facial flushing on the side of the pain have been described but are uncommon. Facial swelling, usually periorbital in location, may develop with repeated attacks. Shorter lived attacks occurring multiple times per day with similar autonomic features suggest a diagnosis of episodic or chronic paroxysmal hemicrania, an indomethacin-responsive syndrome (Goadsby and Lipton 1997). An oculosympathetic paresis is also a common feature associated with ipsilateral interna! carotid artery dissection. In the setting of acute transient or persistent monocular blindness, giant cell arteritis and carotid dissection should be considered. Temporomandibular joint dysfunction often is characterized by jaw pain precipitated by movement of the jaw, clenching of the teeth, reduction in the range of jaw movement, joint clicking, and tenderness over the joint. Headache accompanied by fever suggests an infectious cause. Persistent or progressive diffuse or focal central nervous system symptoms, including seizures, suggest a structural cause for a headache. Purulent or bloody nasal discharge suggests an acute sinus cause for the headaches. Likewise, a red eye raises the possibility of an ocular process, such as infection or acute glaucoma. A history of polymyalgia rheumatica, jaw claudication, or tenderness of the scalp and superficial arteries in an elderly person suggests the possibility of giant cell arteritis. Transient visual obscurations, tinnitus, diplopia, and the finding of papilledema may be associated with increased intracranial pressure from any cause, particularly idiopathic intracranial hypertension {pseudotumor cerebri). An important principle is that symptoms that accompany a headache can be key in accurate diagnosis.
Mitigating Factors Rest, especially sleep and avoidance of light and noise tends to provide relief to the migraineur. Massage or heat may ameliorate the pain associated with a tension-type headache. Local application of pressure over the affected eye or ipsilateral temporal artery, and local application of heat or cold, or rarely short-lasting intense physical activity may alleviate the pain of cluster headache. Headache caused by intracranial hypotension typically is relieved or markedly benefited by recumbency.
Family History of Headaches Migraine is often an inherited disorder, and a family history of migraine or "sick headaches" should he sought. Tensiontype headaches are also frequently familial. Cluster headache is familial in a minority of cases (approximately 7%). Familial hemiplegic migraine is a rare, autosomal dominant variant of migraine with aura, wherein the migraine attack includes hemiparesis lasting minutes to weeks.
Prior Evaluation The patient should be asked about prior consultations and testing for the headaches. If appropriate, the records and imaging study films can be obtained for review.
Prior Medications Response to medications should be sought, including those used to treat individual headache attacks and those used prophylactically. The dose, route of delivery, dosage schedule, and duration of treatment should be established. This information also provides an opportunity to determine whether medications such as ergot preparations and analgesics have been overused. It also establishes whether prophylactic medications were optimized. A history of the use of caffeine-containing substances also should be elicited, because they may cause or aggravate headaches.
Aggravating Factors Disability The worsening of headache as a result of a cough or jolt suggests an intracranial element to the pain, whereas aggravation by torsion of the neck may indicate a musculoskeletal component. Sufferers of cluster headaches tend to endure their pain in an agitated state, pacing and moving about, whereas patients with migraines prefer to lie still. Precipitation or marked aggravation of headache in the upright position suggests intracranial hypotension.
The assessment of head ache-re I a ted disability is important. A baseline determination with follow-up assessments is useful when judging the effects of treatment and can be useful in guiding headache therapy. In addition, disability can be useful in guiding the headache therapy (Upton et al. 2000). The Migraine Disability Assessment Scale (MIDAS) is an example of a useful, validated clinical tool (Stewart et al. 2001).
CRANIAL AND FACIAL PAIN
Patient Concerns Headache pain can produce significant fear and anxiety regarding serious disease. The patient should be allowed to articulate any concerns so each aspect can be appropriately addressed by the physician.
Reason for Seeking Help The question of why the patient is seeking help may be irrelevant if the problem is of recent onset. If the problem is chronic, however, it can be useful to inquire why the patient has come for aid at this point.
Other Medical or Neurological Problems A history of past or current medical and neurological conditions and history of trauma, operations, and medication allergies should be obtained. Additionally, a history of the use of other medications and dietary supplements unrelated to the headaches should be obtained.
EXAMINATION In the patient with headache, the physical examination often shows no abnormalities. However, findings on examination may yield important clues about the underlying cause. Even when the results of the examination are normal, both the physician and the patient gain confidence that nothing has been overlooked. Although, strictly speaking, the history and the examination are separate parts of the evaluation, in practice the examination begins the moment the physician encounters the patient. Careful observation helps determine whether the patient has physical illness, appears anxious or depressed, and whether the patient's history is reliable. For instance, with respect to reliability, a patient who is unable to give a reasonably coherent history is suspected of having an abnormal mental status. It is important to perform a neurological examination, including examination of the mental status, gait, cranial nerves, motor system, and sensory system, as discussed in Chapter 1. A neurovascular examination also should be performed. The skull and cervical spine should be examined. The skull should be palpated for lumps and local tenderness. There may be tenderness over inflamed sinuses. Thickened, tender, irregular temporal arteries with an associated reduction in pulse suggest giant cell arteritis. Occasionally, other scalp lesions may be present that point to a cause for head pain. In tension-type headaches, the scalp muscles may be tender.
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A short neck or low hairline suggests basilar invagination or an Arnold-Chiari malformation. In an infant, separation of the sutures suggests increased intracranial pressure, most commonly caused by hydrocephalus. Measuring the head circumference is always worthwhile in a child. The cervical spine also should be tested for tenderness and mobility. Nuchal rigidity on passive neck flexion and Kernig's sign are evidence of meningeal irritation. Vital signs, especially blood pressure and pulse, always should be assessed. If there is a question of fever, temperature should be measured. The body habitus should be noted. This observation may be relevant especially in young women with headache possibly related to pseudotumor cerebri, who are almost always obese. The general examination also includes auscultation of the heart and lungs, palpation of the abdomen, and examination of the skin.
Differential Diagnosis In most cases, the history and examination are all that are needed to make a diagnosis, especially in the patient with a chronic headache. Migraine, tension-type headaches, and cluster headaches usually can be diagnosed with a high degree of certainty, particularly if the headaches have been recurrent over a long period and the examination is normal. In this case, it may be possible to proceed directly to management. In some situations, however, the diagnosis is uncertain. These situations specifically raise concerns of a serious organic cause for rhe headaches. Headaches that are progressive are a worrisome indication of a possible intracranial process. A new headache of abrupt onset always raises concern about an intracranial process, especially hemorrhage and sometimes a mass lesion. Headaches that interfere with sleep, though sometimes benign, must be considered to have a potential serious cause. Headaches precipitated by exertion, change of position, cough, sneeze, or strain may be benign, although again they raise the possibility of an intracranial lesion, especially in the posterior fossa. Systemic symptoms, such as weight loss, fever, or those associated with another known systemic disease, such as malignancy or human immunodeficiency virus infection, should be investigated with care. Headaches that are associated with neurological symptoms, except those that are typical for migraine, should raise concern. Unexplained findings on neurological examination and a history of seizures should prompt additional evaluation. The investigations used to evaluate a patient with headaches can include almost all of the tests used in neurology and neurosurgery, as well as various medical tests. Selection of the appropriate studies depends on the formulation after the history and examination. Indiscriminate use of batteries of tests is unwarranted.
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Neuroimaging Tests Computed Tomographics! Scanning and Magnetic Resonance Imaging Computed tomographic (CT) scanning and magnetic resonance imaging (MRI) are extremely useful tests in the evaluation of patients with headache. Tumors, hematomas, cerebral infarctions, abscesses, hydrocephalus, and many meningeal processes can be identified with CT scanning and MRI. Abnormalities of the skull base, pituitary gland craniocervical junction, and white matter are better seen with MRI. The cost of an MRI study is severalfold that of a CT scan, but MRI is safer because x-rays are not used to generate the image and the enhancing agent used with MRI {gadolinium) is safer than the iodinated contrast used with CT. CT can detect acute subarachnoid hemorrhage if sufficient bleeding has occurred. If the CT scan is normal and the history is suggestive of recent subarachnoid hemorrhage, a lumbar puncture should be performed. CT scanning can be helpful for evaluating abnormalities of the skull, orbit, sinuses, facial bones, and the cervical spine. Changes associated with intracranial hypotension are best shown with MRI (Mokri 2001). The cervical spinal cord and exiting nerve roots and the craniocervical junction are much better shown with MRI. Magnetic resonance angiography (MRA) is a noninvasive method that can demonstrate intracranial and extracranial vascular occlusive disease including large vessel dissection, intracranial arteriovenous malformations, and aneurysms. Intracranial venous sinus thrombosis is best diagnosed with magnetic resonance venography. Evidence-based guidelines for neuroimaging of patients with nonacute headache {Frishberg et al. 2000) found MRI to be more sensitive in finding white matter lesions and developmental venous anomalies than CT. For the acute onset of headache, CT is the optimal imaging study; in patients with subacute and chtonic headache, MRI is likely to reveal more, but many of rhe abnormalities will be incidental. Plain X-ray Films of the Skull, Sinuses, and Cervical Spine Plain x-ray films of the skull arc unnecessary in the routine evaluation of patients with headache but can he obtained if there has been acute head trauma or if there is an unusual bony abnormality on physical examination. Although plain x-ray films of the sinuses can show infection, hemorrhage, or tumor, CT scanning and MRI provide greatet definition. The role of the cervical spine in the cause of headaches remains uncertain, but occipitonuchal pain may result from degenerative disc and joint disease of the mid- and upper cervical spine. Rheumatoid arthritis can lead to craniocervical junction instability and pain. Tomographic films may be needed to show bony changes in the upper cervical spine and craniocervical junction. Flexion and extension,
odontoid, and pillar views of the cervical spine can help to exclude ligamentous damage and fractures in patients with a history of head and neck injury. Congenital abnormalities of the cervical spine, such as the KlippelFeil syndrome, may be associated with other disorders such as an Arnold-Chiari malformation. Other Imaging
Studies
Panoramic x-ray examination, MRI, or CT of the temporomandibular joints may be helpful in selected patients. The presence of temporomandibular joint disease should not be taken as proof that a patient's headaches arc related. Dental x-ray films are useful if dental-origin pain is suspected. Cerebral
Angiography
Cerebral angiography is rarely needed in the initial investigation of headache. It can be helpful in confirming vascular disease including arterial dissections, arteriovenous malformations, intracranial aneurysms, and the presence of central nervous system vasculitis. Radioisotope and Computed Tomographic Studies for Cerebrospinal Fluid Leaks Isotope cisternography can be helpful in determining the presence and location of a spontaneous, post-trail ma tic, or postoperative CSF leak. Alternatively, CT scanning ol the spine after instillation of contrast into the lumbar spinal fluid can be used to identify the location of CSF leaks.
Cerebrospinal Fluid Tests CSF examination is used to diagnose or exclude meningitis, encephalitis, subarachnoid hemorrhage, and leptomeningeal cancer and lymphoma and is required to confirm increased or decreased intracranial pressure. Measurement of the opening CSF pressure should be performed in all cases,
Electroencephalography Electroencephalography is not useful in the investigation of headache unless the patient also has a history of seizures, syncope, or episodes of altered awareness (Quality Standards Subcommittee of the American Academy of Neurology 1995).
General Medical Tests A few blood tests are important in the investigation of headache. Detetmining the erythrocyte sedimentation rate
CRANIAL AND FACIAL PAIN is essential in the evaluation of giant cell arteritis. Although a normal value does not exclude this condition, it greatly reduces the likelihood (see Chapter 75), Episodic headaches associated with unusual behavior ot impairment of consciousness may suggest an insulinoma. A diagnosis of insulinoma is supported by elevated insulin and C-peptide levels in the face of a low or relatively low fasting glucose level. Levels of carboxyhemoglobin can be measured in patients complaining of early morning headaches during the winter when home heating is used, especially when several members of the same household are affected. Estimation of blood alcohol levels and drug screening may be helpful in certain patients. Sensitive thyroidstimulating hormone and serum thyroxine levels should be measured in patients with chronic headache because hypothyroidism may present with headaches. Urine concentrations of mctancphtines and free catecholamines should be measured if a pheochromocytoma is suspected.
Special Examinations and Consultations Perimetry is helpful in the delineation of visual field defects. Tonometry is necessary to document elevated intraocular pressure in glaucoma, hut unless the eye is red or the cornea is cloudy, glaucoma is an unlikely cause of head or even eye pain. These tests are routinely done by ophthalmologists, who also have the equipment and expertise to perform slit-lamp examinations and other specialized examinations. If pain of dental or temporomandibular joint origin is suspected, a dentist or oral surgeon skilled in the detection and trearment of these disorders should be consulted. Diagnosis of tumors of the sinuses, nasopharynx, and neck, as well as inflammation of the sinuses, is aided by the expertise of an otorhinolaryngologist. Temporal artery biopsy is performed to confirm or exclude giant cell arteritis (see Chapters 55A and 75). In some selected cases (e.g., headaches as a manifestation of a chronic pain disorder with or without a history of drug abuse), psychiatric consultation may be helpful for diagnosis and management.
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Further Observation Sometimes, a definitive diagnosis cannot be reached after history taking, examination, and investigation. In such cases, further observation, perhaps coupled with a trial of therapy, usually reveals the diagnosis.
REFERENCES Cady, R. K. 8c Schreiber, C, P. 2002, "Sinus headache or migraine? Considerations in making a differential diagnosis," Neurology, vol. 58, suppl. 6, pp. S10-S14 Dodiek, D. W. 2002, "Thunderclap headache," J Neurol Neunurg Psychiatry, vol. 72, pp. 6-11 Eross, E. j . , Dodick, D. W., Swanson, J. W., Sc Capobianco, D. J. 2003, "A review of intractable facial pain secondary to underlying lung neoplasms," Cephalalgia, vol. 23, pp. 2-5 Frishberg, B. M., Rosenberg, J. H., Matchar, D. B., et al. 2000, Evidenced-based Guidelines in the Primary Care Setting: Neuroimaging in Patients with Nonacute Headache, American Academy of Neurology. Available at http://www.aan.com/ p rofe ssi o na I s/p ra c ti ce/pd f s/gl 0 0 8 8. pd f Coadsby, P. J. & Lipton, R. B. 1997, "A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases," Brain, vol. 120, pp. 193-209 Langcwitz, W., Denz, M., Keller, A., et al. 2002, "Spontaneous talking time at start of consultation in outpatient clinic: Cohort study," Br Med], vol. 325, pp. 682-683 Lipton, R. B., Stewart W. F., Stone, A. M., et al. 2000, "Stratified care vs step care strategies for migraine: The disability in strategies of care (DISC) study: A randomized trial," JAMA, vol. 284, pp. 2599-2605 Mokri, B. 2001, "Spontaneous intracranial hypotension," C«rr Neurol Neuroses Rep, vol. 1, pp. 109-107 Quality Standards Subcommittee of the American Academy of Neurology. 1995, "Practice parameter: The electroencephalogram in the evaluation of headache," Neurology, vol. 45, pp. 1411-1413 Raskin, N. H. 1997, "Short-lived head pains," Neurol Clin, vol. 15, pp. 143-152 Rasmussen, B. K. & Lipton, R. B. 2000, "Epidemiology of headaches," in The Headaches, eds J. Oleson, P. Tfelt-Hansen, & K. M. A. Welch, Lippincotr Williams & Wilkins, Philadelphia Stewart, W. F., Lipton, R. B., Dowson, A. J., & Sawyer, J. 2001, "Development and testing of the Migraine Disability Assessment (MIDAS) questionnaire to assess headache-related disability," Neurology, vol. 56, no. 6, suppl. 1, pp. S20-S28
Chapter 22 Brainstem Syndromes Michael Wall Ocular Motor Syndromes Combined Vertical Gaze Ophthalmoplegia Upgaze Paresis (Dorsal Midbrain or Parinaud's Syndrome) Downgaze Paresis Internuclear Ophthalmoplegia Horizontal Gaze Paresis Global Paralysis of Gaze One-and-a-Half Syndrome Syndromes Involving Ocular Motor Nuclei Third Cranial Nerve Nucleus Sixth Cranial Nerve Nucleus
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Other chapters in this hook that deal with symptoms emphasize history as the starting point for generating a differential diagnosis. The differential diagnosis is then tefined during the examination. This chaptet calls for a different approach. When the neurologist evaluates a patient with a brainstem disorder, often the most effective method of diagnosis is to organize the differential diagnosis around the objective physical findings, particularly in patients with an altered mental status, such as coma. The symptoms are still integrated in the approach, but the physical findings take centct stage. Organization around physical findings is efficient because very specific neurological localization, which limits the diagnostic alternatives, is often possible. The long tracts of the nervous system traverse the entire brainstem in the longitudinal (rostrocaudal) plane. Cranial nerve nuclei and their respective cranial nerves originate and exit at distinct levels of the brainstem. This allows for exquisite localization of function based on the findings of the neurological examination, The chapter begins with a discussion of the brainstem ocular motor syndromes followed by miscellaneous brainstem, brainstem stroke, diencephalic, and thalamic syndromes.
Other Brainstem and Associated Syndromes Diencephalic Syndrome (Russell's Syndrome) Thalamic Syndrome Tectal Deafness Foramen Magnum Syndrome Syringobulbia Brainstem Ischemic Stroke Syndromes Thalamic Stroke Syndromes Midbrain Stroke Syndromes Pontine Stroke Syndromes Medullary Stroke Syndromes
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which the objective physical findings dictate the diagnostic approach to the problem. Symptoms of vertical gaze ophthalmoplegia, when ptesent, are relatively nonspecific and usually occur in patients who have difficulty looking down, as when reading, eating from a table, and walking down a flight of stairs. In addition, symptoms may be unobtainable because of mental status changes caused by dysfunction of the reticular formation that lies adjacent to the vettical gaze generator in the rostral midbrain (see Chapter 39),
Combined Vertical Gaze Ophthalmoplegia
The neutological examination discloses associated signs of the disorders listed in the differential diagnosis (Table 22.1). Coma may be associated with reticular system involvement. Long-ttact signs and loss of pupillary reflexes are commonly associated. The syndrome of combined vertical gaze ophthalmoplegia is diagnosed when the ocular findings occur in isolation from long-tract signs. With combined vertical gaze ophthalmoplegia, there is loss of vertical saccades and pursuit. This gaze limitation may be overcome by the oculocephalic (doll's head or doll's eye) maneuver, which tests the vestibulo-oculat reflex (VOR; see Chapter 39). It is demonstrated by having the patient focus on an object, rotating the patient's head, and looking for a conjugate eye movement in the opposite direction. Bell's phenomenon (reflex movement of the eyes up and out in response to forced eye closure) is often absent. Skew deviation (vertical malalignment of the eyes) may occur. Absence of convergence and loss of pupillary reactions to light are common.
Combined vertical gaze ophthalmoplegia is defined as paresis of both upward and downward gaze. Vertical gaze ophthalmoplegia is an example of a brainstem syndrome in
The location of the lesion of combined vertical gaze ophthalmoplegia is the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) for loss of vertical pursuit and saccades (Leigh and Zee 1999).
OCULAR M O T O R SYNDROMES
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Table 22.1: Differential diagnosis of combined vertical gaze ophthalmoplegia Stroke Ischemic Hemorrhagic Progressive supranuclear palsy Corticobasal ganglionic degeneration Arteriovenous malformation Multiple sclerosis Thalamic and mesencephalic tumors Whipple's disease Syphilis Vasculitis (e.g., systemic lupus erythematosus) Metabolic disorders Lipid storage diseases Wilson's disease Kern icterus Wernicke's encephalopathy
Table 22.1 lists the disorders involving the rostral mesodiencephalic region (differential diagnosis) that cause combined vertical gaze ophthalmoplegia (see Chapter 39). The most common causes of isolated combined vertical gaze ophthalmoplegia are stroke and progressive supranuclear palsy (PSP). Cortical-basal ganglionic degeneration has similar ocular motility findings to PSP, but they are less severe. Whereas the supranuclear vertical gaze ophthalmoplegia may be prominent early in the course of PSP, obvious vertical and horizontal gaze restriction is usually a late finding in cortical-basal ganglionic degeneration (Rottach et ah 1996). The diagnostic formulation varies with the age of the patient. Isolated combined vertical gaze ophthalmoplegia is usually due to infarction of the rostral dorsal midbrain (Bogousslavsky et al, 1994). When onset is gradual instead of abrupt or the patient is young, other disorders should be considered (see Table 22.1). In the elderly, PSP (see Chapter 77) is likely if the onset is gradual. PSP can be mimicked by the treatable Whipple's disease (AverbuchHeller et ah 1999). For Whipple's disease, the movement disorder oculomasticatory myorhythmia is pathognomonic. Laboratory investigations used to evaluate combined vertical gaze ophthalmoplegia include computed tomographic (CT) scan or, preferably, magnetic resonance imaging (MRI). Care should be taken not to overlook lesions inferior to the floor of the third ventricle. Lumbar puncture, syphilis serology, erythrocyte sedimentation rate, and an antinuclear antibody test complete the evaluation when the cause is not obvious. One should consider small bowel biopsy if Whipple's disease is a possible diagnosis. A polymerase chain reaction (PCR) assay of small bowel biopsy, cerebrospinal fluid (CSF), or other tissues for the 16S ribosomal ribonucleic acid (RNA) gene of Tropberyma whippleii appears to have both sensitivity and specificity for the diagnosis of Whipple's disease (Lee 2002).
Upgaze Paresis (Dorsal Midbrain or Parinaud's Syndrome) Another brainstem syndrome that often occurs without symptoms is the dorsal midbrain syndrome. When symptoms do occur, the patient has difficulty looking up and may have blurry distant vision caused by accommodative spasm. Tin- trtnid of findings in the dorsal midbrain syndrome are (1) loss of upgaze, which is usually supranuclear (loss of pursuit and saccades with preservation of the VOR); (2) normal-to-large pupils with light-near dissociation (loss of the light reaction with preservation of pupilloconstriction in response to a near target) or pupillary areflexia; (3) convergence-retraction nystagmus, in which the eyes make convergent and retracting oscillations after an upward saccade; and (4) lid retraction, The location of the lesion causing the upgaze paresis of the dorsal midbrain syndrome is the posterior commissure and its inrersririal nucleus (Leigh and Zee 1999). The presence of the full syndrome implies a lesion of the dorsal midbrain (including the posterior commissure), a bilateral lesion of the pretectal region, or a large unilateral tegmental lesion. The differential diagnosis is listed in Table 22,2. Other than the mild upgaze limitation that occurs with age, the most common cause of loss of upgaze is a tumor of the pineal region. The next most common causes are stroke and trauma. The upgaze palsy portion of the syndrome can be mimicked by (1) double elevator palsy; (2) PSP; (3) orbital causes, such as thyroid ophthalmopathy and bilateral Brown's superior oblique tendon sheath syndrome; (4) pseudo-dorsal midbrain syndrome, secondary to myasthenia gravis, or the Cuillain-Barre syndrome; and (5) congenital upgaze limitation. Forced ductions Table 22.2:
Differential diagnosis of dorsal midbrain syndrome
Pineal tumors Stroke Ischemic cerebrovascular disease Thalamic hemorrhage I r;nini:l
Hydrocephalus Multiple sclerosis Transtentorial herniation Congenital aqueductal stenosis Metastatic tumors Infections Encephalitis Cysticercosis Midbrain arteriovenous malformation Stereotactic midbrain surgery Metabolic disorders Lipid storage disease Wilson's disease Kern icterus Wernicke's encephalopathy
BRAINSTEM SYNDROMES
(see Chapter 16) may be performed by grasping anesthetized sclera with forceps and moving the globe through its range of motion. The presence of restriction of movement with forced ductions implies a lesion within the orbit, as distinct from a midbrain lesion. The diagnostic formulation of the dorsal midbrain syndrome varies with age. In children and adolescents, pineal region tumors are usually the cause. In young and middle-aged adults, the disorder is uncommon, and the cause may be trauma, multiple sclerosis, or arteriovenous malformation. In the elderly, stroke and PSP are rhc most common causes. The laboratory investigation needed to evaluate dorsal midbrain syndrome is MRi. If no tumor is present and an infectious or inflammatory cause is suspected, a lumbar punctute should be performed.
Downgaze Paresis Isolated downgaze paresis is uncommon. Symptoms, when they occur, are difficulty in reading, eating, and walking down staits. Neurological examination reveals loss of downward pursuit and saccades, although occasionally pursuit may be spared. The vertical oculocephalic maneuver may be normal or may disclose gaze limitation. Convergence may be lost, and gaze-evoked upbeat nystagmus may be present on upwatd gaze. In young patients, one should evaluate forced ductions for evidence of congenital downgaze limitation. The site of the lesion for isolated downgaze paresis is bilateral involvement of the lateral portions of the riMLF. The differential diagnosis is ischemic stroke, PSP, and Whipple's disease. Laboratory investigations to support the clinical diagnosis include CT or preferably MRI. Lesions may be detected in the rostral mesodiencephalic junction inferior to the floor of the third ventricle. The diagnostic formulation of isolated downgaze limitation is uncomplicated. When acute in onset, it is usually due to ischemic cerebrovascular disease. In an elderly patient with a progressive course, PSP should be considered.
In ternu clear Ophthalmoplegia Internuclear ophthalmoplegia (INO) is characterized by paresis of adduction of one eye, with horizontal nystagmus in the contralateral eye when it is abducted. It is due to a lesion of the MLF ipsilateral to the side of the adduction weakness. Surprisingly, most patients with INO have no symptoms. The symptoms that may be associated with INO are diplopia, oscillopsia of one of the two images, and blurred vision. When diplopia is present, it is due to medial rectus paresis (horizontal diplopia) ot skew deviation (vertical diplopia).
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The MLF carries information for vertical pursuit and the vertical VOR. Consequently, other associated findings with MLF lesions are abnormal vertical smooth pursuit and impaired reflex vertical eye movements (doll's eye maneuver, Bell's phenomenon). Voluntary vertical eye movements (pursuit and saccades) are unaffected, daze-evoked vertical nystagmus, usually on upgaze, and skew deviation may be present. Skew deviation is a pure vertical ocular deviation that is not due to a cranial nerve palsy, orbital lesion, or strabismus but to disturbed suptanuclcar input to the third and fourth cranial nerve nuclei. It is thought to be due to unilateral damage to the otolith-oculat pathways or the pathways mediating the VOR. The topic is discussed further in Chapter 39. INO may occur as a false localizing sign. Cases of brainstem compression due to subdural hematoma with transtentorial herniation and cerebellar masses may cause INO. Myasthenia gravis and the Guillain-Barre syndrome may also simulate INO. The differential diagnosis is varied. Kxamination can differentiate a lesion of the MLF from a partial third cranial nerve palsy, myasthenia gravis, strabismus, or thyroid ophthalmopathy. The common causes of INO are stroke (including vertebral artery dissection) in older age-groups (Eggenberger et al. 2002) and multiple sclerosis in the young. Laboratory investigations are performed to elucidate the cause including MRI. An edrophonium (Tensilon) test should be performed to evaluate for myasthenia gravis unless there are associated signs of obligatory brainstem dysfunction. The diagnostic formulation for INO first necessitates accurate localization of the lesion. Limitation of adduction is initially formulated simply as an adduction deficit. It may be due to (1) a lesion of the midbrain or third cranial nerve disrupting innervation, (2) a disorder of the neuromuscular junction (myasthenia gravis), or (3) a lesion directly involving the medial rectus muscle.
Horizontal Gaze Paresis Although there are no common symptoms of horizontal gaze paresis, this condition seldom occurs in isolation. Patients may complain of inability to see or to look to the side. Because supranuclear gaze pareses are conjugate by definition, diplopia does not occur. On examination, with unilateral isolated involvement of the paramedian pontine reticular formation (PPRF), there is loss of ipsilateral saccades and pursuit. However, full horizontal eye movements are demonstrated with the oculocephalic maneuver. Lesions of the sixth cranial nerve nucleus cause horizontal gaze paresis with inability of the oculocephalic maneuver to overcome the gaze limitation. Although there is usually an associated ipsilateral peripheral facial palsy
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from involvement of the fascicle of the seventh cranial nerve coursing over the sixth cranial nerve nucleus, cases of isolated horizontal gaze paresis caused by sixth nerve nuclear lesions have been reported (Miller et al. 2002). With bilateral lesions, there is loss or limitation of horizontal saccades and (usually) pursuit in both directions. Gaze-paretic nystagmus may be present. In the acute phase, transient vertical gaze paresis and vertical nystagmus or upgaze paresis can occur. In the chronic phase, vertical eye movements are full, although there may be nystagmus on upgaze. The location of the lesion for horizontal gaze paresis is the frontopontine tract, mesencephalic reticular formation, PPRF, and sixth cranial nerve nucleus. The explanation of gaze palsy occurring with a nuclear lesion is given in Syndromes Involving Ocular Motor Nuclei, later in this chapter. The differentia] diagnosis is varied. As with other ocular motility disorders, myasthenia gravis may cause gaze limitation that simulates a central nervous system (CNS) lesion. The diagnostic formulation varies with age, rapidity of onset, and associated clinical findings. For patients with an acute onset whose age is older than 50 years, cerebrovascular disease, ischemic or hemorrhagic, is a likely cause. With a subacute onset before age 50 years, one should consider multiple sclerosis. Congenital cases are usually due to Mobius' syndrome. Systemic lupus erythematosus, syphilis, and Wernicke's encephalopathy should be considered for any acquired cases. Laboratory investigations for horizontal gaze paresis include MRI. If there are no obligatory signs of CNS dysfunction, myasthenia gravis needs to be considered.
Table 22,3:
Differential diagnosis of total ophthalmoplegia
Oculomotor a praxis Guillain-Barre syndrome Myasthenia gravis Thyroid ophthalmopathy (especially in combination with myasthenia gravis) Chronic progressive external ophthalmoplegia syndromes Wilson's disease Pituitary apoplexy Botulism Tetanus Progressive supranuclear palsy Anticonvulsant intoxication Wernicke's encephalopathy Acute bilateral pontine or mesodieneephalic lesions
gravis (sometimes in combination with thyroid ophthalmopathy) and Guillain-Barre syndrome are much more likely possibilities if the onset is subacute. If the presentation is long-standing, slowly progressive, and accompanied by eyelid ptosis, the CPF.O syndromes, such as Kearns-Sayre syndrome, should be considered. In these extra-axial disorders, oculocephalic reflexes do not overcome the gaze limitations. PSP is a diagnostic possibility in the elderly, whereas Wernicke's encephalopathy should be considered in alcoholics and nutritionally deprived patients, Whipple's disease can also cause this rare clinical presentation. Laboratory investigations for patients with global paralysis of gaze should include MRI. An edrophonium test is performed when myasthenia gravis is suspected. When botulism is suspected, elecrtomyography with repetitive stimulation and serum assay for botulinum toxin should be performed.
Global Paralysis of Gaze One-and-a-Half Syndrome The common symptoms of the global paralysis of gaze arc inability to look voluntarily (saccades and pursuit) in any direction. Global paralysis of gaze rarely occurs in isolation, however, and signs and symptoms of involvement of other local structures are usually present. The location of the lesion is the frontopontine tract for saccades, and the parieto-occipito-pontinc tract for pursuit, where they converge at the subthalamic and upper midbrain level. The differential diagnosis for total ophthalmoplegia is given in Table 22.3. The common causes for this presentation arc diseases outside the CNS, such as Guillain-Barre syndrome, myasthenia gravis, and chronic progressive external ophthalmoplegia (CPEO); for intraaxial lesions, consider stroke, Wernicke's encephalopathy, and PSP. The diagnostic formulation is usually concerned with extra-axial (cranial nerve, neuromuscular junction, or muscle) pathology, because isolated complete ophthalmoplegia is rarely caused by a brainstem lesion. Myasthenia
The one-and-a-half syndrome is characterized by a gaze palsy when looking toward the side of the lesion, together with INO on looking away from the lesion. The common symptoms are diplopia, oscillopsia (the illusion that objects or scenes are oscillating), and blurred vision. Associated findings arc skew deviation and gaze-evoked nystagmus on upgaze or lateral gaze, and less commonly on downgaze. Acutely, in the primary position there may be exotropia (one eye deviated outward). There may also be limitation of upgaze, saccadic vertical pursuit, and loss of convergence. The location of the lesion is the PPRF or sixth cranial nerve nucleus with extension to involve the intemuclear fibers crossing from the contralateral sixth cranial nerve nucleus, which causes the INO. The differential diagnosis is multiple sclerosis, stroke (Kataoka et al. 1997), arteriovenous malformation, or tumor of the lower pons. A pseudo-one-and-a-half syndrome may occur with myasthenia gravis or the Giiill.lm-l'.urc syndrome. The diagnostic formulation tor
BRAINSTEM SYNDROMES
the one-and-a-half syndrome is similar to that for INO. Before age 50 years, the wusc is usually multiple sclerosis; after age 50 years, it is usually cerebrovascular disease. Laboratory investigations for the one-and-a-half syndrome are MRI and if indicated lumbar puncture.
SYNDROMES INVOLVING OCULAR M O T O R NUCLEI Patients with lesions of the third or sixth cranial nerve nucleus not only present with accompanying long-tract signs but also show different ocular motility disturbances than with lesions of the third or sixth cranial nerve.
Third Cranial Nerve Nucleus The common symptoms of nuclear third cranial nerve palsies are diplopia and eyelid ptosis. The signs present on the side of the lesion are weakness of the inferior and medial recti and the inferior oblique muscles. Upgaze limitation is present in both eyes because the superior rectus subnucleus is conttalateral, and the axons cross within the nuclear complex. In addition, eyelid ptosis and dilated, unreactive pupils may be present on both sides because the levator subnucleus and EdingerWestphal nuclei arc bilaterally represented. To localize a lesion to the third cranial nerve nucleus, both eyes must have some involvement because of the bilateral representation. The superior rectus and levator of the eyelid, however, are bilaterally represented and thus cannot demonstrate single muscle involvement. In addition, because the medial rectus subnucleus is in the most ventral portion of the nucleus, and all the dorsal subnuclei send axons through it, single muscle involvement of the medial rectus may not be possible. The eyelid levator subnucleus may be spared, because it is located at the dorsocaudal periphery of the nuclear complex. The differential diagnosis is stroke (either ischemic or hemorrhagic), metastatic tumor, and multiple sclerosis. Of these diagnoses, only ischemic stroke is common. Disorders that simulate nuclear third cranial nerve palsy are myasthenia gravis, CPEO, thyroid ophthalmopathy, and the Guillain-Barre syndrome. The laboratory investigation for this syndrome is MRI, which usually demonstrates the ischemic cerebrovascular lesion. Once the proper localization has been made, the diagnostic formulation is straightforward.
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at the level of the sixth cranial nerve nucleus, join the MLF, and terminate on the medial rectus subnucleus of the third cranial nerve. Therefore a lesion of the sixth cranial nerve nucleus causes ipsilateral gaze palsy. Patients with isolated horizontal gaze paresis are usually asymptomatic. If they do have symptoms, they complain of difficulty looking to one side. On examination, there is conjugate horizontal gaze paresis not overcome by an oculocephalic maneuver or caloric stimulation. This occurs because the fibers mediating this response, the VOR, synapse in the sixth cranial nerve nucleus. A peripheral seventh cranial nerve palsy invariably accompanies a lesion of the sixth cranial nerve nucleus. The differential diagnosis is stroke (Miller et al. 2002), Wernicke's encephalopathy, multiple sclerosis, and a tumor of the pontomcdullary junction. Laboratory investigations for evaluating a lesion of the sixth cranial nerve nucleus are MRI, possibly lumbar puncture, and an edrophonium test to evaluate for myasthenia gravis if there are none of the long-tract signs obligatory for intra-axial disease.
OTHER BRAINSTEM AND ASSOCIATED SYNDROMES Diencephalic Syndrome (Russell's Syndrome) The common symptoms of diencephalic syndrome are emaciation with increased appetite, euphoria, vomiting, and excessive sweating (Pcrilongo et al. 1997). Patients may also have an alert appearance with motor hyperactivity. Most cases occur in children younger than 3 years. The differential diagnosis at this stage is hyperthyroidism, diabetes mellitus, a tumor in the region of fourth ventricle, vein of Galen malformation, and a hypothalamic tumor. Most patients appear pale despite lack of anemia. Ophthalmological findings include optic atrophy and less commonly nystagmus. Laboratory investigations for diencephalic syndrome may show an elevated serum growth hormone level that is incompletely suppressed by hyperglycemia. MRI usually demonstrates a hypothalamic mass lesion. Malignant cells may be present in the CSF, which are diagnostic. The CSF may also contain human chorionic gonadotropin in cases of germinomas. A lumbar puncture should not be performed if neuroimaging studies demonstrate a mass effect.
Thalamic Syndrome Sixth Cranial Nerve Nucleus The sixth cranial nerve nucleus has two populations of neurons. The abducens motor neurons terminate on the ipsilatetal lateral rectus muscle. Internuclear neurons cross
Thalamic syndrome was first described by Dejerine and Roussy in 1906. The common symptoms of this syndrome are pain (thalamic pain), numbness, and hemisi'nsory loss. The pain may be spontaneous or evoked by any form of stimulation. It often has a disagreeable and lasting quality.
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Patients may also complain of a distorted sense of taste. Right thalamic lesions appear to predominate. On examination, there is marked hemianesthesia, which may be dissociated; that is, pain and temperature or light touch and vibration sense may be separately lost. There is usually proprioceptive loss, often with astereognosis. A transitory hemiparesis sometimes occurs. The location of the lesion for this type of pain is usually the ventroposterolateral nucleus of the thalamus. In addition to the thalamus, thalamic-type pain can occur with lesions of the parietal lobe, medial lemniscus, and dorsolateral medulla (MacGowan et a I. 1997), The differential diagnosis is stroke or tumor. The diagnostic formulation depends on the rate of onset of symptoms, associated signs, and neuroimaging studies. The apoplectic onset of symptoms implicates cerebrovascular disease. Gradual onset with progressive worsening of symptoms and signs is characteristic of brain tumor, Neuroimaging studies should confirm the clinical impression. The imaging modality of choice is MRI.
Tectal Deafness The symptoms associated with tectal deafness are bilateral deafness associated with other related CNS symptoms, such as poor coordination, weakness, or vertigo. The differential diagnosis of the deafness is conduction-type hearing loss, cochlear disorders, bilateral eighth cranial nerve lesions, tectal deafness, and pure word deafness (sec Chapter 19). On examination, there is deafness that usually spares pure tones. Pure word deafness with lesions of the inferior eolliculi has been reported (Vitte et a I. 2002). Other brainstem signs, including the dorsal midbrain syndrome, are often associated. The location of the lesion is the inferior eolliculi, with the most common causes being a tumor of the brainstem, cerebellum, or pineal region, trauma, and stroke. The diagnostic formulation for hearing loss caused by lesions rostral to the cochlear nuclei is the presence of hearing loss characterized by sparing of pure tone, with marked deterioration when background noise distortion or competing messages are added. In addition, signs of damage to adjacent nervous system structures are present. Neuroimaging studies may confirm the diagnosis. The pertinent laboratory investigations include MRI and an audiogram. Tests that reveal CNS auditory loss are distorted speech audiometry, dichotic auditory testing, and auditory brainstem-cvoked responses, although the latter may be normal (Vitte et al. 2002).
Foramen Magnum Syndrome Foramen magnum syndrome is characterized by upper motor neuron-type weakness and sensory loss in any
modality below rhe head. Detecting this syndrome is important, because it is often caused by benign tumors, such as meningiomas or fibromas, which may be removed completely when detected early in their course. Its only manifestations may be those of a high spinal cord syndrome {see Chapter 27). The common, initial symptoms are typically neck stiffness and pain, which may radiate into the shoulder. Occipital headache also may be an early symptom. Other common symptoms are weakness of the upper or lower extremities, numbness (most commonly of hands or arms}, clumsiness, and a gait disturbance. The differential diagnosis at this stage is cervical spondylosis, syringomyelia, multiple sclerosis, transverse myelitis, atlantoaxial subluxation, Chiari malformation, and foramen magnum or upper cervical cord tumor. On examination, hemiparesis or quadriparesis and sensory loss are common. The loss of sensation may involve all modalities. It may be dissociated and capelike or occurring in a C2 distribution. Some patients have a hemisensory pattern below the cranium or involvement of only the lower extremities. Pseudoathctosis resulting from loss of joint position sense may be an early sign. Atrophy of muscles of the upper extremities may occur at levels well below the lesion (e.g., intrinsic muscles of the hands). Electric shock-like sensations radiating down the spine, which may be transmitted into the extremities, may occur with neck flexion (Lhermitte's sign). This finding occurs with lesions of the posterior columns, most commonly multiple sclerosis. Lower cranial nerve patsies are less common. The presence of downbeat nystagmus in primary position or lateral gaze strongly suggests a lesion of the cranioccrvical junction. This sign may be missed unless the eyelids are manually elevated and the nystagmus is sought when the patient gazes laterally and slightly downward. The differential diagnosis at this stage is a foramen magnum or upper cervical cord tumor. The tumor type is usually meningioma, neurofibroma, glioma, or metastasis. Cervical spondylosis, multiple sclerosis, syringobulbia, and the Chiari malformation (often accompanied by a syrinx) are other diagnostic considerations. The definitive laboratory investigation for evaluation of the foramen magnum syndrome is MRI. Patients with foramen magnum tumors may have a relapsing-remitting course that simulates multiple sclerosis. Because many of these tumors are meningiomas, one slit HI Id lv alert for patients at. risk. Meningiomas occur with increased frequency in women in their childbcaring years and increase in size during pregnancy. Cervical spondylosis is usually associated with a related radiculopathy and is not accompanied by downbeat nystagmus or lower crania] nerve abnormalities. Diagnosis requires a high index of suspicion early in the patient's course. Foramen magnum tumors are known to present difficult diagnostic problems because signs may be minimal despite a large tumor.
BRAINSTEM SYNDROMES
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Syringobulbia Syringobulbia is a disorder of the lower brainstem caused by progressive enlargement of a fluid-filled cavity that involves the medulla and almost invariably the spinal cord (syringomyelia). The symptoms and signs are primarily those of a disorder of the central spinal cord region (see Syringomyelia in Chapter 79; also sec Chaprct 66). The common symptoms of syringobulbia and syringomyelia arc painless burns, hand numbness, neck and arm pain, leg stiffness, and headache together with oscillopsia, diplopia, or vertigo. On examination, there are signs of lower brainstem dysfunction. Lower motor neuron signs of the ninth through twelfth cranial nerves may be present. Nystagmus, if present, is hotizontal, vertical, or rotatory. Signs of a spinal cord lesion characteristically coexist. In the upper extremities, there may be dissociated anesthesia of an upper limb or forequartet (i.e., loss of pain and temperature sensation with sparing of other modalities). The sensory loss may also be in a hemisensory distribution. Absent or decreased deep tendon reflexes in the upper extremities are the rule. Spastic patapatesis, usually asymmettic, may occur. Loss of facial sensation can occur in an onionskin pattern emanating from the corner of the mouth. Charcot's (neuropathic) joints and trophic skin disorders can appear in long-standing cases. Horner's syndrome and bowel and bladder disturbances are other occasional findings. The lesion is located in a rostrocaudal longitudinal cavity from the medulla into the spinal cord. The cavity is usually located near the fourth ventricle or central canal of the spinal cotd. The definitive laboratoty investigation fot syringobulbia is MRl, the most reliable and sensitive test to demonsttate a syrinx. The differential diagnosis is intrinsic central cord and lowet brainstem lesion (syrinx, tumor, or trauma) and compressive foramen magnum syndrome caused by a tumor. Less likely causes are multiple sclerosis and spinal arachnoiditis. The diagnostic formulation for syringobulbia involves history, examination, and laboratory evaluation. It is usually a disease of young adults, with a peak incidence in the third and fourth decades. Painless burns and dissociated segmental anesthesia of the upper extremities are of major diagnostic significance. Multiple sclerosis requires the presence of other noncontiguous lesions, oligoclonal bands in the CSF, and characteristic MRl findings. Tumors usually produce a more rapid course. Williams (1993) reviewed the treatment.
BRAINSTEM ISCHEMIC STROKE. SYNDROMES Caplan, Pesin, and Mohr (1992) found that vcrtcbtobasilar ischemic lesions often have a rostrocaudal or patchy localization (Figure 22.1}, rather than the simplified
FIGURE 22.1 A postmortem examination of a patient of Kubik and Adams with embolism of the basilar artery. Note the rostrocaudal extension of the infarction along with its patchy nature. (Reprinted with permission from Kubik, C. S. &c Adams, 11. D. 1946, "Occlusion of the basilar artery: A clinical and pathological study," P>rain, vol. 69, pp. 73-121.)
transverse localization that is usually schematized. In addition, all the patient's symptoms and signs may not be explainable in anatomical terms; thai is, clinicopathological correlation may not be precise. The cardinal manifestations of brainstem stroke are involvement of the long tracrs of the brainstem in combination with cranial nerve deficits. Crossed cranial nerve and motor or sensory long-tract deficits are characteristic. The cranial nerve palsy is ipsilatetal to the lesion and the long-tract signs are contralateral, hence the term crossed. Coma, ataxia, and vertigo, which ate common with vcrtcbtobasilar stroke, ate uncommon with internal carotid artery circulation stroke. INO, unreactive pupils, lower motor neuron cranial nerve impairment, and ocular skew deviation, when caused by stroke, occur only with posterior circulation lesions. The same is usually true fot nystagmus and most other ocular oscillations. Another characteristic of vertebrobasilar ischemia is bilateral involvement of the long tracts. This can result in locked-in syndrome. This syndrome, usually caused by a lesion of the basis pontis, is characterized by quadriplegia with corticobulbar tract involvement and loss of the ability to produce speech. The reticular activating system is spared, and thus consciousness is preserved. Lye movements or blinking may be all that is left under voluntary control. Anothet manifestation of bilateral lesions of the long tracrs is pseudobulbar palsy. The symptoms resemble those that occut with lesions of the medulla (bulb). However, cranial nerve nuclei have been disconnected from cortical input. This causes dysarthria, dysphagia, bilateral facial weakness, extremity weakness, and emotional lability.
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
A m o r e descriptive term for this s y n d r o m e is supranuclear bulbar palsy. Blindness occurs with bilateral posterior cerebral a r t e r y occlusion a n d c o n c o m i t a n t occipital lobe infarction. Ischemic stroke s y n d r o m e s a r c outlined in the following sections. These s y n d r o m e s o c c u r in isolation, as presented here, and in c o m b i n a t i o n . T h e c o m b i n a t i o n s can be medial, with lateral or often r o s t r o c a u d a l extension.
T h a l a m i c Stroke S y n d r o m e s T h e blood supply of t h e t h a l a m u s is from t h e posterior cerebral, posterior c o m m u n i c a t i n g , basilar c o m m u n i c a t i n g (Figure 22,2), and anterior a n d posterior c h o r o i d a l arteries. T h a l a m i c stroke s y n d r o m e s are listed in T a b l e 2 2 . 4 . T h e y have been reviewed by K u m r a l et al. 2 0 0 1 ,
M i d b r a i n Stroke S y n d r o m e s
FIGURE 22.2 Branches of the basilar communicating artery as seen in a sagittal section of the brainstem. (1) Thalamic polar, (2) posterior communicating, (3) posterior th alamo subthalamic paramedian, (4) superior paramedian, (5) inferior paramedian, and (6) mesencephalic paramedian. (Reprinted with permission from Percheron, G. 1976, "Les arteres et territoires du thalamus humain: II. Arteres et territoires thalamiques paramedians de 1'artere basilare communicante," Rev Neurol, vol. 132, pp. 309-324.)
Ischemia of t h e m i d b r a i n is characterized by long-tract signs c o m b i n e d with involvement of the third and fourth Tabic 22.4:
Ischemic stroke syndromes of the diencephalon
Anterolateral Common symptoms Contralateral weakness, vision loss Confusion Disorientation Language disturbance Signs Contralateral I Icimparesis Hemiataxia Hemisensory loss Homonymous hemianopia Right-sided lesion: visuospatial abnormalities, hemincglect, nonverbal intellect affected Left-sided lesion: disorientation, aphasia Arterial territory involved: thalamic polar (tuberothalamie) artery (see Figures 22.2 and 22.3) Medial Common symptoms Disorientation and confusion Coma with occlusion of mainstem variant Visual blurring Signs Vertical gaze ophthalmoplegia Loss of pupillary reflexes Loss of convergence Disorientation and confusion, stupor, coma, and various neuropsychiatry disturbances Arterial territory involved: posterior tliaUunosLtbthahimic paramedian artery (thalamic paramedian or deep interpeduncular profundus artery [see Figures 22.2 and 22.3]) Lateral and posterior internal capsule Common symptoms Contralateral
Hemiparesis Numbness Confusion Signs Contralateral Hemiparesis Diminished pain and temperature Dysarthria Homonymous hemianopia; characteristically with a tongue of visual field spared along the horizontal meridian (Figure 22.4] Memory impairmenr With right-sided lesions: visuoperceptual abnormalities Arterial territory involved: anterior choroidal artery (see Figure 22.3) Posterolateral Common symptoms Contralateral Weakness Numbness Vision loss Neglect Confusion Signs Contralateral Loss of touch, pain, temperature, and vibration sense (common) Hemiparesis in some Hemiataxia Homonymous hemianopia Left hemispatial neglect Poor attention span Arterial territory involved: gcniculothalamic artery (see Figure 22.3)
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Blood flows to the upper mesencephalon via perforating btanches of the basilar communicating artery. The basilar communicating artery (PI segment of the posterior cerebral artery or mesencephalic artery) connects the basilar artery with the posterior communicating artery. A simplified scheme used here divides the vasculat tctritories into median and lateral transverse regions. The medial midbrain syndromes are characterized by an ipsilateral thitd cranial nerve palsy associated with a contralateral hemi paresis. Loss of the discriminative sensations (proprioception, vibration, and stereognosis) with involvement of the medial lemniscus may occur. The lateral syndromes are composed of contralateral loss of pain and temperature sensation and ipsilateral Horner's syndrome and loss of facial sensation. Ataxia may occur on either side. Ischemic stroke syndromes of the mesencephalon are outlined in Table 22.5, and the eponymic designations are given in Table 76.1.
Pontine Stroke Syndromes FIGURE 22.3 Schematic computed tomography sections showing the five arterial territories of the thalamus: (A) geniculothalamic (inferolateral) artery territory; (B) anterior thalamosubthalamic paramedian (tuberorhalamic} territory; (C) posterior choroidal territory; (D) posterior thalnmosubrhalamic paramedian territory; (E, F) anterior choroidal territory. (Modified with permission from Bogousslavsky, J„ Regti, F., & Uske, A. 1988, "Thalamic infarcts: Clinical syndromes, etiology and prognosis," Neurology, vol. 38, pp. 837-848.) cranial nerves (Kumral et al. 2002b). Supratentorial (anterior circulation) stroke syndromes may present with midbrain signs when rostrocaudal deterioration occurs, causing transtentorial herniation. There are numerous classifications of the blood supply to the brainstem, and this is nowhere more apparent than in the midbrain.
Acuity
20'?°
The pons is supplied by numerous penetrating branches of the basilar artery. These arteries have little collateral supply; consequently, lacunar syndromes (see Chapter 57A) commonly occur (Table 22.6). These syndromes may be clinically indistinguishable from lacunar syndromes due to lesions of the interna! capsule. The medial syndromes are characterized by contralateral hemiparcsis and ipsilateral ataxia, 1NO, and conjugate horizontal gaze paresis. The lateral syndromes arc distinguished by contralateral hemianesthesia and loss of discriminative sensation with ipsilateral Horner's syndrome, facial hemianesthesia, and ataxia. Ipsilatetal lower motor neuron-type facial paresis, sixth cranial nerve paresis, deafness, and vertigo occur with inferior pontine lesions.
Nov 28. 1983
RE
Acuity 2 0 / 2 5
FIGURE 22.4 Typical homonymous hemianopia associated with anterior choroidal artery infarction. Notice the tongue of preserved vision along the horizontal meridian. This pattern is highly localizing to the lateral geniculate nucleus. (LE = left eye; RE = right eye.) (Reprinted with permission from Hclgason, C, Caplan, L., Goodwin, J., et al. 1986, "Anterior choroidal artery territory infarction: Report of cases and review," Arch Neurol, vol. 43, pp. 681686.)
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 22.5:
Ischemic sttoke syndromes of the mesencephalon
Middle median midbrain syndrome Common symptoms Contralateral Weakness Ataxia Numbness I psi lateral Eyelid ptosis Ataxia Diplopia Signs Contralateral Weakness Ataxia Supranuclear horizontal gaze paresis lpsilateral Third cranial nerve palsy Nuclear Fascicular [nternuclear ophthalmoplegia Arterial territory involved: median and paramedian perforating branches of the hasilar or mesencephalic arteries Middle lateral midbrain syndrome (Figure 22.5) ( .ominoii symptoms Numbness: contralateral Clumsiness: ipsilateral Signs Contralateral Hemianesthesia Ataxia Ipsilateral Facial hemianesthesia (or contralateral)
Horner's syndrome Ataxia (if lesion is ventral to brachium conjunctivum) Atterial territory involved: superior cerebellar artery Inferior medial midbrain syndrome (Figure 22.6) Common symptoms Diplopia Contralateral weakness (Itiiusiuess Signs Contralateral Fourth cranial nerve palsy Ataxia (may he ipsilateral, depending on whether the lesion is before or after the crossing of the brachium conjunctivum) Hcmiparesis Supranuclear horizontal gaze paresis (ipsilateral if below decussation in lower midbrain) Ipsilateral Internuclear ophthalmoplegia Arterial territory involved: median branches of the hasilar artery Inferior lateral midbrain syndrome (sec Figure 22.6) Common symptoms Contralateral numbness Signs Contralateral Hemianesthesia Ipsilateral Hemianesthesia of face Horner's syndrome Arterial territory involved: superior cerebellar artery
Superior col lieu I us
BRAINSTEM SYNDROMES
283
Tabic 22.6: I sell emit stroke syndromes of the pons Superior medial pontine syndrome (Figure 22.7) Common symptoms Contralateral weakness Clumsiness Signs On side of lesion Ataxia Inter nuclear ophthalmoplegia Myoclonus of palate, pharynx, vocal cords On side opposite lesion Paralysis of face, arm, and leg Arterial territory involved: median branches of the basilar artery Superior lateral pontine syndrome (see Figure 22.7) Common symptoms Clumsiness; ipsilateral Contralateral numbness Dizziness, nausea, vomiting Signs On side of lesion Ataxia of limbs and gait, falling to side of lesion Horner's syndrome Facial hemianesthesia Paresis of muscles of mastication On side opposite lesion Hemianesthesia (trigeminothalamic tract) impaired touch, vibration, and position sense Arterial territory involved: superior cerebellar artery .Middle medial pontine syndrome (Figure 22.8) Common symptoms Contralateral hemiparesis Ipsilateral clumsiness Signs On side of lesion Ataxia of limbs Conjugate gaze paresis toward the side of the lesion Internuclear ophthalmoplegia On side opposite lesion Paresis of face, arm, and leg With bilateral lesions, locked-in syndrome may occur Arterial territory involved: median branches of the basilar artery Middle lateral pontine syndrome (sec Figure 22.8) Common symptoms Numbness Clumsiness Chewing difficulty Signs
M e d u l l a r y Stroke S y n d r o m e s M e d i a l medullary ischemia can c a u s e crossed hypoglossal hemiparesis s y n d r o m e (Table 2 2 . " ) . In a d d i t i o n , patients may have loss of discriminative-type sensation (position sense, graphesthesia, a n d stereognosis) w h e n there is associated medial lemniscus involvement. K u m r a l et al. (2002a) h a v e described four p a t t e r n s of medial medullary stroke: (1) the most frequent classic crossed hypoglossal hemiparesis s y n d r o m e , (2) s e n s o r i m o t o r s t r o k e w i t h o u t
Contralateral Hemisensory loss Ipsilateral Ataxia of limbs Paralysis of muscles of mastication Impaired pain sensation over side of face Horner's syndrome Arterial territory involved: long lateral branches of basilar a r t e r y
Inferior medial pontine syndrome (Foville's syndrome) (Figure 22.9) Common symptoms Contralateral weakness and numbness Facial weaknesses: ipsilateral Diplopia Signs Contralateral Paralysis of arm and leg Impaired tactile and proprioceptive sense over half the body Internuclear ophthalmoplegia Ipsilateral Paresis of conjugate gaze to side of lesion; to oeulocephalic maneuver also if the sixth cranial nerve nucleus is involved One-and-a-half syndrome Nystagmus Diplopia on lateral gaze Lower motor neuron—type facial palsy Arterial territory involved: median branches of the basilar artery Inferior lateral pontine syndrome (anterior inferior cerebellar artery syndrome) (see Figure 22.9) Common symptoms Vertigo, nausea, vomiting Oscillopsia Deafness, tinnitus Facial numbness Dyscoordination Signs Contralateral Impaired pain and thermal sense over half the body (may include the face) Ipsilateral Deafness Facial paralysis Ataxia Impaired sensation over face Arterial territory involved: anterior inferior cerebellar artery
lingual palsy, (3) p u r e hemiparesis, a n d (4) bilateral medial medullary s t r o k e . Lateral medullary s y n d r o m e (Wallenberg's s y n d r o m e ) is o n e of t h e m o s t d r a m a t i c clinical presentations in neurology (see T a b l e 2 2 . 7 ) . Long-tract signs (i.e., c o n t r a l a t e r a l loss of pain a n d t e m p e r a t u r e sensation over half the b o d y , ipsilateral a t a x i a , a n d H o r n e r ' s s y n d r o m e ) are a c c o m p a n i e d by i n v o l v e m e n t of the nuclei a n d fasciculi of cranial nerves V, VIII, IX, a n d X, N y s t a g m u s is often present. T h e critical sign t h a t distinguishes this from a lateral
2K4
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
11RA1NSTEM SYNDROMES
Table 22.7:
285
Ischemic stroke syndromes of the medulla
Medial medullary syndrome (Figure 22.10) Common symptoms Contralateral weakness Dysarthria Signs Contralateral Paralysis of arm and leg, sparing face Impaired tactile, vibratory, and proprioceptive sense over half the body I psi lateral Paralysis with atrophy (late) of hall the Longue Prima ry-posh ion upbeat nystagmus Arterial territory involved: occlusion of vertebral artery or branch of vertebral or lower basilar artery or anterior spinal artery Lateral medullary syndrome (Wallenberg's syndrome) (see Figure 22.10) Common symptoms Ipsilateral facial pain and numbness Vertigo, nausea, and vomiting Ipsilateral clumsiness Diplopia, oscillopsia Numbness ipsilateral or contralateral to lesion
Dysphagia, hoarseness Signs Contralateral Impaired pain sensation over half the body, sometimes including the face Ipsilateral Impaired sensation over half the face Ataxia of limbs, falling to side of lesion Horner's syndrome Dysphagia, hoarseness, paralysis of vocal cords Diminished gag reflex Loss of taste Other Nystagmus Primary-position rotatory Gaze-evoked horizontal Downbeating on lateral gaze Ocular skew deviation Hiccup Arterial territory involved: occlusion of any of five vessels may be responsible: vertebral; posterior inferior cerebellar; or superior, middle, or inferior lateral medullary arteries
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APPROACH TO COMMON NEUROLOCICAI. PROBLEMS
pontine s y n d r o m e is involvement of the nucleus a m b i g u u s or its fasciculus and c o n s e q u e n t w e a k n e s s of the ipsilatcral palate and vocal c o r d . (A m o r e detailed discussion of s t r o k e is found in C h a p t e r 57A.)
REFERENCES Averbuch-Heller, L, Paulson, G. W., Daroff, R. B., & Leigh, R.J. 1999, "Whipple's disease mimicking progressive supranuclear palsy: The diagnostic value of eye movement recording," j Neurol Neurosurg Psychiatry, vol. 66, pp. 532-535 Bogousslavsky, J., Macder, P., Rcgli, F., & Meuli, R. 1994, "Pure midbrain infarction: Clinical syndromes, MRI, and etiologic patterns," Neurology, vol. 44, pp. 2032-2040 Ciplan,!.. R„ Pesin, M . S . , & Mohr,J. P. 1992, "Vertebrobasilar occlusive disease," in Stroke: Pathophysiology, Diagnosis and Management, eds H. M. J, Barnett, J, P. Mohr, B. M. Stein, et al., Churchill Livingstone, New York Eggenberger, E., Golnik, K., Lee, A., et al. 2002, "Prognosis of ischemic interiuiclcar ophthalmoplegia," Ophthalmology, vol. 109, pp. 1676-1678 Graff-Red ford, N. R., Damasio, H., & Yamada, T. 1985, "Nonhacmorrhagic thalamic infarction: Clinical, neuropsychological and electrophysiological findings in four anatomical groups defined by computerized tomography," Brain, vol. 108, pp. 485-516 Kataoka, S., Hori, A., Shirakawa, T., & Hirose, G. 1997, "Paramedian pontine infarction. Neurological/topographical correlation," Stroke, vol. 28, pp. 809-815 Kubik, C. S. & Adams, R. D. 1946, "Occlusion of the basilar artery: A clinical and pathological study," Brain, vol. 69, pp. 73-121 Kumral, E., Afsar, N., Kirbas, D., et al. 2002a, "Spectrum of medial medullary infarction: Clinical and magnetic resonance imaging findings," / Neurol, vol. 249, pp. 85-93
Kumral, E., Bayulkem, G., Akyol, A., et al. 2002b, "Mesencephalic and associated posterior circulation infarcts," Stroke, vol. 3 3 , pp. 2224-2231 Kumral, E., Evyapan, D., Balkir, K., ct al. 2001, "Bilateral thalamic infarction. Clinical, etiological and MRI correlates," Acta Neurol Scand, vol. 103, pp. 35-42 Lee, A. G. 2002, "Whipple disease with supranuclear ophthalmoplegia diagnosed by polymerase chain reaction of cerebrospinal fluid," j Neuro-Ophthalmol, vol. 22, pp. 18-21 Leigh, R. J. & Zee, D. S. 1999, The Neurology of Eye Movements, 3rd ed, Davis, Philadelphia MacGowan, D. G. L., Janal, M, N., Clark, W. C, et al. 1997, "Central poststroke pain and Wallenberg's lateral medullary infarction. Frequency, character, and determinants in 6i patients," Neurology, vol. 49, pp. 120-125 Miller, N. R., Biousse, V., Hwang, T., et al. 2002, "Isolated acquired unilateral horizontal gaze paresis from a putative lesion of the abducens nucleus," j Neuro-Ophthalmol, vol. 22, pp. 204-207 Morgan, D. Sc Williams, R. 1992, "Syringobulbia: A surgical appraisal," / Neurol Neurosurg Psychiatry, vol. 55, pp. 1132-1141 Pcrilongo, G., Carollo, C, Salviati, L., et al. 1997, "Diencephalic syndrome and disseminated juvenile pilocytic astrocytomas of the hypothalamic-optic chiasm region," Cancer, vol. 80, pp. 142-146 Rottach, K. G., Riley, D. E., DiSccnna, A. O., et al. 1996, "Dynamic properties of horizontal and vertical eye movements in parkinsonian syndromes," Ann Neurol, vol. 39, pp. 368-377 Tatemichi, T. K., Steinke, W„ Duncan, C, et al. 1992, "Paramedian thalamopeduncular infarction: Clinical syndromes and magnetic resonance imaging," Ann Neurol, vol. 32, pp. 162-17 ] Vitte, E., Tankerc, F., Bernat, I., et al. 2002, "Midbrain deafness with normal brainstem auditory evoked potentials," Neurology, vol. 58, pp. 970-973 Williams, R. 1993, "Surgical treatment of syringobulbia," Neurosurg Clin North Am, vol. 4, pp. 553-571
Chapter 23 Ataxic Disorders S. H. Subramony Symptoms and Signs of Ataxic Disorders Symptoms in Patients with Ataxia Neurological Signs in Patients with Cerebellar Ataxia
287 287 288
The term ataxia is used by clinicians to denote a syndrome of imbalance and incoordination involving gait and limbs, as well as speech; it usually connotes a disorder involving the cerebellum or its connections (Middleton and Strick 1998). Ataxia can also result from disturbances of sensory input to the cerebellum, especially proprioceptive input. The clinical approach to patients with ataxia involves differentiating ataxia from other sources of imbalance and incoordination, distinguishing cerebellar from sensory ataxia, and designing an evaluation based on knowledge regarding various causes of ataxia and cerebellar disorders (Massaquoi and Hallett 2002). This chapter describes the clinical features of ataxia and outlines a basic approach to patients presenting with ataxia.
SYMPTOMS AND SIGNS OF ATAXIC DISORDERS In the case of cerebellar diseases, a few general statements can be made. In lateralized lesions of the cerebellum, signs and symptoms occur ipsilateral to the lesion. Generalized cerebellar lesions give rise to symmetrical symptomatology. Acute cerebellar lesions often produce severe abnormalities early but may show remarkable recovery with time. Chronic progressive diseases of the cerebellum tend to cause a gradually declining balance with longer lasting effects. To some extent, signs and symptoms have a relation to the location of the lesions in the cerebellum (Fine, Ionita, and Lohr 2002). Thus vestibulocerebellar lesions cause disequilibrium and an ataxic gait. Lesions of the vermis, which is primarily a "spinocerebellar organ," cause truncal and gait ataxia with relative sparing of the limbs. Neocerebellar lesions (cerebellar hemispheres) produce more severe appendicular ataxia.
Symptoms in Patients with Ataxia 1. Gait disturbances: Patients with cerebellar and sensory ataxia often present with abnormalities of gait. The
Neurological Signs in Patients with Sensory Ataxia Approach to Patients with Ataxia
290 290
initial symptom may be a sense of insecurity while walking, especially when doing acts that require a bit more skill such as turning or balancing on a narrow ledge. Even before gait becomes abnormal, patients may note problems with specialized skills they have previously learned, such as skiing, bicycling, or climbing. Patients may report the sense of imbalance as dizziness, but the sensation is more like being on a boat rather than vertigo. Patients and family notice that the patient feels more secure with feet progressively apart. An increase in imbalance when visual cues are removed suggests a sensory component to the ataxia. 2. Limb ataxia: Ataxic diseases cause a variety of symptoms in the upper limbs, resulting from incoordination and tremor. Patients report clumsiness with activities such as writing, picking up small objects, and buttoning. Patients become slow in their movements in an attempt to be more accurate. These symptoms are one sided with lateralized lesions of the cerebellum. 3. Truncal ataxia: Midline cerebellar lesions cause truncal ataxia. Patients may experience head tremor and a truncal instability leading to oscillatory movement of the head and trunk while sitting or standing {tituhation). Because of associated hypotonia, they may need back support while sitting. 4. Dysarthria and bulbar symptoms: Ataxic diseases of cerebellar origin result in slurred speech and abnormalities of pitch and volume control. Dysphagia may result from incoordination of swallowing muscles. 5. Visual symptoms: Patients may experience blurriness or a sense of environmental movements as a result of ocular oscillations associated with cerebellar disease. 6. Symptoms in sensory ataxia: Patients with a sensory basis for ataxia usually do not experience dysarthria or visual symptoms. They may report other symptoms of peripheral nerve disease such as paresthesias and numbness. 28?
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Neurological Signs in Patients with Cerebellar Ataxia Gordon Holmes (1922; 19.39) is often credited with the initial descriptions of cerebellar deficits, although certainly earlier works had reported on the effects of cerebellar lesions. Lesions of the cerebellum can cause deficits involving gait and stance, limb incoordination, muscle tone, speech, and oculomotor system. There is also recent interest in the possibility that the cerebellum may have some role in cognitive function. 1. Stance and gait: Patients with cerebellar disease experience an increase in body sway, initially when the feet are placed together. The trunk moves excessively in the sideways direction (latcropulsion). With more severe disease, patients experience the increased sway with even normal stance and learn that balance is better with feet apart. Healthy persons have a spread of feet during normal stance of usually less than 12 cm; patients with cerebellar disease tend to have a much larger spread of feet during quiet stance (Manto 2002). In the clinic, one can detect problems with balance even earlier by asking the patient to do a tandem stance or stand on one foot; normal adults can do these maneuvers for at least 30 seconds. The Romberg test is usually positive in patients with cerebellar ataxia, although this tends to be more prominent in patients with proprioceptive or vestibular lesions. Lastly, many patients experience rhythmic oscillations of the trunk and head known as titubation. Severe truncal ataxia can also result in inability to sit without back support. Gait can be tested by asking the palienl lo walk naturally down a straiglil path. Ataxic gait is characterized by a widened base and an irregular staggering appearance resembling alcoholic intoxication. Overall, the speed of movements is not severely impaired, although patients may deliberately slow down to keep their balance. The steps are irregular and the patient may lurch in unpredictable ways. Ataxic gait disturbance can be detected even earlier by testing tandem gait; patients with cerebellar lesions lose their ability to do heel-to-toe walking in a straight line. 2. Limb incoordination: A number of clinical tests have been designed to test limb incoordination and the presence of tremor usually associated with cerebellar lesions. The finger-to-nose test involves touching the tip of the nose with the tip of the index finger repeatedly after extending the arm. The finger-tofinger test is done by asking the patient to touch the examinct's finget repeatedly and rapidly as the examiner moves his or her finger to a different location. Action tremor can be examined by placing the arms in the outstretched position and asking the patient to point the index fingers at each other at about chest level separated by about 1 cm. Rapid alternating
movements are examined by asking the patient to supinatc and pronatc the forearm in the unsupported position. This can also be done by having the patient clap one hand on the other (stationary) hand alternately with the palm and dorsum of the clapping hand. Rebound is examined by allowing the patient to flex the elbow against the examiner's hand and then abruptly removing the resistance and assessing the ability of the patient to arrest the sudden flexion movement. In the lower limbs, the heel-to-shin maneuver is done by having the patient bring the heel of the leg being tested to the opposite knee and then sliding it in a straight line down the anterior aspect of the tibia to the ankle. The foot should be nearly vertical while doing this. Having the patient rest the heel on the opposite knee for a period can elicit tremor in the leg. The toc-to-finger test is done by asking the patient to touch the examiner's finger repeatedly as the examiner moves the finget to a new position. Lower limb testing is best done in the supine position. These tests detect the following abnormalities in patients with ataxia: a. Dysmetria: This term refers to an error in the path of movement so that the desired target is either under-reached (hypometria) or over-reached (hypermetria). Dysmetria is evident in the finger-to-finger and toe-to-finger tests. Holmes thought of dysmetria as a disturbance of the rate, range, and force of movement. Dysmetria is often increased by adding a mass to the hand. b. Intention (kinetic) tremor: Oscillations of the limbs that show a characteristic increase in amplitude at the end of a voluntary movement intended to reach a target are typically seen with cerebellar lesions. The oscillations appeat to result from instability at the proximal, rather than the distal, portions of the limbs and are typically perpendicular to the axis of motion. In contrast, patients with essential tremor who do not have any other cerebellar signs may exhibit an cxaggctation of their tremor at the termination of a purposeful movement that is primarily in the distal portions of their limbs. The finger-to-nose and heel-to-shin maneuvers detect the kinetic tremor. Kinetic tremor is better evaluated when mass is added to the hand. c. Action tremor: Cerebellar lesions can give rise to a postural tremor initiated by keeping the arms outstretched or pointing the fingers steadily at each other. In the legs, maintaining one heel on the opposite knee can bring out such a tremor. d. Other types of tremor: Ataxic patients can exhibit an axial tremor involving the head and shoulders. Also, a severe tremor in the upper limbs that has both an intention and a postural component can appear in cerebellar outflow tract disease. This has been also
ATAXIC DISORDERS called a "rubral" tremor or "wing-beating" tremor. This cerebellar outflow tremor is often seen in multiple sclerosis, Wilson's disease, and midbrain strokes. e. Dysdiadochokinesis: This term refers to irregularity of the rhythm and amplitude of rapid alternating movements. Simple tapping movements such as the index finger on the thumb crease or the feet on the floor can also detect the disturbance in rhythm (dysrhyth mokincsis). f. Decomposition of movements; The characteristic jerkiness and the appearance that the movements are composed of their elemental components rather than a smooth finished product are referred to as decomposition of movements. This overall feature of ataxic movements can be conceptualized as being secondary to a combination of dysdiadochokinesis, dysmetria, and kinetic tremor, 3. Abnormalities of muscle tone and strength; Although hypotonia can occur with acute cerebellar lesions, this is not a major feature of most cerebellar diseases. The inability of patients to check forearm movement in the rebound test is often quoted to result from hypotonia but may have other explanations. Similarly, cerebellar lesions do not cause a loss of strength in the traditional sense, but many patients experience problems with sustaining a steady force during sustained hand use (isometrataxia) (Manto 2002). 4. Oculomotor disturbances (Martin and Corbett 2000): Routine eye movement examination can detect most of the signs of cerebellar disease. Fixation abnormalities are examined by asking the patient to maintain sustained gaze at the examiner's finger held about 2 feet in front. Then the patient is asked to follow the finger as it is moved slowly in all directions of gaze (pursuit). Eccentric gaze is maintained (at about 30degree deviation) to check for nystagmus. Saccades are tested by having the patient shift gaze quickly between an eccentrically held finger and the examiner's nose in the middle. More sophistication can be brought to clinical examination by looking at the vestibulo-ocular reflex (VOR), with the patient in a rotary chair and looking at an object that moves with the chair. Rotating striped drum is used to examine for optokinetic nystagmus (OKN) and Frenzel goggles can be used to remove fixation. a. Disorders of pursuit: Pursuit movements include fixation (pursuit at 0 degree velocity). Small, 0.1-0.3-degrce square wave movements of the eyes are often seen even in normal persons during fixation. Square wave jerks exceeding 10 per minute are indicative of central nervous system (CNS) disease but arc not as specific for cerebellar ataxia as are large-amplitude square wave jerks. Square wave jerks larger than 10 degrees in
289
amplitude are called macrosquare wave jerks. The square wave jerks are so called because in eye movement recordings they appear as 2 saccades in opposite directions separated by a short period of no movement, giving a "square" appearance to the waveform. Cerebellar disease also slows down pursuit movements, requiring catch-up saccades to keep up with a moving target. Such saccadic intrusions and intrusions of square wave jerks give a "ratchety" appearance to pursuit movement. b. Disorders of saccades: Saccade velocity is normal in cerebellar disease, but its accuracy is impaired so that both hypermetric and hypomctric saccades are seen. Such saccades are followed by a corrective saccade in the appropriate direction (Munoz 2002). c. Other saccadic intrusions: Ocular flutter differs from square wave jerks in that the back and forth horizontal saccades are not separated by an intcrsaccade interval. Opsoclonus is characterized by continuous saccades in all directions in a chaotic fashion. Both ocular flutter and opsoclonus are associated with cerebellar disease, especially paraneoplastic or postinfectious syndromes. d. Nystagmus: Gaze-evoked nystagmus is elicited when eccentric gaze is maintained at about 30 degrees from the midline. There arc repetitive drifts of the eyes toward midline followed by saccades to the eccentric position. The fast phase of the nystagmus is always to the side of the eccentric gaze. This nystagmus is usually seen in cerebellar disease. When typical gaze-evoked nystagmus fatigues and reverses direction after a few seconds, this is called rebound nystagmus. Rebound nystagmus may also appear as a transient nystagmus in the opposite direction when the eye is first returned to the midline. Rebound nystagmus is also seen in cerebellar disease. Downbeat nystagmus is characterized by a rapid phase in the down direction in primary position of the eyes. Such downbeat nystagmus becomes more prominent with downgaze or gaze to the side. Downbeat nystagmus is typically seen in abnormalities of cranio vertebral junction such as A moldChiari malformation but can also occur in some degenerative ataxias such as spinocerebellar ataxia type 6. Finally, upbeat primary position nystagmus can be seen in lesions ot the anterior vermis. e. VOR; In a rotary chair, normal individuals can suppress the VOR and keep their eyes on an object moving slowly with the chair. Patients with cerebellar disease cannot inhibit the VOR, so the eyes tend to drift away from the object and make catchup saccades as the chair is rotated, 5. Speech and bulbar function: Speech is evaluated by listening to the spoken words and asking the patient
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS to speak a s t a n d a r d p h r a s e . Speech in cerebellar disease is characterized by s o m e s l o w n e s s , slurring of t h e w o r d s , a n d a general inability to c o n t r o l process of articulation, leading to unnecessary hesitations a n d stops, omission of pauses w h e n needed, a n d an accentuation of syllables w h e n n o t needed Also, there is a m o m e n t t o - m o m e n t variability in t h e v o l u m e a n d pitch c o n t t o l and i n a p p r o p r i a t e c o n t r o l of t h e b r e a t h ing needed for speech, causing a scanning d y s a r t h r i a . M i l d dysphagia is n o t u n c o m m o n in cerebellar disease. In children, a form of "cerebellar m u t i s m " has been described after posterior fossa surgery. T h i s is transient and followed by m o r e typical cerebellar d y s a r t h r i a . Cognitive function ( S c m a h m a n n 2 0 0 2 ) : A cerebellar cognitive affective s y n d r o m e h a s been described a n d includes defective executive function, visuospatial difficulties, mild language disturbances such as a g r a m matism, a n d behavioral changes including i n a p p r o p r i ate behavior and attention deficits. Such cognitive deficits arc m o d e s t c o m p a r e d with t h e m o t o r difficulties in these patients.
Neurological Signs in Patients with Sensory A t a x i a In this situation, t h e major basis of a t a x i a is defective proprioception. Patients can be s h o w n to have i m p a i r e d position and vibration sense and t h e deep t e n d o n reflexes a r e often lost because of t h e afferent fiber p a t h o l o g y . T h e R o m b e r g test is positive. M a n y " d e g e n e r a t i v e " a t a x i c s y n d r o m e s c o m b i n e features of cerebellar a n d p r o p r i o c e p tive deficits in a variable c o m b i n a t i o n . This led Greenfield to classify ataxic disorders as spinal, cerebellar, or spinocerebellar in n a t u r e .
Tabic 23.2: Age at onset Infancy Childhood
APPROACH T O PATIENTS W I T H ATAXIA T h e recognition of an ataxic basis to the gait and c o o r d i n a t i o n p r o b l e m s a patient m a y h a v e is usually easy (see C h a p t e r 7H: Disorders of the Cerebellum, including the Degenerative Ataxies). O t h e r neural d i s o r d e r s t h a t can give
Table 23.1:
Acquired and genetic causes of ataxias
Acquired disorders causing ataxia Ataxic cerebral palsy; other early insults Congenital Ischemic strokes, hemorrhagic stroke, Vascular: AV malformations Acute cet'cbellins; postinfectious Infectious: encephalomyelitis; cerebellar abscess; HIV; CJD Toxic: Alcohol; anticonvulsants; mercury; 5-FU; cytosine arabinoside Gliomas, ependymomas, meningiomas; Neoplastic: basal meningeal carcinomatosis Immune: Multiple sclerosis; paraneoplastic syndromes; anti-GAD, gluten ataxia Deficiency: Hypothyroidism, vitamin B ^ , vitamin Bi Genetic disorders causing ataxia Recessive: Friedreich's ataxia, AT, other DNA repair defects; metabolic errors SCA type 1 through SCA type 23; episodic Dominant: ataxias linked Mitochondrial NARP; MERRF; others including Kearns-Sayre syndrome and MELAS AT = ata x la -te I a ng icctasi a; A V = atri o ven tri c u la r; CJ D = G reutzCreut/feldr-Jakob disease; DNA = deoxyribonucleic acid; 5-FU = 5-fluorouracil; GAD = glutamate decarboxylase; HIV = human immunodeficiency virus; MELAS = mitochondrial, encephalopathy, lactic acidosis, and strokelike episodes; MF.RRF = myoclonus epilepsy and ragged red fibers; NARP = neuropathy, ataxia, and retinitis pigmentosa; SCA = spinocerebellar ataxia.
Causes of ataxia related to age at onset Acquired Ataxic cerebral palsy, other intrauterine insults
Infections like acute cerebellitis, abscess; posterior fossa tumors like cerebellar gliomas, ependymomas, pontine glioma; vascular malformations; congential anomalies like Arnold-Chiari malformation; toxic such as anticonvulsants; immune related to neoplasms, especially opsoclonus-myoclonus Young adults Infections such as abscesses, HIV; posterior fossa mass lesions such as meningiomas, gliomas; congenital anomalies including vascular malformations, Arnold-Chiari malformation; hypothyroidism; toxic such as anticonvulsants and alcohol; immune causes such as MS Older adults Same as above plus idiopathic ("sporadic") ataxias; immune lesions such as paraneoplastic ataxias; anti-GAD and anti-gliadin antibodies
Genetic Inherited congential ataxias such as Joubert's syndrome, Gillespie's syndrome Ataxias related to "inborn errors of metabolism" such as the aminoacidurias, organic acidurias, Wilson's disease, etc.; Friedreich's ataxia; AT; ataxia with oculomotor apraxia; vitamin E deficiency syndromes; some dominant SCAs like SCA-7, SCA-13, and DRPLA, as well as episodic ataxia syndromes Friedreich's ataxia; dominantly inherited SCAs such as SCA-1, SCA-2, MJD, SCA-7; inherited tumor syndromes such as von Hippel-I.andau syndrome
More benign SCAs such as SGA-6
AT = ataxia-telangiectasia; DRPLA = dentatorubral-pallidoluysian atrophy; HIV = human immunodeficiency virus; GAD = glutamate decarboxylase; MJD = Machado-Joseph disease; MS = multiple sclerosis; SCA = spinocerebellar ataxia.
ATAXIC DISORDERS Table 23.3:
291
Causes of ataxia based on mode of onset and subsequent course
'ii-ui/iu
Acquired
diseases
Genetic diseases Many "metabolic ataxias" of childhood; autosomal dominant episodic ataxia syndromes
Episodic Acute (hours to days)
Subacute (weeks to months)
Chronic (years)
Strokes, ischemic and hemorrhagic; MS; infections and parainfectious causes such as acute ccrcbcllitis and abscesses; toxic disorders Mass lesions such as gliomas, ependymomas, meningeal infiltrates; infections such as HIV and CJD; deficiency syndromes such as B| 2 and B,; hypothyroidism; immune causes such as paraneoplastic and anti-GAD/anri-gliadin; alcohol Some mass lesions such as meningiomas, cranio vertebra I junction anomalies; alcoholic; idiopathic cerebellar and "olivopontocerebellar" atrophies; MSA
Most genetic disorders such as FA, AT, and other recessive ataxias; all progressive SCA (dominant inheritance)
AT = ataxia-telangiectasia; CJD = Creutzfeldt-Jakob disease; FA = Friedreich's ataxia; CAD = glutamate decarboxylase; HIV : human immunodeficiency virus; MS = multiple sclerosis; MSA = multiple system atrophy; SCA — spinocerebellar ataxia.
rise to such p r o b l e m s with gait a n d dexterity, including nerve a n d muscle diseases, spinal cord diseases, and basal ganglia disorders, can usually be distinguished on the basis of physical signs alone. Some patients with bilateral frontal lobe lesions m a y have a gait disorder superficially resembling a t a x i a (Bruns' ataxia or frontal ataxia}. H o w e v e r , limb a n d eye m o v e m e n t signs of cerebellar disease are a b s e n t a n d the gait is n a r r o w e r based. O t h e r gait disorders such as those associated with dystonia or c h o r e a m a y also be occasionally mistaken for cerebellar a t a x i a . T h e next task is to determine w h e t h e r the a t a x i a is primarily cerebellar, primarily proprioceptive, ot a c o m b i nation of b o t h . F u r t h e r diagnostic c o n s i d e r a t i o n s a n d avenues for investigations a n d t h e r a p y arc d e p e n d e n t on arriving at a specific diagnosis (Table 2 3 . 1 ) . T h i s can be a d a u n t i n g task, especially w h e n the disease a p p e a r s to be " d e g e n e r a t i v e " in n a I lire (i.e., associated with cerebellar a t r o p h y ) . As an e x a m p l e , the O n l i n e M e n d e l i a n Inheritance in M a n W e b site lists m o r e t h a n 4 0 0 genetic disorders alone
Table 23.4; Ataxias that are primarily cerebellar, proprioceptive, and cerebellar, primarily proprioceptive and associated with spasticity
in which a t a x i a c a n occur. In a patient with a t a x i a , m a n y additional pieces of information m a y be useful in arriving at a diagnosis. T h e s e include the age at onset (Table 2 3 . 2 ) ; the t e m p o of disease (Table 2 3 . 3 ) ; w h e t h e r the a t a x i a is p r e d o m i n a n t l y spinal, spinocerebellar, cerebellar, or associated with spasticity (Tabic 2 3 . 4 ) ; the presence or absence of nonccrebellar neurological signs (Table 2 3 . 5 ) ; the occurrence of any distinctive systemic features (Table 2 3 . 6 ) ; and t h e n a t u r e of imaging a b n o r m a l i t i e s (Table 2 3 . 7 ) . Table 23,5: Systemic signs that may be useful in the differential diagnosis of ataxia Systemic
feature
Short stature Hair loss Conjunctival telangiectasia ( annuls KF rings Cervical lipoma Abnormal ECG, echocardiogram Organomegaly Hypogonadism
t 20 cm amplitude. 5. Trunk tremor: Subject is comfortably seated in a chair. The subject flexes both legs at rhe hips 30 degrees above parallel to the ground for 5 seconds. The knees are passively bent so that the lower leg is perpendicular to the ground. The legs are not allowed to touch. Tremor is evaluated around the hip joints and the abdominal muscles. 0 = No tremor, 1 = Present only with hip flexion. 2 — Obvious but mild tremor. 3 = Moderate tremor. 4 = Severe tremor. 6. Leg tremor action: Subject is comfortably seated. The subject is asked to raise his or her legs parallel to the ground with knees extended for 5 seconds. The legs are slightly abducted so that they do nor touch. The tremor .miplinide is assessed at the end of the feet. 0 = No tremor. 1 = Barely perceptible. 1 — Obvious but mild tremor. 3 = Moderate tremor is 5 cm. 7. Leg tremor rest: Subject is comfortably seated with knees flexed and feet resting on the ground. The tremor amplitude is assessed at the point of maximal displacement. 0 = No tremor. 1 = Barely perceptible. 1 — Obvious but mild tremor. 3 = Moderate tremor is S cm. 8. Standing tremor: Subject is standing, unaided if possible. The internal malleoli are 5 cm apart. Arms are down at the subject's side. Tremor is assessed at any point on the legs or trunk. 0
No rreiiior.
1 = Barely perceptible tremor, 2 = Obvious but mild tremor. 3 = Moderate tremor. 4 = Severe tremor.
9. Spiral drawings: Ask rhe subject to draw rhe requested figures. Test each hand without leaving the hand or arm on the table. Use only a ballpoint pen. 0 = Normal. 1 = Slightly tremulous. May cross lines occasionally. 2 = Moderately tremulous or crosses lines frequently. 3 = Accomplishes the task with great difficulty. Figure still recognizable. 4 = Unable to complete drawing. Figure not recognizable, 10. Handwriting: Have patient write "Today is a nice day." 0 = Normal. 1 = Mildly abnormal. Slightly untidy, tremulous. 2 = Moderately abnormal. Legible, but with considerable tremor.
3 = Markedly abnormal. Illegible. 4 = Severely abnormal. Unable to keep pencil or pen on paper without holding down with the orher hand. 11. Hold pencil approximately 1 mm above a point on a piece of paper for 10 seconds. 0 = No tremor. 1 = Tremor is barely visible, 1.5 = Tremor is visible but less than 1 cm. 2 = T r e m o r is 1-3 cm amplitude. 2.5 = Tremor is i-S cm amplitude. 3 = Tremor is 5-10 cm amplitude. 3.5 = Tremor is 10-20 cm amplitude. 4 = Tremor is >20 cm amplitude. 12. Pour water from one glass inro another, using Styrofoam coffee cups filled 1 cm from rop. Rated separately for right and left hands. 0 = Absolutely no visible tremor. 1 = More careful than a person without tremor. No water is spilled. 2 = Spills a small amount ( II. Secondary dystonia (dystonia-pius syndromes) A. Sporadic Parkinson's disease Progressive supranuclear palsy Multiple system atrophy Corticobasal degeneration B. Inherited 1. Autosomal dominant Dopa-responsive dystonia (DYT5, GTP cyclohydrolase I 14q22.1) Myoclonus-dystonia ( l l q 2 3 ) Alternating hemiplegia of childhood Mach ado-Joseph disease (SCA3) Dystonia-ataxia (SCA6) 2. Autosomal recessive Dopa-responsive dystonia (11 p 11,5) Tytosine hydroxylase deficiency (chromosome 21) Bioptenn deficient diseases Aromatic amino acid decarboxylase deficiency (dopamine agonist-responsive dystonia) III. Hcredodegc iterative diseases (typically not pure dystonia) A. X-linked recessive [.tiling (X-linka! dystonia-parkinsonism, DYT3, Xql2-Xq21) Pelizaeus-Merzbacher disease Lesch-Nyhan syndrome Dystonia-dcafness (Xq22) Deafness, dystonia, retardation, blindness B. Autosomal dominant Rapid-onset dystonia-parkinsonism Juvenile parkinsonism-dystonia Huntington's disease (IT15, 4pl6.3) Spinocerebellar degenerations (SCA1-SCA8) Dentato-rubral-pallidoluysian atrophy Hereditary spastic paraplegia with dystonia Thalamo-olivary degeneration with Wernicke's encephalopathy C. Autosomal recessive Wilson's disease (Cu-ATPase, 13ql4.3) Ncurodegeneration with brain iron accumulation type 1 (Hallervorden-Spatz disease, 2 0 p l 2 . 3 - p l 3 ) Hypoprcbetahpoptoteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degenetation Ataxia telangiectasia Associated with metabolic disorders I, Amino acid disorders Glutaric acidemia Methylmalonic acidemia Homocystinuria Harm up disease Tyrosinosis 2. Lipid disorders Metachromatic leukodystrophy Ceroid lipofuscinosis
Niemann-Pick type C (dystonic lipidosis, "sea blue" histiocytosis); defect in cholesterol esterification; caused by mutation in NPC1 gene ( 1 8 q l l ) and HE1 gene(14q24.3) Gangliosidoses G M 1 , GM2 variants Hexosaminidase A and B deficiency 3. Other metabolic disorders Biopterin deficient diseases Triosephosphate isomerase deficiency Aromatic amino acid decatboxylase deficiency (dopamine agonist-responsive dystonia) Biotin-responsive basal ganglia disease D. Mitochondrial Leigh disease Leber's disease E. Unknown inheritance N e u roac a nrhocy rosi s Rett's syndrome Intraneuronal inclusion disease Infantile bilateral striatal necrosis Familial basal ganglia calcifications Hereditary spastic paraplegia with dystonia Deletion of 18q Of a known specific cause Perinatal cerebral injury and kernicterus: athetoid cerebral palsy, delayed-onset dystonia Infection: Viral encephalitis, encephalitis lethargica, Rcyc's syndrome, subacute sclerosing panencephalitis, Creutzfeldt-Jakob disease, human immunodeficiency virus infection Other: tuberculosis, syphilis, acute infectious torticollis Drugs: i,-dopa and dopamine agonists, dopamine receptor-blocking drugs, fenfluramine, anticonvulsants, flecaiuide, ergots, certain calcium channel blockers Toxins: magnesium, carbon monoxide, carbon disulfide, cyanide, methanol, disulfiram, 3-nitroproprionic acid, wasp sting Metabolic: hypoparathyroidism Pataneoplastic brainstem encephalitis Vitamin E deficiency Primary antiphospholipid syndrome Cerebral vascular or ischemic injury, Sjogren's syndrome Multiple sclerosis Central pontine myelinolysis Brainstem lesions Spinal cord lesions Syringomyelia Brain tumor Arteriovenous malformation Head trauma and brain surgery (thalamotomy) Lumbar stenosis Peripheral trauma (with causalgia) Electrical injury IV. Other hyperkinetic syndromes associated with dystonia A. Tic disorders with dystonic tics B. Paroxysmal dyskinesias 1. Paroxysmal kinesigenic dyskinesia ( 1 6 p l l . 2 - q l 2 . 1 ) 2. Paroxysmal nonkinesigenic dyskinesia (2q33-35) 3. Paroxysmal exertion-induced dyskinesia (16pl2-ql2) 4. Paroxysmal hypnogenic dyskinesia (20ql3.2-13.3) Continued
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APPROACH TO COMMON NEUROLOGICAI. PROBLEMS
Tabic 24.9:
Etiologic classification of dystonia—cont'd
V. Psychogenic VI. Pseudodystonia Atlanto-axial subluxation Syringomyelia Arnold-Chiari malformation Trochlear nerve palsy Vestibular torticollis Posterior fossa mass Soft tissue neck mass
Congenital postural torticollis Congenital Klippel-Feil syndrome Isaac's syndrome Sandiffer's syndrome Satoyoshi syndrome Stiff man syndrome Dupuytren's contractures Trigger digits Ventral hernia
Source: Modified from Jankovic, J. &c Halm, S. 2002, "Dysronic disorders," in Parkinson's Disease and Movement Disorders, 4th ed, eds J. Jankovic & E. Tolosa, Lippincott Williams 5c Wilkins, Philadelphia, pp. 331-357.
such as casting. Such peripherally induced dystonia may be associated with a complex regional pain syndrome, depression, and personality changes and may occur on a background oi secondary gain or litigation.
Common Symptoms Dystonia can affect almost all striated muscle groups. Common symptoms include forced eyelid closure (blepharospasm); jaw clenching, forced jaw opening, or involuntary tongue protrusion (otomandibular or lingual dystonia); a harsh, sttaincd, or breathy voice (laryngeal dystonia or spasmodic dysphonia); and involuntary deviation of the neck in any plane or combination of planes (cetvical dystonia or spasmodic torticollis). Other symptoms are spasms of the trunk in any direction, which vatiably interfere with lying, sitting, standing, or walking (axial dystonia); interference with manual tasks (often only specific tasks in isolation: the occupational cramps); and involvement of the leg, usually with inversion and plantar flexion of the foot causing the patient to walk on the toes. All these disorders may slowly progress to the point of complete loss of voluntary function of the affected part. On the othet hand, only certain actions may be impaired, and the disorder may remain focal in distribution. Chapter 77 deals with each of these forms of dystonia in mote detail. "I lie age at onset and distribution of dystonia often are helpful in determining the possible cause. The many causes of secondary dystonia ate detailed in Table 24,9. Whereas some patients with dystonia have "pure dystonia" without any other neurological deficit (primary dystonia), others have additional clinical features (dystonia-plus syndrome), such as parkinsonism, spasticity, weakness, myoclonus, dementia, seizures, and ataxia. Typically, childhood-onset primary dystonia (e.g., classic, Oppenheim's DYT1 dystonia) begins in distal parts of the body (e.g., graphospasm or foot inversion) and spreads to a generalized dystonia. On the other hand, dystonia beginning in adult life usually is limited to one or a small number of contiguous regions, such as the face and neck, and it remains focal or segmental and rarely becomes generalized. Ceneralized involvement or onset in the legs in an adult nearly always implies the
possibility of a secondary cause, such as PD or some other parkinsonian disorder. Involvement of one side of the body (hemidystonia) is strong evidence of a lesion in the contralateral basal ganglia, particularly the putamen. Most ptimary dystonias start as action dystonia occurring during some activity such as writing and walking or running, but when the dystonia occurs at rest and consists of a fixed postutc, secondary causes, such as peripheral or central trauma, should be considered. A fixed posture maintained during sleep implies superimposed contractures or a musculoskeletal distutbance mimicking the postutes of dystonia. Although many patients find that dystonia is lessened by test and sleep, some note a striking diurnal variation. The diurnal variation manifests with little ot no dystonia on rising in the morning, followed by the progressive development of problems as the day goes on, sometimes to the point of becoming unable to walk late in the day. This diurnal variability strongly suggests a diagnosis of dopa-responsive dystonia. The natute of the onset of the symptoms (sudden versus slow) and their course, whether rapid progression, slow changes, or episodes of spontaneous remission, all provide important clues to the possible cause. The family history must be reviewed in detail, with the awareness that affected relatives may have limited or distinctly different involvement from that of the patient. A birth and developmental history must be obtained in view of the frequency of dystonia after birth trauma, birth anoxia, and kernicterus. As with the other dyskinesias, a history of such features as previous encephalitis, drug use, and head trauma must be sought. Thete is also increasing support for the ability of peripheral trauma to precipitate various forms of dystonia, and occasionally this is combined with the syndrome of complex regional pain, also called reflex sympathetic dystrophy.
Examination Action dystonia is commonly the earliest manifestation of primary (idiopathic) dystonia. It is important to observe patients performing the acts that ate most affected. Later, other tasks precipitate similar problems, the use of other
MOVEMENT DISORDERS: DIAGNOSIS AND ASSESSMENT
parts of the body causes the dystonia to become evident in the originally affected site, and the dystonia may overflow to other sites. Still later, dystonia is evident periodically at rest, and even later the posturing may be persistent and difficult to correct passively, especially when secondary joint contractures develop. A significant deviation from this progression, particularly with the early appearance of dystonia at rest, should encourage the physician to search carefully for a secondary cause (see Table 24.9). It is important to recognize the natural variability of dystonia, especially the effects of stress and anxiety, which may be somewhat paradoxical. This is especially the case with blepharospasm, in which the increased concentration or anxiety associated with a visit to the doctor often mil lies the severity lit" the problem. It reliance is placed only on the degree of disability seen in the office, the physician may underestimate the severity of the blepharospasm and may misdiagnose the problem as hysterical. Depending on the cause of the dystonia, several other neurological abnormalities may be associated. Wilson's disease should be considered in any patient with onset of dystonia before age 60 (Svctcl ct al. 2001). Many secondary dystonic disorders (listed in Table 24.9) result in additional psychiatric or cognitive disturbances, seizures, or pyramidal ttaet or cerebellar dysfunction. Ocular motor abnormalities suggest a diagnosis of I.eigh disease, dystonic lipidosis, ataxia telangiectasia, Huntington's disease, MachadoJoscph disease, or other spinocerebellar atrophies. Optic nerve or retinal disease raises the possibility of Leigh disease, other mitochondrial cytopathics, G M 2 gangliosidosis, ceroid lipofuscinosis, and neurodegeneration with brain iron accumulation or pantothenate kinase-associated neurodegeneration, previously called Hallervorden-Spatz disease (Hayflick ct al. 2003). Lower motor neuron and peripheral nerve dysfunction may be seen with neuroacanthocytosis, ataxia telangiectasia, metachromatic leukodystrophy, Machado-Joseph disease, and other multisystem degenerations. The dystonia itself may cause additional neurological problems, such as spinal cord or cervical root compression from long-standing torticollis and peripheral nerve entrapment from limb dystonia. Also independent of the cause, long-standing dystonic muscle spasms often result in hypertrophy of affected muscles {e.g., the sternocleidomastoid in cervical dystonia). Although the general medical examination must be thorough, it is usually unrevealing. As always, the ophthalmological and systemic signs of Wilson's disease must be carefully sought. Abdominal organomegaly also may indicate a storage disease. Severe self-mutilation is typical of Lesch-Nyhan syndrome. Minor tongue and lip mutilation is seen in neuroacanthocytosis, in which orolingual action dystonia may be prominent. Oculocutaneous telangiectasia and evidence of recurrent sinopulmonary infections suggest ataxia telangiectasia. Musculoskeletal abnormalities may simulate dystonia and, rarely, dysmorphic features may serve as a clue to a mucopolysaccharidosis.
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TICS Tics are the most varied of all movement disorders. Patients with Tourcttc's syndrome, the most common cause of tics, manifest both motor, vocal, or phonic tics and a wide variety of associated symptoms (Jankovic 2001). Tics are brief and intermittent movements (motor tics) or sounds (phonic tics). Motor tics typically consist of sudden, abrupt, transient, often repetitive and coordinated (stereotypical) movements that may resemble gestutes and mimic fragments of normal behavior, vary in intensity, and are repeated at irregular intervals. The movements are most often brief and jerky (clonic); however, slower, more prolonged movements (tonic ot dystonic tics) also occur, Several other characteristic features arc helpful in distinguishing this movement disorder from other dyskinesias. Patients usually cxpcticncc an inner urge to make the movement or a local premonitory sensation, which is temporarily relieved by its performance. Tics are voluntarily suppressible for variable periods, but this occurs at the expense of mounting inner tension and the need to allow the tic to occur. Indeed, a large proportion of these patients, when questioned carefully, admit that the movements or sounds that make up their tics are produced intentionally (in contrast to most other dyskinesias) in response to the uncontrollable inner urge or a premonitory sensation, Table 24.10 provides examples of the various types of tics. Motor and phonic tics can be further subdivided as simple or complex. Simple motor tics are random, brief, irregular muscle twitches of isolated body segments, particularly the eyelids and other facial muscles, the neck, and the shoulders. In contrast, complex motor tics are coordinated, patterned movements involving a number of muscles in their normal synergistic telationships. A wide variety of other motor disturbances may be
Table 24.10:
Phenomenological classification of tics
Simple motor tics: eye blinking; eyebrow raising; nose flaring; grimacing; mouth opening; tongue protrusion; platysma contractions; head jerking; shoulder shrugging, abduction, or rotation; neck stretching; arm jerks; fist clenching; abdominal tensing; pelvic thrusting; buttock or sphincter lightening; hip flexion or abduction; kicking; knee and foot extension; toe curling Simple phonic tics: sniffing, grunting, throat clearing, shrieking, yelping, barking, growling, squealing, snorting, coughing, clicking., hissing, humming, moaning Complex motor tics: head shaking, teeth gnashing, hand shaking, finger cracking, touching, hitting, jumping, skipping, stamping, squatting, kicking, smelling hands or objects, rubbing, finger twiddling, echopraxia, copropraxia, spitting, exaggerated startle Complex phonic tics: coprolalia (wide variety, including shortened words), uninrelligible words, whistling, panting, belching, hiccoughing, stuttering, stammering, eeholalia, palilalia (also mental coprolalia and palilalia)
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
associated with tic disorders, and it is sometimes difficult to separate complex tics from some of these. These motor disturbances include obsessive-compulsive behavior, copropraxia (obscene gestures), echopraxia (mimicked gesnires), hyperucriviry with aitcnrional deficits ;uul impulsive behavior, and externally directed and self-destructive behavior, including self mutilation. Some Tourette's patients also manifest sudden and transient cessation ot all motor activity (blocking tics), including speech, without alteration of consciousness. These "blocking" tics are caused by either prolonged tonic or dystonic tics that interrupt ongoing motor activity such as speech ("intrusions") or a sudden inhibition of ongoing motor activity ("negative tic"). Simple and complex phonic ties comprise a wide variety of sounds, noises, ot formed words (see Table 24.10). Possibly the best known (although not the most common) example of complex vocal tics is coprolalia, the utterance of obscenities or profanities. These are often slurred or shortened or may intrude into the patient's thoughts but not become verbalized (mental coprolalia). Like most dyskinesias, tics usually increase with stress. In contrast to other dyskinesias, however, relaxation (e.g., watching television at home) often results in an increase in the tics, probably because the patient docs not feel the need to suppress them voluntarily. Distraction or concentration usually diminishes tics, which also differs from most other types of dyskinesia. Many patients with idiopathic tics note spontaneous waxing and waning in their nature and severity over weeks to months, and periods of complete remission are possible. Many people with tics are only mildly affected, and many are even unaware that they demonstrate clinical features. This must be kept in mind when reviewing the family history and planning treatment. Finally, tics are one of the few movement disorders that can persist during all stages of sleep.
Common Symptoms The causes of tic disorders are listed in Table 24.11. Most are primary or idiopathic, and within this group the onset is almost always iu childhood or adolescence (Tourette's syndrome). Men are affected more often than women. Idiopathic tics occur on a spectrum from a mild, transient, single, simple motor tic to chronic, multiple, simple, and complex motor and phonic tics. Patients and their families complain of a wide variety of symptoms (see Table 24.10). They may have seen numerous other specialists (e.g., allergists for repetitive sniffing, otolaryngologists for throat clearing, ophthalmologists for excessive eye blinking or eye rolling, and psychologists and psychiatrists for various neurobehavioral abnormalities). The true diagnosis of Tourette's syndrome often is first suggested after someone close to the patient has learned about it in the media. Children may verbalize few complaints
Table 24.11:
Etiological classification of tics
1. Physiological tics A. Mannerisms II. Pathological tics A. Primary Sporadic 1. Transient motor or phonic tics (1 year) 3. Adult-onset (recurrent) tics 4. Tourette's syndrome Inherited 1. Tourette's syndrome 2. Huntington's disease 3. Primary dystonia
4. Neuroacanthocyrosis B. Secondary ("tourettism") 1. Infections: encephalitis, Creutzfeldt-jakob disease, Sydenham's chorea 2. Drugs: stimulants, i.-dopa, carbamazepine, phenytoin, phenobarbital, antipsychotics 3. Toxins: carbon monoxide 4. Developmental: static encephalopathy, mental retardation, chromosomal abnormalities 5. Other: head trauma, stroke, neurocutaneous syndromes, chromosomal abnormalities, schizophrenia, neuroacanthocytosis degenerative disorders HI. Related disorders 1. Stereotypies 2. Self-injurious behaviors 3. Hyperactivity syndrome 4. Compulsions 5. Excessive srartle 6. Jumping disease, latah, myriachit Source: Modified from [ankovic, j. 2001, "Tourette's syndrome," N Engl J Med, vol. 345, pp. 1184-1192.
or feel reluctant to speak of the problem, especially if they have been subject to ridicule by others. Even young children, when questioned carefully, can provide the history of urge to perform the movement that gradually culminates in the release of a tic and the ability to control the tic voluntarily at the expense of mounting inner tension. Children may be able to control the tics for prolonged periods but often complain of difficulty concentrating on other tasks while doing so. Some give the history of tequesting to leave the schoolroom and then releasing the tics in private (e.g., in the washroom). Peers and siblings often chastise or ridicule the patient, and parents or teachers, not recognizing the nature of the disorder, may scold or punish the child for what are thought to be voluntary bad habits (indeed, an older term for tics is habit spasms). The hisrory may include an exposure to stimulants for hyperactivity. The family history must be reviewed for rhe wide range of potential manifestations (especially obsessivecompulsive behavior). Additional neurological complaints, including other dyskinesias, suggest the possibility of a secondary cause of the tics.
MOVEMENT DISORDERS: DIAGNOSIS AND ASSESSMENT
Examination In most patients with tics, the neurological examination is entirely normal. In patients with primary tic disorders, the presence of other neurological, cognitive, behavioral, and neuropsychological disturbances may simply relate to extension of the underlying cerebral dysfunction beyond the core that accounts for pure tic phenomena. Patients with secondary forms of tics (e.g., neuroacanthocytosis, tardive tics) may demonstrate other involuntary movements, such as chorea, dystonia, and other neurological deficits (see Table 24.11). Careful interview stressing the subjective features that precede or accompany tics usually allows the distinction between true dystonia or myoclonus, and dystonic or clonic tics. Despite bitter complaints by the family, it is common for patients to show no evidence of a movement disorder during an office appointment. Aware of this, the physician must attempt to observe the patient at a time when he or she is less likely to be exerting voluntary control, such as in the waiting room. If no movements have been witnessed during the interview, the physician should seemingly direct attention elsewhere (e.g., to the parents) while observing the patient out of the corner of the eye. The patient often releases the tics while changing in the examining room, particularly if they have been held back during the interview. The physician should attempt to view the patient at this time or at least listen for the occurrence of phonic tics. Despite these maneuvers, one may have to ask the patient to voluntarily mimic the movements. This, in combination with associated symptoms, such as urge, voluntary release and control, and the often varied and complex nature of the movements, usually is enough to provide the diagnosis, even if the spontaneous tics are not witnessed in the office. Finally, the parents should be asked to provide home videos of the patient.
MYOCLONUS Myoclonus can be defined as sudden, brief, shocklikc involuntary movements that may be caused by active muscle contraction (positive myoclonus) or inhibition of ongoing muscle activity (negative myoclonus). The differential diagnosis of myoclonus is broader than that of any other movement disorder (Table 24.12). To exclude muscle twitches, such as fasciculations caused by lower motor neuron lesions, some authors have insisted that an origin in the CNS be a component of the definition. Although the majority of causes of myoclonus originare in the CNS, occasional cases of brief shocklike movements, clinically indistinguishable from CNS myoclonus, occur with peripheral nerve disease. A wide range of clinical patterns of myoclonus exist. The frequency varies from single, rare jerks to constant, repetitive contractions. The amplitude may range from a
315
small contraction that cannot move a joint to a very large jerk that moves the entire body. The distribution ranges from focal involvement of one body part, to segmental (involving two or more contiguous regions), to multifocal, to generalized. When the jerks occur bilaterally, they may be symmetrical or asymmetrical. When they occur in more than one region, they may be synchronous in two body parts (within milliseconds) or asynchronous. Myoclonus usually is arrhythmic and irregular, but in some patients it is very regular (rhythmic), and in others there may be jerky oscillations that last for a few seconds and then fade away (oscillatory). Myoclonic jerks may occur spontaneously, without a clear precipitant, or in response to a wide variety of stimuli, including sudden noise, light, visual threat, pinprick, touch, or muscle stretch. Attempted movement (or even the intention to move) may initiate the muscle jerks (action or intention myoclonus). Palatal myoclonus is a form of segmental myoclonus manifested by rhythmic contractions of the soft palate. Symptomatic palatal myoclonus, usually manifested by contractions of the levator palatini, may persist during sleep; this form of palatal myoclonus usually is associated with some brainstem disorder. In contrast, essential palatal myoclonus consists of rhythmic contractions of the tensor palatini, often associated with a clicking sound in the ear, and disappears with sleep. When the tensor muscle contracts, as in essential palatal myoclonus, the entire soft palate moves, whereas only the edges of the soft palate move when the levator muscle contracts. Symptomatic but not essential palatal myoclonus often is associated with hypertrophy of the inferior olive.
Common Symptoms As may be seen from the foregoing description and the long list of possible causes of myoclonus, the symptoms in these patients are quite varied. For simplification, we briefly review the possible symptoms with respect to four major etiological subcategories in Table 24.12. Physiological forms of myoclonus occurring in normal subjects vary depending on the precipitant. Probably the most common form is the jerking most of us have experienced on falling asleep (hypnagogic jactitation). This very familiar phenomenon is rarely a source of concern. Occasionally, patients do become concerned by anxiety- or exercise-induced myoclonus. The history usually is clear, and there is little to find (including abnormal movements) when the patient is seen. In the essential myoclonus group, patients usually complain of isolated muscle jerking in the absence of other neurological deficits (with the possible exception of tremor and dystonia). The movements may begin at any time from early childhood to late adult life and may remain static or progress slowly over many years. The family history may be positive, and some patients note a striking
iU
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 24.12:
Etiological classification of myoclonus
Physiological myoclonus (normal subjects} Sleep jerks (hypnic jerks) Anxiety-induced Exercise-induced Hiccough (singultus) Benign infantile myoclonus with feeding Essential myoclonus (no known cause and no other gross neurological deficit) Hereditary Sporadic Epileptic myoclonus (seizures dominate and no encephalopathy, at least initially) Fragments of epilepsy Isolated epileptic myoclonic jerks Epilepsia partialis continua Idiopathic stimulus-sensitive myoclonus Photosensitive myoclonus Myoclonic absences in petit mal Childhood myoclonic epilepsies Infantile spasms Myoclonic astatic epilepsy (Lennox-Castaut) Cryptogenic myoclonus epilepsy (Aicardi's) Awakening myoclonus epilepsy of Janz Benign familial myoclonic epilepsy (Rabot's) Progressive myoclonus epilepsy: Baltic myoclonus (Unvcrricht-Lundborg) Symptomatic myoclonus (progressive or static encephalopathy dominates) Storage disease I.afora body disease Lipidoses, such as GM2 gangliosidosis, Tay-Sachs, Krabbe's Ceroid lipofuscinosis (Batten's, Kufs's) Sialidosis (cherry-red spot) Spinocerebellar degeneration Ramsay Hunt syndrome (many causes) Friedreich's ataxia Ataxia telangiectasia Basal ganglia degenerations Wilson's disease Torsion dystonia Hallervorden-Spatz disease Progressive supranuclear palsy Huntington's disease
Parkinson's disease Cortical basal degeneration Pallidal degenerations Multiple system atrophy Mitochondrial encephalopathies, including myoclonic epilepsy and ragged-red fibers Dementias Creutzfeldt-Jakob disease Alzheimer's disease Viral encephalopathies Subacute sclerosing panencephalitis Encephalitis lethargica Arbovirus encephalitis Herpes simplex encephalitis Postinfectious encephalitis Metabolic [ lepacic failure Renal failure Dialysis syndrome Hyponatremia Hypoglycemia Infantile myoclonic encephaloparhy (polymyoclonus, wirh or without neuroblastoma) Nonketotic hyperglycemia Multiple carboxylase deficiency Toxic encephalopathies Bismuth Heavy metal poisons Methyl bromide, dichlorodiphenyltrichloroethane Drugs, including 1-dopa, tricyclics Physical encephalopathies Posthypoxia (Lance-Adams syndrome) Post-trau marie Heat stroke l.livtnc ^lidL'k
Decompression injury Focal central nervous system damage Posts troke Post-th a la m otomy Tumor Trauma Olivodenrare lesions (palatal myoclonus) Spinal cord lesions (segmental or spinal myoclonus)
Source: Modified from Fahn, S., Marsden, C. D., & van Woert, M. H. 1986, "Definition ;ind classification of myoclonus," Adv Neurol, vol. 4 3 , pp. 1-5.
beneficial effect of alcohol. Associated d y s t o n i a , present in some patients, also m a y r e s p o n d to e t h a n o l . M y o c l o n u s occurring as o n e c o m p o n e n t of a w i d e r a n g e of seizure types is called epileptic myoclonus. M a n y of these patients give a clear history of seizures as t h e d o m i n a n t feature. M y o c l o n i c jerks m a y be infrequent a n d barely noticeable to t h e patient or may occur frequently a n d c a u s e p r o n o u n c e d disability. M y o c l o n u s on w a k i n g in t h e m o r n i n g or an increasing frequency of the m y o c l o n i c jerks may forewarn of a seizure soon to c o m e . T h e clinical pattern of m y o c l o n u s in this instance also varies widely. Sensitivity to photic stimuli a n d o t h e r sensory input m a y be p r o m i n e n t . Occasional patients d e m o n s t r a t e isolated
m y o c l o n i c jerks in t h e absence of a d d i t i o n a l seizure activity. In these cases, the family history m a y be positive for seizures, a n d the e l e c t r o e n c e p h a l o g r a m often d e m o n s t r a t e s a typical centrencephalic seizure p a t t e r n t h a t is otherwise a s y m p t o m a t i c (such as a 3 - H z spike a n d w a v e p a t t e r n ) . In o t h e r s , m y o c l o n u s a n d seizures a r e equally p r o m i n e n t (the m y o c l o n i c epilepsies). T h e s e m a y or m a y n o t be associated with an a p p a r e n t progressive e n c e p h a l o p a t h y (most often with cognitive dysfunction a n d ataxia} in t h e absence of a definable, underlying, s y m p t o m a t i c cause. In the d i s o r d e r s classified as causing s y m p t o m a t i c m y o c l o n u s , seizures m a y o c c u r , b u t the e n c e p h a l o p athy (either static or progressive) is the feature t h a t
MOVEMENT DISORDERS: DIAGNOSIS AND ASSESSMENT
predominates. All sorts of myoclonic patterns are seen in this broad category. As can be appreciated from review of Table 24.12, a plethora of other neurological and systemic symptoms may accompany the encephalopathy. Two clinical subcategories of this larger grouping have been distinguished to assist in differential diagnosis. In progressive myoclonic epilepsy, myoclonus, seizures, and encephalopathy predominate, whereas in progressive myoclonic ataxia (often called Ramsay Hunt syndrome), myoclonus and ataxia dominate the clinical picture, with less frequent or severe seizures and mental changes. Myoclonus may also originate in the brainstem and spinal cord. Spinal segmental myoclonus often is rhythmic and limited to muscles innervated by one or a few contiguous spinal segments. Propriospinal myoclonus is another type of spinal myoclonus that usually results in flexion jerks of the trunk.
Examination Considering the varied causes, a wide range of neurological
findings are possible. Alternatively, despite the complaint of abnormal movements, some patients with myoclonus (like those with tics and certain paroxysmal dyskinesias) have little to reveal on examination. This is particularly the case for the physiological forms of myoclonus and for those associated with epilepsy and some symptomatic causes. When myoclonus is clearly present on examination, the physician should try to characterize the movement, as outlined earlier in the chapter. When the jerks are single or repetitive but arrhythmic, one must differentiate these movements from tics. Myoclonus usually is briefer and less coordinated or patterned. Furthermore, myoclonus is not associated with a premonitory urge or sensation. Rhythmic forms of myoclonus may be confused with tremors. Here, the pattern of movement is more one of repetitive, abrupt-onset, square wave movements caused by contractions of the agonists, in contrast to the smoother sinusoidal activity of tremor produced by alternating or synchronous contractions of antagonist muscles. Rhythmic myoclonus usually is in the 1- to 4-Hz range, in contrast to the faster frequencies seen in most types of tremor. The oscillations of so-called oscillatory myoclonus may be faster. These are distinguished by their bursting or shuddering nature, usually precipitated by sudden stimulus or movement, lasting for a few seconds and then fading away. The distribution of the myoclonus is helpful. Focal myoclonus may be more common in disturbances of an isolated region of the cerebral cortex. Segmental involvement, particularly when rhythmic, may occur with brainstem lesions (such as branchial or palatal myoclonus) or spinal lesions (spinal myoclonus). Multifocal or generalized myoclonus suggests a more diffuse disorder, particularly involving the reticular substance of the brainstem. When multiple regions of the body arc involved, it is helpful to attempt to estimate whether movements are occurring in
317
synchrony. It is sometimes difficult to do this clinically, and multichannel electromyographic (EMG) monitoring may be needed. Throughout the examination, it is important to define whether the movements occur spontaneously or with various precipitants, such as sudden loud noise, visual threat, perturbation, or a pinprick. A number of special sense and somesthctic sensory inputs should be tested. In addition, it is important to evaluate the effects of passive and active movement. In the case of action or intention myoclonus, jerking occurs during voluntary motor activity, especially when the patient attempts to perform a fine motor task, such as reaching for a target. This disturbance is often confused with severe ataxia. Action myoclonus may be evident in such activities as voluntary eyelid closutc, pursing of lips or speaking, holding the arms out, finger-tonose testing, writing, bringing a cup to the mouth, holding the legs out against gravity, heel-to-shin testing, and walking. In addition to the positive myoclonus that results from a brief active muscle contraction, negative myoclonus also may occur. Although clinically these, too, appear as brief jerks, they are caused by periodic inhibition of ongoing muscle activity and sudden loss of muscle tone. The most common example of negative myoclonus is asterixis, which may be seen in liver failure ("liver flap") and, to a lesser extent, in other metabolic encephalopathies, and occasionally with focal brain lesions. The bestrecognized location of asterixis is the forearm muscles, where it causes a flapping, irregular tremor-like movement when the wrists are held extended. When mild and of low amplitude, this may be confused with 5- to 6-Hz postural tremor. A similar form of negative myoclonus accounts for the periodic loss of postural tone in axial and leg muscles in some patients with action myoclonus syndromes, such as postanoxic action myoclonus. This results in a bobbing movement of the trunk while standing and may culminate in falls.
MISCELLANEOUS MOVEMENT DISORDERS Hemifacial spasm is a common disorder in which irregular tonic and clonic movements involve the muscles of one side of the face innervated by the ipsilateral seventh cranial nerve. Unilateral eyelid twitching usually is the first symptom, followed at variable intervals by lower facial muscle involvement. Rarely, both sides of the face are affected, in which case the spasms are asynchronous on the two sides, in contrast to other pure facial dyskinesias, such as cranial dystonia. The term akatbisia refers to a sense of restlessness and the feeling of a need to move. This was first used to describe what was thought to be a hysterical condition, and later the term was applied to the restlessness with inability to sit or stand still (motor impatience) seen in patients with idiopathic and postencephalitic parkinsonism. The syndrome is
318
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
now most commonly seen as a side effect of major tranquilizing or antiemetic drugs (neuroleptics) that act by blocking dopamine receptors. Akathisic movements occur in response to the subjective inner feeling of restlessness and need to move, although some authors believe that the subjective component is not necessary. The movements of akathisia are varied and complex. They include repetitive rubbing; crossing and uncrossing the arms; stroking the head and face; repeatedly picking at clothing; abducting and adducting, crossing and uncrossing, swinging, or up-and-down pumping of the legs; and shifting weight, rocking, marching in place, or pacing while sitting and standing. Occasionally, patients demonstrate a variety of vocalizations, such as moans, grunts, and shouts. Akathisia can be an acute ot delayed complication of antipsychotic drug therapy (acute akathisia and tardive akathisia, respectively). It also occurs in PD, secondary to selective serotonin reuptake inhibitors, and in cerrain confusional states or dementing processes. Anothet disotder in which movements occur secondary to the subjective need to move is the restless legs syndrome (Ondo, Vuong, and Jankovic 2002). Here, unlike in akathisia, the patient typically complains of a variety of sensory disturbances in the legs, including pins and needles, creeping or crawling, aching, itching, stabbing, heaviness, tension, burning, or coldness. Occasionally, similar symptoms are appreciated in the upper limbs. These complaints usually are experienced during recumbency in the evening and often are associated with insomnia. This condition commonly is associated with another movement disorder, periodic leg movements of sleep, sometimes inappropriately called nocturnal myoclonus. These periodic, slow, sustained (1- to 2-second) movements range from synchronous or asynchronous dorsiflexion of the big toes and feet to triple flexion of one or both legs. More rapid myoclonic movements or slower, prolonged dystonic-like movements of the feet and legs also may be present in these patients while awake, and these too may have a natutal periodicity. Leg myoclonus or foot dystonia may be the presenting feature of the stiff man syndrome. Another uncommon but well-defined movement disorder of the lower limbs has been called painful legs and moving toes. Here, the patient typically complains of a deep pulling or searing pain in the lower limb and foot associated with continuous wriggling or writhing of the toes, occasionally the LT.IIkle-. and less commonly more proximal muscles of the leg. Rarely, a similar problem is seen in the upper limb as well. In some cases, there is a history of root or nerve injury, and the examination may demonstrate evidence of peripheral nerve dysfunction. Some dyskinesias occur intermittently rather than persistently. This is typical of tics and certain forms of myoclonus. Dystonia often occurs only with specific actions, but this is usually a consistent response to the action rather than a periodic and unpredictable occurrence. Some patients with dystonia have a diurnal variation (dopa-responsive
dystonia) characterized by essentially normal motor function in the morning with emergence or worsening of dystonia as the day progresses so that by the end of the day the patients are unable to ambulate because of severe generalized dystonia. A small group of patients with chorea or dystonia have bouts of sudden-onset, short-lived, involuntary movements known as paroxysmal cboreoathetosis or, more appropriately, paroxysmal dyskinesia (Table 24.13). Certain features characterize these disorders and sometimes help to separate them into diagnostic categories (such as precipitants, duration, frequency, age of onset, and family history} (sec Chapter 77). Thus, paroxysmal dyskinesias may be categorized as kinesigenic (precipitated by voluntary movement such as arising from a chair or starting to tun), nonkinesigenic, exertional, or nocturnal. In many cases, the movements are so infrequent that the physician never sees them, and so a careful history is needed to determine the nature of the disorder (Jankovic and Demirkiran 2002). There may be a family history of seizures or migraines. Periodic ataxias often are included in the group of paroxysmal movement disorders. There are also disorders in which an abnormal or excessive response to startle occurs. In some patients, one simply finds an exaggerated startle response, which habituates poorly after repeated stimuli. In others, there is an abnormal response to the stimuli that normally evoke startle. Hyperekplexia, also known as startle disease, may be more akin to certain forms of myoclonus than to a normal startle response. A variety of other unusual disorders, first described in the nineteenth century together with Tourette's syndrome, manifest excessive startle. Jumping disease, latah, and myriacbit also involve sudden striking out, echo phenomena, automatic obedience, and several other less common features. It is believed that these disorders arc quite distinct from Tourette's syndrome and possibly represent culturally related operant-conditioned behavior rather than true neurological disease, although this point remains conrroversial. Tahle 24.13:
Classification of paroxysmal dyskinesias
Paroxysmal kinesigenic dyskinesia Paroxysmal nonkinesigenic dyskinesia Paroxysmal exertion-induced dyskinesia Paroxysmal nocturnal dyskinesia Paroxysmal psychogenic dyskinesia Each category includes the following: Short-lasting (5 minutes) Idiopathic (familial or sporadic) Secondary Source: Modified from Jankovic, J. 8c Demirkiran, M. 2002, "Classification of paroxysmal dyskinesias and ataxias," in Myoclonus and Paroxysmal Dyskinesias, Advances in Neurology, eds S. Fruchr & S. Fahn, Lippineott Williams &c Wilkins, Philadelphia, pp. 387-400.
MOVEMENT DISORDERS: DIAGNOSIS AND ASSESSMENT
Finally, psychogenic movement disorders, characterized by abnormal slowness or excessive movements or postures that cannot be directly attributed to a lesion or an organic dysfunction in the nervous system, are emerging as one of the most common groups of disorders encountered in movement disorder clinics (Miyasaki et al, 2003). Derived primarily from psychiatric or psychological disorders, because of their rich spectrum of phenomenology and variable severity, psychogenic movement disorders present a major diagnostic and therapeutic challenge. Diagnosis of psychogenic movement disorders is facilitated by various clues that include somatic and psychiatric complaints and movement disorders whose phenomenology is incongruous with typical movement disorders. These include sudden onset often related to some emotional trauma, secondary gain, variable frequency of tremor, distractibility, exaggeration of symptoms, or lack of concern, called "la belle indifference" (Table 24.14).
Tabic 24.14: disorder
319
Clues to the presence of a psychogenic movement
Physical Factors Movement disorder Abrupt onset Incongruous movements Inconsistent movements Response to placebo or suggestion Selective disability Dramatic resolution Maximum early disability Deliberate slowing Rhythmic shaking Bizarre gait Other neurological findings Transient weakness Sensory symptoms Dizziness and fainting Seizures Convergence spasm Bursts of verbal gibberish Visual disturbances
INVESTIGATION OF MOVEMENT DISORDERS The nature and extent of the investigation of a patient presenting with a movement disorder vary depending on the clinical circumstances. When the historical and clinical features are typical of certain primary (idiopathic) disorders, further investigations may be unnecessary. Examples of these include normal physiological tremor and myoclonus, essential tremor {especially if familial), adult-onset focal dystonias, childhood tic disorders, and even PD. However, one must always he mindful of the possibility of additional occult aggravating factors superimposed on a known preexisting movement disorder. The reverse is also possible, in which the presumed cause is actually an aggravating factor or simply a coincidental association, particularly in the case of patients thought to have drug-induced disturbances. For example, chorea apparently caused by the birth control pill (or chorea gravidarum) may be a manifestation of underlying SLE. When dealing with presumed neurolepticinduced movement disorders, it is important to consider the possibility that the antipsychotic drug was given for initial psychiatric manifestations of a disease that is now causing the movement disorder in question. Huntington's disease and Wilson's disease are two disorders in which this may occur, The importance of excluding Wilson's disease cannot be overemphasised. This includes slit-lamp examination, measurement of serum ceruloplasmin and copper, liver function tests, and, if necessary, measurement of 24-hour urinary copper excretion and liver biopsy. Children, adolescents, and young adults presenting with parkinsonism, chorea, or a dystonic or myoclonic syndrome need additional careful hematological and biochemical assessment, as indicated in Table 24.15. Although in the majority of movement disorders the diagnosis depends on the recognition of typical clinical
Headache Pain Amnesia Insomnia Exhaustion Multiple somatizations Self-inflicted injuries Unwitnessed paroxysmal disorders Psychiatric Problems Depression Anxiety disorder
Somatization disorder Malingering factitious disorder Predisposing Event Trauma Surgery Major life event Social Factors Work-related injuries Litigation
Relationship problems (spouse or children) Physical abuse Sexual abuse Substance abuse Secondary gain
phenomenology, diagnosis of certain movement disorders can be aided by blood tests. Ncuroacanthocytosis, usually presenting in adolescence or early adulthood with chorea, dystonia, tics, and progressive weakness, may be diagnosed by demonstrating blood acanthocytes, elevated serum creatine kinase, and altered nerve conduction studies (Thomas and Jankovic 2003a). Biochemical screening may also reveal evidence of hypoparathyroidism, which can cause calcification of the basal ganglia, resulting in several movement disorders. Hyperthyroidism, polycythemia rubra vera, and SLE are common enough causes of
320
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 24.15:
Investigation of movement disorders
Movement disorder investigation
A
Routine hematology (including sedimentation rate) Routine biochemistry (including Ca , uric acid, liver function tests) Scrum copper, ceruloplasmin (with or without 24-hour urine Cu, liver biopsy, radiolabeled Cu studies) Slit-lamp examination Thyroid function Antistreptolysin O test, anti-DNase B, antihyaluronidase Antinuclear factor, LE cells, other immunological studies, anticardiolipin antibodies, Venereal Disease Research Laboratories test Blood acanthocytes Lysosomal enzymes Urine organic and amino acids Urine oligosaccharides and mucopolysaccharides Scrum lactate and pyruvate DNA tests for gene mutations Bone marrow for storage cells (including electron microscopy) Electron microscopy of leukocytes; biopsy ot liver, skin, and conjunctiva Nerve or muscle biopsy Oligoclonal bands Computed tomography or magnetic resonance imaging Electroencephalography Electromyography and nerve conduction studies Evoked potentials Elec t ro re ti nogra m Neuropsychological testing
•
+
++ 11
+ + + + + + + + +
C
B
D
T
M
+ + ++
-
-
-
+ ++
1 1
+ + -
++ ++ + ++
+
++ + + +
+ + -
+ +
+
-
+
+ + + + + +
+ + + 1
+ + + +
1
1
1
1
++
++ + + + + +
++ -
1
\
+
+ +
+ + + + + + + +4+ + + -
1
+ + + + + + + + h t 4
++ 1 •f+
+ -
Note: The extent of investigation depends on factors such as age of onset, nature of progression, and presence of historical or clinical atypical features suggesting a secondary cause of the movement disorder in question. A = akinetic rigid syndrome; B = hemiballism; C = chorea; l) = dystonia; M = myoclonus; T = tics. ++ = very important or often useful; + = sometimes helpful; + = questionably helpful; - tarely or never helpful.
undiagnosed chorea in an adult to necessitate exclusion in all cases. Early clues are a history of recurrent fetal loss, an elevated partial thromboplastin time, a false positive Venereal Disease Research Laboratories test, and thrombocytopenia, which indicates the presence of amiphospholipid immunoglobulins, such as the lupus anticoagulant and anticardiolipin ami bodies. Sydenham's chorea must be considered in a child presenting with chorea of unknown origin; antistreptolysin O titer, antihyaluronidase, and electrocardiogram should be obtained, In a patient with hemiballism, one should search for potential risk factors for vascular disease by measuring levels of blood sugar, hemoglobin, platelets, erythrocyte sedimentation rale, cholesterol, and triglycerides. Adults with generalized dystonia or dystonia beginning in the legs must be suspected of having a symptomatic cause and investigated accordingly. A test for DYT'l dystonia is available commercially, and some research laboratories perform tests for e-sarcoglycan (SGCE) gene responsible for the myoclonus-dystonia syndrome. Other DNA tests that may be helpful in the diagnosis of movement disorders include tests for Huntington's disease; spinocerebellar atrophies; Friedreich's ataxia; dentatorubral-pallidoluysian atrophy; pantothenate kinase-associatcd neurodegeneration (PKAN), formerly known as Ilallervorden-Spatz
disease; Unverricht-Lundborg disease (EPM1), celiac disease (antigliadin antibodies), anti-GAD antibodies (stiff man syndrome}, and antibodies for various paraneoplastic syndromes. Imaging studies, such as computed tomography (CT) and, particularly, magnetic resonance imaging (MRI), are useful in certain disorders. Most patients with heimdystoiua have a definable lesion in the contralateral basal ganglia (most often the putamen). Hemiballism or hemichorea usually is caused by a structural lesion in the contralateral subthalamic nucleus or striatum. The cause is commonly a small lacunar infarction, so MRI typically is more successful than CT in localizing the lesion. In patients with parkinsonism, imaging must assess the possibility of hydrocephalus (either obstructive or communicating), midbrain atrophy (as in PSP), and cerebellar and brainstem atrophy (as in olivopontocerebellar atrophy). MRI clearly is much more effective in demonstrating these posterior fossa abnormaiities than is CT. Atrophy of the bead of the caudate nucleus is found in Huntington's disease, but it is not specific for this disorder and does not correlate with the presence or severity of chorea. Multiple infarctions, intracerebral calcification (better seen on CT), mass lesions (such as tumors and arteriovenous malformations), and basal ganglia lucencies (as seen in various disorders) may be found in patients with
MOVEMENT DISORDERS: DIAGNOSIS AND ASSESSMENT
several movement disorders, such as parkinsonism, chorea, and dystonia. In patients with striatonigral degeneration (one subcategory of MSA with prominent parkinsonism), T2-weighted and proton density MRf scans often demonstrate a combination of striatal atrophy and hypointensity, with linear hypcrintensity in the posterolateral putamen. Striatal Tl hyperintensity is seen in hyperglycemia, manganese toxicity, hepatocerebral disease, Wilson's disease, abnormal calcium metabolism, neurofibromatosis, hypoxia, and hemorrhage; striatal T1 hypointensity and T2 hyperintensity suggest mitochondria] disorders; striatal T2 hypointensity with hyperintensity of the mesencephalon sparing the red nucleus and the lateral aspect of the substantia nigra gives the appearance of "face of the giant panda sign," the typical MRI appearance of Wilson's disease; and striatal T2 hypointensity is typically seen in MSA, PSP, and pantothenate kinase-associated neurodegeneration. In the latter disorder, a T2-weighted MRI brain scan typically shows hypointensity in the globus pallidus surrounding an area of hyperintensity, the "eye of the tiger" sign. The "hot cross bun" sign in the pons also suggests MSA, as does T2-weighted gradient echo MRI, which often demonstrates hypointense putaminal changes. Further developments in MRI promise to improve our ability to differentiate between various degenerative disorders, especially if they are associated with characteristic pathological features, such as deposition of pigments or heavy metals. Magnetic resonance spectroscopy also holds promise for differentiating disorders with various neurodegenerative patterns or ncurometabolic disturbances. Positron emission tomography using fluorodeoxyglucosc, fluorodopa, and other radiolabeled compounds (e.g., demonstrating labeling of dopamine receptors) has shown reproducible changes in such conditions as Huntington's disease and parkinsonian disorders. For example, F-dopa positron emission tomography scans show reduced uptake in both the putamen and caudate in patients with atypical parkinsonism, such as PSP and MSA, whereas the caudate usually is preserved in patients with PD. The patterns of abnormalities seen may predict the underlying pathological changes and thus may be useful in differential diagnosis. Developments in single photon emission CT suggest that this will probably become a useful diagnostic tool in evaluating and diagnosing certain movement disorders. Routine electrophysiological testing, including electroencephalography, somatosensory evoked potentials, EMG, and nerve conduction studies, may provide supportive evidence of disease involving structures outside the basal ganglia. EMG analysis of the activity in various muscle groups has been used extensively to study most movement disorders, and tremor can be further documented by accelerometric recordings. Although these and other electrophysiological procedures have contributed to the understanding of the pathophysiology of movement disorders, they have been most crucial to the study of
321
myoclonus. Here, a variety of disturbances may be found on routine electroencephalography, such as spikes, spikeand-wave patterns, and periodic discharges. Occasionally, spikes are seen ro precede EMG myoclonic discharges, particularly if the myoclonus is associated with epilepsy. In the majority of cases, however, it is impossible to determine a correlation between spike discharges and myoclonic jerks by simple visual inspection. Special electrophysiological techniques averaging cortical activity that occurs before a myoclonic jerk (triggered back-averaging) may show focal contralateral central negativity lasting 15-40 milliseconds, preceding the muscle jerk by 10-25 milliseconds in the upper limbs or 30-35 milliseconds in the legs. This is evidence of so-called cortical myoclonus, indicating that cortical activity results in the muscle jerks. In other forms of myoclonus that originate in subcortical areas, cortical discharges may be seen but arc not time-locked in the same fashion to the jerks. In these cases, there may be generalized 25- to 40-millisecond negativity before, during, or after the muscle jerking. The muscle bursts as seen on EMG typically are synchronous in antagonistic muscles and usually are less than 50 milliseconds in duration. In one form of essential myoclonus, ballistic reflex myoclonus, the EMG bursts show alternating activity in antagonists that lasts 50-150 milliseconds. With multichannel EMG recording, it may be possible to demonstrate the activation order of muscles. In cortical myoclonus, muscles are activated in a rostrocaudal direction, with cranial nerve muscles firing in descending order before the limbs. In myoclonus originating from subcortical or reticular sources, it may be possible to show that the myoclonus propagates in both directions from a point source, up the brainstem, usually starting in muscles innervated by the eleventh cranial nerve, and down the spinal cord. In propriospinal myoclonus, the spread up and down the spinal cord occurs at a speed that suggests the involvement of a slowly conducting polysynaptic pathway, Somatosensory evoked potentials and late EMG responses (C reflexes) often are enhanced in patients with myoclonus. Giant sensory evoked potentials can be seen in the hemisphere contralateral to the jerking limb in patients with cortical myoclonus. This is especially true in patients with focal myoclonus that is sensitive to a variety of sensoty stimuli applied to the affected part (cortical reflex myoclonus). The cortical components of the sensory evoked potentials usually are not enhanced in subcortical or spinal myoclonus, but the latencies may be prolonged, depending on the location of the disease process. In caring for a patient with a movement disorder, the clinician must always keep an open mind to the possibility of finding a secondary cause. This should be the case even when the onset, progression, and clinical features of the movement disorder in question ate typical of an idiopathic condition and the pteliminary laboratory testing has not revealed another cause. Thorough neurological examination should be repeated periodically in a search for clues
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
that might indicate the need to p u r s u e the investigation further,
REFERENCES Ahele, M., Burk, K., Schols, L., et al. 2002, "The aetiology of sporadic adult-onset ataxia," Brain, vol. 125, pp. 961-968 Fahn, S., Marsden, C. D., & Van Woerr, M. H. 1986, "Definition and classification of myoclonus," Adv Neurol, vol. 4 3 , pp. 1-5 Hayflick, S. J., Westaway, S. K., Levinson, B., et al. 2003, "Genetic, clinical, and radiographic delineation of Hallcrvordcn-Spatz syndrome," N Engl} Med, vol. 348, pp. 33-40 Jankovic, J. 1995a, "Tardive syndromes and other drug-induced movement disorders," Clin Neurapharmacol, vol, IS, pp, 197-214 Jankovic, J. 1995b, "Treatment of parkinsonian syndromes," in Treatment of Movement Disorders, ed R. Kurlan, JB Lippincott, Philadelphia, pp. 95-114 Jankovic, J. 2001, "Tourette's syndrome," N Engl J Med, vol. 345, pp. 1184-1192 Jankovic, J. 2002, "Essential tremor: A heterogenous disorder," Moii Disord, vol. 17, pp. 638-644 Jankovic, J. 2003, "Pathophysiology and assessment of parkinsonian symptoms and signs," in Handbook of Parkinson's Disease, ed R. Pahwa, K. Lyons, 8c W. C. Roller, Marcel Dekker, New York
Jankovic, J. & Ashizawa, T, 2003, "Huntington's disease," in Neurologic Therapeutics: Principles and Practice, ed J. Noseworthy, Martin Dunitz, London jankovic, J. Sc Demirkiran, M. 2002, "Classification of paroxysmal dyskinesias and ataxias," in Myoclonus and Paroxysmal Dyskinesias, Advances in Neurology, eds S. Frueht & S. Fahn, Lippincott Williams & Wilkins, Philadelphia, pp. 387-400 Jankovic, J. &c Fahn, S. 2002, "Dystonic disorders," in Parkinson's Disease and Movement Disorders, 4th ed, eds J. Jankovic & E. Tolosa, Lippincorr Williams &c Wilkins, Philadelphia, pp. 331-357 Jankovic, J., Nurt, J. G., & Sudarsky, L, 2001, "Classification, diagnosis and etiology of gait disorders," Gait Disorders. Advanced in Neurology, vol. 87, eds F„ Ruzicka, M. Hallctt, 8c J. Jankovic, Lippincott Williams 8c Wilkins, Philadelphia, pp. 119-134 Miyasaki, J. M., Sa, D. S., Galvez-Jimenez, N., 8; Lang, A. E. 2003, "Psychogenic movement disorders," Can J Neurol Set, vol. 30, suppl. 1, pp. S94-100 Ondo, W. G., Vuong, D. K., 8c Jankovic, J. 2002, "Exploring the relationship between Parkinson's disease and restless legs syndrome," Arch Neurol, vol. 59, pp. 421-424 Svetel, M., Ko/ic, D,, Stefanoval, E., et al. 2 0 0 1 , "Dystonia in Wilson's disease," Mov Disord, vol. 16, pp. 719-723 Thomas, M. 8c Jankovic, J. 2003a, "Neuroacanthocytosis," in Neurologic Therapeutics: Principles and Practice, ed J, Noseworthy, Martin Dunitz, London Thomas, M. &c Jankovic, J. 2003b, "Parkinson-plus syndromes," in Neurologic Therapeutics: Principles and Practice, ed J. Noseworthy, Martin Dunitz, London
Chapter 25 Gait Disorders Philip D. Thompson Physiological and Riomechnnical Aspects of Gait Anatomical Aspects of Gait History and Common Symptoms of Gait Disturbance Weakness Slowness Loss of Balance Falls Sensory Symptoms and Pain Incontinence Examination of Posture and Walking Posture Walking Motor and Sensory Examination Discrepancies on Examination of Gait Multiple Sensory Deficits The Cautious Gait Physical Signs and Investigations Spastic Gait Cerebellar Ataxia
323 323 324 324 324 325 325 325 325 326 326 327 328 328 328 328 328 ;is 329
The maintenance of an upright posture and the act of walking are among the first and the most complex motor skills humans acquire. From an early age, these skills are modified and refined. In later years, the interplay between voluntary and automatic control of posture and walking provides a rich and complex repertoire of movement. The pattern of walking may be so distinctive that an individual can be recognized by the "motor fingerprint" of his or her gait. Many diseases of the motor system produce characteristic disturbances of gait and posture that permit the identification of an underlying disease by the manner in which gait is altered.
PHYSIOLOGICAL AND BIOMECHANICAL ASPECTS OF GAIT Humans assume a stable upright posture before beginning to walk. Mechanical stability when standing is based on musculoskeletal linkages between the trunk and legs. Dynamic equilibrium in the upright posture is maintained by a hierarchy of postural reflexes. These postural responses are generated by the integration of visual, vestibular, and proprioceptive inputs in the context of voluntary intent and any ongoing changes in the environment in which the subject is moving. Postural responses consist of coordinated synergistic axial and limb muscle contractions, correcting for and controlling body sway and
Spastic Ataxia Sensory Ataxia Akinetic-Rigid Gait Dystonic Gait Choreic Gait Mixed Movement Disorders and Gait Action Myoclonus and Tremor of the Legs Action Myoclonus Tremor of the Trunk and Legs Gait in the Elderly Nomenclature of Gait in the Elderly Myopathic Weakness and Gait Neurogenic Weakness and Gait Hysterical and Psychogenic Gait Disorders Miscellaneous Gait Disorders Space Phobia and Gait Painful (Antalgic) Gaits Skeletal Deformity and Joint Disease Epileptic Falls in Childhood
330 330 330 331 332 .332 332 332 33.3 333 334 335 335 335 336 336 336 336 3.36
maintaining an upright posture of the trunk. These range from automatic righting reflexes keeping the head upright on the trunk, supporting reactions controlling antigravity muscle tone, anticipatory postural reflexes occurring before limb movement (feed forward) or in response to perturbation during movement (feedback), and reactive postural responses counteracting body perturbations, to actions that are modified by voluntary control in accordance with the circumstances, such as rescue reactions to preserve the upright posture (a step or windmill arm movements), and protective reactions to prevent injury (an outstretched arm to break a fall). Once the trunk is upright and stable, locomotion may begin. The initiation of gait is heralded by a complex shift in the center of pressure beneath each foot, first posteriorly, then laterally toward the stepping foot, and finally away toward the stance foot to allow the stepping foot to swing forward {Elble et al. 1994). This sequence is then followed by the stetcoryped stance, swing, and step phases of the gait cycle.
ANATOMICAL ASPECTS OF GAIT The ncuroanatomical structures responsible for these components of normal walking are poorly understood in humans. Studies in lower species suggest two basicanatomical components. Supraspinal centers signal when to .12.1
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start walking, when to stop, the speed of locomotion, and the size and direction of stepping. These signals descend to the spinal level where spinal locomotor centers elaborate walking patterns of muscle activity. In quadripedal animals, spinal locomotor centers are capable of maintaining and coordinating rhythmic stepping movements after spinal transection. This spinal stepping is generated by assemblies of interneurons, referred to as central pattern generators, which activate limb muscles in a locomotor synergy. They exist for the hind limb, forelimb, and trunk and are interlinked by propriospinal networks to facilitate interlimb coordination. In monkeys, spinal stepping requires preservation of the ventrolateral tracts of the spinal cord containing descending reticulospinal and vestibulospinal pathways. The isolated spinal cord in humans can produce spontaneous movements, but cannot genetate rhythmic stepping or maintain truncal balance. Higher brainstem and cortical connections are therefore necessary for bipedal walking. Brainstem locomotor centers arc present in lower species and probably exist in humans, High-frequency stimulation in the region of the mesencephalic locomotor region in the posterior midbrain elicits locomotor activity in the thalamic monkey. This region overlaps with the peduneulopontinc nucleus, which is thought to be important in rhythm generation. The basal ganglia are involved in the initiation of walking and the quality of stepping, mediated through the cerebral cortex and brainstem structures such as the pedunculopontine nucleus. The cerebellum is important in modulating the rate, thythm, amplitude, and force of voluntary movement and accordingly regulates these aspects of stepping. The cerebral cortex is required for precision movements of the legs when walking. Corticospinal activation modifies spinal locomotor activity to start and stop walking, conveying the voluntary commands. Sensory feedback during the walking cycle in turn modifies motor cortical activity. Brainstem structures arc important in maintaining postural righting reflexes that control axial extensor tone. Lesions of the medial brainstem interrupt descending reticulospinal, vestibulospinal, and tectospinal systems rh.it innervate proximal and axial muscles, resulting in dysequilibrium. In humans, postural reflexes controlling truncal equilibrium are organized by a poorly understood network involving the flocculonodular and anterior lobes of the cerebellum, the brainstem, central vestibular pathways, basal ganglia, thalamus, and frontal lobes. Lesions of each of these areas interfere with postural control, particularly when standing.
HISTORY AND C O M M O N SYMPTOMS OF GAIT DISTURBANCE A detailed account of the walking difficulty and its evolution provides the first clues to the underlying diagnosis. When evaluating the history, we find it helpful
to note the particular circumstances in which the walking difficulty occurs, the leg movements most affected, and any associated symptoms. Because disorders at many levels of the peripheral and central nervous systems give rise to difficulty walking, it is necessary to consider whether the problem is primarily motor, caused by muscle weakness, a defect of higher motor control, or imbalance, due to cerebellar disease or proprioceptive sensory loss. Walking on uneven ground exacerbates most walking difficulties and leads to tripping, stumbling, and falls. A ligamentous ankle strain or even a bony fracture may result from tripping and falling in this situation and may be the presenting symptom of a gait disorder. Fear of falling may lead to various voluntary protective measures to minimize the risk of injury. In some patients, particularly the elderly, a fear of falling and a "cautious" gait may dominate the clinical picture and be a presenting feature.
Weakness Weakness of the legs may be described several ways. Complaints of stiffness, heaviness, or "legs that do not do what they arc told" may be the presenting symptoms of a spastic paraparesis or hemiparesis. Patients with spastic paraparesis often report that they drag their legs to walk or their legs may suddenly give way, causing them to stumble and fall. Weakness of certain muscle groups also may be described in terms of difficulties in performing particular movemenrs. A tendency to trip because of catching or scraping the toe on the ground may be the presenting symptom of hemiplegia {causing a spastic cquinovarus foot posture) or footdrop caused by weakness of ankle dorsiflexion. Similarly, weakness of certain movements may first become apparent in particular situations; for example, difficulty in climbing stairs or rising from a seated position is suggestive of proximal muscle weakness, which is most commonly caused by a myopathy. Rarely, these complaints may be the presenting symptoms of an acute inflammatory polyneuropathy (Guillain-Barre syndrome). Weakness of knee extension (caused by a femoral neuropathy or quadriceps myopathy) may impose difficulty walking down stairs.
Slowness Slowness of walking and limb stiffness are common in extrapyramidal disease. These symptoms are produced by difficulty engaging the legs in brisk motion and increased muscle tone (rigidity). This slowness of movement may be accompanied by shuffling with small shallow steps. Difficulty initiating the first few steps when starting to walk (start hesitation), pronounced shuffling for a few steps, and freezing at the slightest obstacle, a doorway, or
GAIT DISORDERS other distraction are common. Some patients, particularly those with Parkinson's disease, overcome the shuffling and facilitate stepping and walking by carefully watching and treading over lines on the floor or other objects such as the handle of an upturned walking stick. It is useful to inquire about axial mobility. Difficulty rising from a chair or getting out of bed may be due to a loss of truncal mobility and axial rigidity in diffuse cerebrovascular disease, hydrocephalus, and extrapyramidal diseases. Axial muscle weakness resulting from peripheral neuromuscular diseases may also interfere with truncal mobility. Fatigue during walking occurs in muscular weakness of any cause and is often a symptom of the extra effort required to walk in upper motor neuron (UMN) syndromes and extrapyramidal disease. The circumstances in which leg stiffness occurs when walking may be revealing. For example, the presenting symptom of idiopathic torsion dystonia in childhood may be stiffness and abnormal posturing of one leg, with inversion and plantar flexion of the foot and a tendency to walk on the toes, because of an action dystonia of the leg and foot. This may be evident only when walking or running. Patients with dopa-rcsponsive dystonia and prominent diurnal fluctuation develop their symptoms only in the afternoon.
Loss of Balance Symptoms of poor balance and unsteadiness are cardinal features of the ataxic syndromes caused by cerebellar disease or proprioceptive sensory loss. The patient with a cerebellar gait ataxia complains of unsteadiness and an inability to walk in a straight line or turn and change direction suddenly without veering to one side or staggering as if intoxicated. A sensory ataxia may first give rise ro symptoms of unsteadiness when walking in the dark because visual compensation for the proprioceptive loss is not possible. Patients with impaired proprioception and sensory ataxia complain of being uncertain of the exact position of their feet when walking. They may be unable to appreciate the texture of the ground beneath their feet and describe abnormal sensations in the feet that give the impression of walking on a spongy surface or cotton wool. Acute disturbances of balance and equilibrium suggest a vascular insult to the cerebellum, thalamus, or basal ganglia. Acute severe vertigo caused by a peripheral vestibulopathy may also lead to a sensation of imbalance and a tendency to veer toward one side.
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shallow steps, the effect of which may be exaggerated when walking on uneven ground. Proximal muscle weakness may result in the legs giving way. Unsteadiness and poor balance in an ataxic syndrome may lead to falls. Spontaneous falls or falls following postural adjustments, either forward or backward, suggest an impairment of postural reflexes. Falls when looking upward are common in the elderly. In the extreme form of loss of postural reflexes, patients may fall backward "like a board". In the setting of the early stages of an akinetic-rigid syndrome, spontaneous falls are an important clue to diagnoses such as multiple system atrophy or progressive supranuclear palsy {SteeleRichardson-Olszewski syndrome) rather than Parkinson's disease.
Sensory Symptoms and Pain The distribution of any accompanying sensory complaints provides further information about the site of the lesion producing walking difficulties. A common example is cervical spondylosis and myelopathy presenting with cervical radicular pain or paresthesias and a spastic paraparesis. Paresthesias in a radicular distribution (caused by radiculopathy) and sensations of tight bands around the trunk {caused by spinal sensory tract compression), or a combination of truncal and limb sensory symptoms and a spastic paraparesis, are suggestive of a myelopathy. Distal symmetrical paresthesias affecting the limbs point toward a peripheral neuropathy. It is important to determine whether complaints of leg pain and weakness in patients with difficulty walking share a common cause or whether the pain is of musculoskeletal origin and exacerbated by walking. An example of the former is cxcrcisc-induccd pain and weakness of the legs caused by neurogenic intermittent claudication of the cauda equina. These symptoms are often accompanied by transient paresthesias or radicular sensory loss in the legs, which is relieved after a few minutes by sitting and leaning forward. This should be distinguished from vascular intermittent claudication in which ischemic muscle pain, usually of the calves, interrupts walking but is relieved after a few seconds of rest. Skeletal pain caused by degenerative joint disease is common in elderly patients. It is often present at rest and aggravated by leg movements. The normal pattern of walking is often modified in these situations. The patient may voluntarily engage various strategies to minimize pain by avoiding bearing the full weight on the affected limb and by limiting its range of movement (antalgic gait).
Falls Incontinence When taking a history of falls, wc must establish the circumstances in which they occur and whether there are any clear precipitants. Tripping may be due to footdrop or
Loss of the voluntary control of sphincter function in a patient with a spastic gait suggests a spinal cord lesion.
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Parasagittal cere bra I lesions Mich as frontal lobe rumors (parasagittal meningioma), frontal lobe infarction caused by anterior cerebral artery disease, and hydrocephalus should also be considered, in addition to spinal cord disease. Impairment of higher mental function may be an important clue to a cerebral cause of paraparesis.
pattern, the clinician should examine a number of specific aspects of gait, as outlined in rhe checklist for clinical examination of posture and gait (see Table 25.1).
Posture Trunk
Posture
EXAMINATION OF POSTURE AND WALKING The examination of posture and walking is summarized in Table 25.1. A convenient starting point is to observe the overall pattern of whole-body movement during walking. Normal walking progresses in a smooth and effortless manner, with an upright posture of rhe trunk. The legs swing in a free and fluid motion with regular strides of appropriate length accompanied by flowing associated synergistic head, trunk, and upper limb movement. Careful observation of the overall pattern of body movement during walking often enables rhe experienced observer to decide whether the gait problem is caused by a focal leg abnormality, muscle weakness, or a more generalized disorder ol movement, and whether it is unilateral or bilateral. After observing the overall walking
Table 25.1: and gait
Checklist for the clinie.il examination of posture
Posture Trunk posture (upright or stooped) Postural reflexes (displace the paiii-m's center of gravity forward and backward) Stance (narrow or wide based) Walking Initiation (start hesitation, shuffling, magnetic feet) Stepping Rhythm (regular, irregular) Length (normal, short) Trajectory (shallow, high stepping) Speed Festi nation Freezing Associared trunk movement and arm swing Special maneuvers ] led to roe walking Romberg test Walking backward or running Formal motor and sensory examination (supine) Leg size and length Range of j o i n t movement Muscle bulk
Muscle tone Muscle strength Voluntary movement Trunk movement (rolling over) Leg movement when not standing Tendon reflexes Sensation: proprioception I kel-shin test
The trunk is normally upright during standing and walking. Flexion of the trunk is a prominent feature of Parkinson's disease but also may be seen in cautious gait syndromes in which the center of gravity is lowered to minimize body sway and the risk of falling. Neck and trunk extension is characteristic of progressive supranuclear palsy. Tilt of the trunk to one side may be a sign of dystonia but can also be seen in acute thalamic, basal ganglia, and vestibular lesions. An exaggerated lumbar lordosis, caused by hip-girdle weakness, is typical of proximal myopathies. Paraspinal muscle spasm and rigidity also produce an exaggerated lumbar lordosis and are striking features of the stiff person syndrome. A variety of axial muscle spasms are seen in torsion dystonia, with the most common being exaggerated flexion of rhe trunk and hip when walking. Abnormal thoracolumbar postures also may result from spinal ankylosis and spondylitis. Paraspinal myopathies may lead to severe rruncal weakness and a posture of marked truncal flexion (bent spine or eamptocormia). A restricted range of spinal movement and persistence of an abnormal spinal posture when supine or during sleep are useful pointers toward a bony spinal deformity as the cause of an abnormal trunk posture. Altered truncal postures, particularly in the lumbar region, may occur either to compensate for a shortening of one lower limb or disease of the hip, knee, or ankle or in response to leg pain. Postural
Reflexes
Postural teflcxes arc examined with patients standing and gently pulling the upper trunk backward or forward. The examiner should sr.md in front of or behmd patients and be prepared to catch or support them to prevent them from falling. An impairment of postural righting reactions is evident after each displacement by a few short shuffling steps backward (retropulsion) or forward (propulsion).
Severe loss of postural reflexes abolishes reflex stepping or compensatory arm movements to adjust posture and restore balance and may render a patient susceptible to falls after minor perturbations or postural changes. A tendency to fall backward spontaneously is a sign of impaired postural reflexes in progressive supranuclear palsy. A pronounced rruncal rilr is observed in some thalamic and basal ganglia hemorrhages with rhe rrunk leaning away from the side of the lesion, leading to a fall to that side or backward (Masdeu and Gorelick 1988; Labadie et al. 1989). In the lateral medullary syndrome, the trunk may sway or tilt
GAIT DISORDERS Tabic 25.2:
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Summary of the major clinical features distinguishing different types of gait ataxia
Vi-atum
Cerebellar ataxia
Sensory ataxia
Frontal lobe ataxia
Trunk posture Stance Postural reflexes Initiation of gait Steps Speed Heel-toe test Turning corners Romberg test Heel-shin test Falls
Stooped, leans forward Wide based Variable Normal Staggering, lurching Normal, slow Unable Veers away Variable Usually abnormal Uncommon
Stooped, upright Wide based Intact Normal f ligh stepping Normal, slow Variable Minimal effect Increased unsteadiness Variable Yes
Upright Wide based Impaired or absent Start hesitation Short, shuffling Very slow Unable Freezing, shuffling Variable Normal Very common
Stepping
regular, and shallow steps or shuffling is characteristic of the akinetic-rigid syndromes. Shuffling is usually most evident when starting to walk, stopping, ot turning corners. Repeatedly observing these maneuvers may highlight a subtle tendency to shuffle. Once underway, freezing may interrupt walking with further shuffling and start hesitation. Jerky steps of irregular rhythm and variable length and trajectory suggest an ataxic syndtome. Abnormal leg and foot trajectories occur in sensory ataxia, footdrop, spasticity, and dystonia. Each is associated with a distinctive leg posture during stepping. The speed of walking is revealing. Slowness is charactetistic of the akinetic-rigid syndromes but is also seen in ataxic and spastic syndromes. Festination (increasingly rapid, small steps) is common in Parkinson's disease but is rare in other a kinetic-rigid syndromes, which usually are associated with poor balance and falls rather than festination. A reduction in associated trunk movement and arm swing is most evident in unilateral UMN, extrapyramidal, and acute cerebellar syndromes. Bilateral loss of synergistic arm movement when walking is a valuable sign of Parkinson's disease in the early stages, when most symptoms are unilateral. Subtle degrees of cerebellar ataxia may be unmasked by asking the patient to walk in a straight line heel to toe (tandem gait), to stand on one leg, or to walk and turn quickly. If vision is important in helping maintain balance, as in sensory ataxia caused by proprioceptive loss, the removal of vision greatly exaggerates the ataxia. This is the basis of the Romberg test in which eye closure leads to a dramatic increase in unsteadiness and even falls in the patient with sensory ataxia. When pctforming the Romberg test, the patient must be standing comfortably before eye closure and the observer must remember that normal subjects and patients with cerebellar ataxia also show a modest increase in body sway with eye closure.
Once walking is undetway, the rhythm of stepping and the length and trajectory of each step should be noted. Short,
It may be necessary to examine the patient running to identify an action dystonia of the legs in the early stages of primary torsion dystonia.
toward the side of the lesion as a result of the acute imbalance in vestibulat postural control (lateropulsion). The presence of injuries to the knees, shins, face, or back of the head sustained during falls provides a clue to the loss of postural reactions, including impairment of the rescue reaction of an outstretched arm to break a fall. Stance Stance base (the distance between the feet during quiet standing) and walking give some indication of balance. Wide-based gaits are typical of cerebellar or sensory ataxia but may be seen in diffuse cetebtal vascular disease and frontal lobe lesions {Table 25.2). People whose balance is insecure for any reason tend to adopt a wider stance, adopt a posture of mild generalized flexion, and take shorter steps. Widening the stance base is an efficient method of reducing body sway in the lateral and anteroposterior planes. Those who have attempted to walk on ice ot other slippery surfaces will recognize this phenomenon.
Walking Initiation
of Gait
Difficulty initiating the first step (start hesitation) is a featutc of Parkinson's disease and frontal lobe disease and is occasionally seen in relative isolation in the syndrome of gait-ignition failure (Atchison et al. 1993). Start hesitation ranges in severity from a few shuffling steps, to small shallow steps on the spot without forward progress ("slipping clutch'"), to complete immobility with the feet seemingly glued to the floor ("magnetic feet"). Patients may make exaggerated upper body movements in an effort to engage their legs in motion.
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APPROACH TO COMMON NtUROLOGlCAL PROBLtMS
M O T O R AND SENSORY EXAMINATION After observing the patient walking, the clinician examines motor and sensory function in the limbs with the patient supine in the conventional examination position. The size and length of the limbs should be measured in any child presenting with a limp. An asymmetry in leg si/e is suggestive of a congenital malformation of the spinal cord, brain, or (rarely) local overgrowth of tissue. The spinal column should be inspected for scoliosis and the lumbar region for skin defects or hairy patches, which are indicative of spin a 1 dysraphism. Changes in muscle tone such as spasticity, lead-pipe or cogwheel rigidity, or paratonic rigidity (gegenhalten) point toward diseases of the UMN, basal ganglia, and frontal lobes, respectively. In the patient who complains of symptoms in only one leg, a detailed examination of the other leg is important. If signs of a UMN syndrome are presenr in both legs, a disorder of the spinal cord or parasagittal region is likely. Muscle bulk and strength are examined, and evidence of muscle wasting and the presence and distribution of muscle weakness are documented. Examination reveals whether the abnormal posture of the leg in a patient with a footdrop (Table 25.3) is caused by spasticity or weakness of ankle dorsiflexors, which in turn may be due to anterior horn cell disease, a peripheral neuropathy, a peroneal compression neuropathy, or an L5 root lesion. Subtle degrees of ankle dorsiflexion weakness may be detected by observing the patient walking on his or her heels. Joint position sense should he examined for defects of proprioception in the ataxic patient.
Discrepancies on Examination of Gait Several conditions are notable for producing minimal abnormal signs on physical examination of the recumbent patient, in striking contrast to the observed difficulty when walking.
Tabic 25.3: Causes of footdrop and an cquinovarus foot posture when walking Peripheral nerve L5 radiculopathy Lumbar plexopathy Sciatic nerve palsy Peroneal neuropathy (compression) Peripheral neuropathy (bilateral) Anterior horn cell disease (motor neuron disease) Myopathy Sc a p uIo peronea 1 syndromes Spastieity Dystonia Sensory
;lt;l\i;l
Patients with a cerebellar gait ataxia caused by a vermis lesion may perform the heel shin test normally when supine but when standing are unable to walk heel to toe. The finding of normal muscle strength, muscle tone, and tendon reflexes is common in dystonic syndromes in which an action dystonia causes abnormal posturing of the feet only when walking. A dystonic gait may exhibit a striking discrepancy between the difficulty walking forward, which may not be evident when walking backward. Gegenhalten, with or without brisk tendon reflexes, may be the only abnormal signs in the legs of the recumbent patient with a frontal lobe lesion, hydrocephalus, or diffuse cerebrovascular disease who is totally unable to walk. Moreover, such patients may be able to perform the heel-shin test and make bicycling movements of their legs when lying on a bed. A similar discrepancy can be seen in spastic paraplegia caused by hereditary spastic paraplegia, cerebral palsy (Little's disease), or cervical spondylotic myelopathy, in which only minor changes in muscle tone, strength, and tendon reflexes are evident during the supine examination in contrast to the profound leg spasticity apparent when walking.
Multiple Sensory Deficits Elderly patients with walking difficulties and falls often have signs of multiple deficits. The most common are cervical spondylotic myelopathy with a mild spastic paraparesis and a degree of proprioceptive loss, as well as a peripheral neuropathy with absent ankle reflexes and mild proprioceptive loss. Additional sensory deficits such as visual, hearing, and vestibular impairment also contribute to imbalance, falls, and gait difficulties. Musculoskeletal factors and postural hypotension also interfere with mobility in this age-group.
The Cautious Gait Finally, due account must be taken of the fear of falling that often accompanies gait difficulties. This may lead to a marked loss of confidence when walking and a cautious or protected gait (Nutt, Marsden, and Thompson 1993). Such patients may be unable to walk without support. They hold on to furniture, lean on walls, and avoid crowded or open spaces because of a fear of falling. Their gait may improve dramatically when support is provided.
PHYSICAL SIGNS AND INVESTIGATIONS Spastic Gait Spasticity of the arm and leg on one side produces the characteristic clinical picture of a spastic hemlparesis. The arm is held adducted, internally rotated at the shoulder,
GAIT DISORDERS
and flexed at the elbow, with pronation of the forearm and flexion of the wrist and fingers. The leg is slightly flexed at the hip and extended at the knee, with plantar flexion and inversion of the foot. The swing phase of each step is accomplished by slight lateral flexion of the trunk toward the unaffected side, and hyperextension of the hip on that side to allow the slow circumduction of the stiffly extended paretic leg, as it is swung forward from the hip, dragging the toe or catching it on the ground beneath. A minimum of associated arm swing occurs on the affected side. The stance may be slightly widened, and the speed of walking is slow. Balance may he poor because the hemiparesis interferes with corrective postural adjustments on the affected side. Muscle tone in the affected limbs is increased, clonus may be present, and the tendon reflexes are abnormally brisk with an extensor plantar response. Examination of the sole of the shoe may reveal wear of the toe and outer borders of the shoe, suggesting that the spastic gait is long standing. After identifying a spastic hemiparesis, the next step is to determine the level of the lesion that is responsible. Attention should be paid to the face, because UMN facial weakness on the same side indicates that the level probably lies above the pons, the most common cause of which is cerebral infarction, suggested by a history of acute onset. A UMN type of facial weakness on the side opposite the hemiparesis (crossed hemiparesis) suggests a pontine lesion. When the face is not involved, ciues to the site of the lesion must he sought by examining the motor function of the lower cranial nerves. Weakness of shoulder shrugging on the same side points to a lesion above the foramen magnum. A cervical spinal cord lesion involves the arms unci legs only, whereas a lesion ot the thoracic cord affects only the legs. When lesions of the spinal cord are suspected, magnetic resonance imaging (MRI) of the cord is indicated. Spasticity of both legs gives rise to a spastic paraparesis. The legs are stiffly extended at the knees, plantar flexed at the ankles, and slightly flexed at the hips. The gait is slow and labored. The legs are dragged forward with each step, both legs circumduct, and there is a tendency of adduction of the legs, particularly when the disorder begins in childhood. This appearance gave rise to the term scissor gait. The causes of a spastic paraparesis include hereditary spastic paraplegia, in which the arms and sphincters are unaffected and there may be little or no leg weakness, and other myelopathies. An indication of the extent and level of the spinal cord lesion can be obtained from the presence or absence of weakness or sensory loss in the arm, a spinothalamic sensory level or posterior column sensory loss, and alterations in sphincter function. Most patients with paraparesis of recent onset should be investigated with MRI of the spinal cord or myelography, to exclude potentially treatable causes, such as spinal cord compression. Occasionally, bilateral leg dystonia (dystonic paraparesis) may mimic a spastic paraparesis. This typically occurs
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in dopa-responsive dystonia in childhood, which may be misdiagnosed as hereditary spastic paraplegia or cerebral diplegia. Differentiation between these conditions can be difficult. Brisk tendon reflexes may occur in both, and spontaneous extension of a great toe in patients with striatal disorders may be interpreted as a Babinski response. Fanning of the toes and knee flexion suggest the latter. Other distinguishing features include changes in muscle tone, such as spasticity in hereditary spastic paraparesis and rigidity in dystonic paraparesis. In young children, the distinction is important, because a proportion of such patients can be treated successfully with L-dopa {discussed in the following sections).
Cerebellar Ataxia The gait disorder that accompanies disease of the vermis and anterior lobe of the cerebellum consists of a loss of normal truncal balance resulting in increased body sway and dyseqiulibrium. The patient adopts a wide-based stance and may flex the hips slightly to crouch forward and minimize body sway. Patients with anterior lobe atrophy develop a 3-Hz anteroposterior sway of the trunk, which may be accompanied by a rhythmic truncal and head tremor (titubation). Patients with lesions of the flocculonodular lobe of the cerebellum (the vestibulocerebellum) exhibit multidirectional body sway and dysequilibrium and may fall. Limb ataxia resulting from involvement of the cerebellar hemispheres is characterized by a decomposition of normal leg movement with steps that are irregular and variable in timing (dyssynergia), length, and direction (dysmetria). Steps are taken slowly and carefully to reduce the tendency to lurch and stagger. These defects are exacerbated when attempting to walk heel to toe in a straight line. Ataxia is also made worse by the rapid postural adjustments needed when changing direction to turn a corner, avoid obstacles, and when stopping or starting to walk. Cerebellar ataxia may be improved by minor support, such as holding the patient's hand during walking. Visual compensation helps the patient with a cerebellar ataxia reduce body sway or plot a secure path ahead while walking. Eye closure may increase anxiety about falling but does not produce the dramatic deterioration in balance seen in a sensory ataxia, With lesions confined to one cerebellar hemisphere, ataxia is limited to the affected (ipsilateral) limb and affects coordination of limb movement more than balance, if the vermis is not involved. Conversely, a purely truncal ataxia may be the sole feature of a midline (anterior lobe and vermis) cerebellar syndrome. As discussed earlier, this may escape notice if the patient is not examined when standing because leg coordination during the heel-shin test may be relatively normal when the patient with a vermis lesion is examined in the supine position.
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
An isolated cerebellar gait ataxia may be caused by malnutrition in alcoholism, producing a relatively selective vermis and anterior lobe syndrome. Midline cerebellar masses and paraneoplastic, hereditary, or sporadic cerebellar degenerations may also produce a predominantly truncal cerebellar ataxia.
Spastic Ataxia A combination of spasticity and ataxia produces a characteristic springing or bouncing gait. Such gaits may be seen in multiple sclerosis, the Amold-Chiari malformation, and hydrocephalus in young people. The gait is wide based, and clonus is readily elicited by stretching the leg muscles when examining muscle tone or tapping the tendon reflexes. Even voluntary leg movements may precipitate clonus, which throws the ataxic patient off balance. Compensatory reflex and voluntary movements, made in an effort to regain balance, set up a vicious cycle of ataxic movements, clonus, and increasing unsteadiness, so such patients may be totally unable to stand and walk. Bouncing gaits must be distinguished from action myoclonus of the legs and from leg and truncal tremors seen in cerebellar disease (see Action Myoclonus and Tremor of the Legs, later in this chapter).
Sensory Ataxia The loss of proprioceptive input from the legs deprives patients of knowledge of their position in space, the progress of ongoing movement, the state of muscle contraction, and finer details of the texture of the surface of the ground on which they are walking. Patients without such information tend to adopt a wide base and take slow steps, advancing cautiously with the aid of visual guidance. The feet are thrust out with each step, and the sole of the foot strikes the floor forcibly, giving rise to a slapping noise (slapping gait). Patients with sensory ataxia find it difficult to walk on uneven surfaces or at night. Lesions at any point in the sensory pathways that interrupt large-diameter proprioceptive afferent fibers may produce this clinical picture. Peripheral neuropathies, posterior root or dorsal root ganglion lesions such as tabes dorsalis, and dorsal column lesions, for example, in vitamin B ] 2 deficiency, are some of the diseases responsible for a sensory ataxia of gait.
Akinetic-Rigid Gait The most common akinetic-rigid gait disturbance is that seen in Parkinson's disease. The patient adopts a stooped posture with flexion of the shoulders, neck, and trunk. Tremor of the upper limbs may be evident when walking
(but parkinsonian tremor of the legs rarely affects walking). The gait is typically slow and shuffling, with small shallow steps on a narrow stance base. These signs may be dramatically reversed by L-dopa treatment. There is little associated body movement. Arm swing is reduced or absent and the arms are held immobile at the sides or slightly forward of the trunk. A characteristic feature is the tendency to begin walking with a few rapid, short shuffling steps {start hesitation) before breaking into a more normal walking rhythm. Walking, once underway, may be interrupted by further shuffling or even complete cessation of movement (freezing) if a doorway or other obstacle is encountered. Freezing becomes increasingly troublesome in the later stages of Parkinson's disease when it is helped more by sensory cues to trigger a step than L-dopa medication. The posture of generalized flexion of the patient with Parkinson's disease exaggerates the normal tendency to lean forward when walking. To maintain balance when walking and avoid falling forward, the patient may advance with a series of rapid small steps (festination). Rctropulsion and propulsion are similar manifestations of a flurry of small-si/.ed parkinsonian steps made in an effort to preserve equilibrium in response to external perturbations. Instead of a single large step, a series of small steps are taken to restore balance. If these compensatory festinating steps are too small to maintain or restore balance, the patient may fall forward. Other causes of falls in Parkinson's disease include tripping or stumbling over rough surfaces, because each step is too small or shallow to clear obstacles, as well as profound start hesitation or freezing. In each of these examples, falling stems from locomotor hypokinesia and a lack of normal-sized, rapid, compensatory voluntary movements, Late in the illness, falls may occur either spontaneously or after minor perturbations resulting from loss of postural and righting reflexes. These deficits do not respond to L-dopa medication, unlike the hypokinetic steps and flexed truncal posture early in the disease, A similar slowness of leg movement and shuffling when walking may occur in various other akinetic-rigid syndromes (Table 25.4). These include multiple system atrophy, cerebrovascular disease, and progressive supranuclear palsy. A number of clinical signs help distinguish between these conditions (Table 25.5). In progressive supranuclear palsy, the typical neck posture is one of extension rather than flexion, as in Parkinson's disease. A stooped posture with exaggerated neck flexion is sometimes a feature of multiple system atrophy. A distinguishing feature of progressive supranuclear palsy and multiple system atrophy is the early loss of postural and righting reflexes in comparison ro the preservation of these reflexes in Parkinson's disease until the late stages of the illness. There also may be an element of ataxia in these akinetic-rigid syndromes, which is not evident in Parkinson's disease. Accordingly, the patient who presents with falls and an akinetic-rigid syndrome is more likely to
GAIT DISORDERS Tabic 25.4: Differential diagnosis in the patient presenting with an a kinetic-rigid syndrome and a gait disturbance Parkinson's disease Drug-induced parkinsonism Multiple system atrophy Stria ton igral degeneration Shy-Drager syndrome (idiopathic orthostatic hypotension) Olivopontocerebellar atrophy Progressive supranuclear palsy (Steele-Riehardson-Olszcwski syndrome) Pick's disease (frontotemporal dementia) Corticobasal degeneration Creutzfeldt-Jakoh disease Cerebrovascular disease (Binswanger's disease) Hydrocephalus Frontal lobe tumor juvenile Huntington's disease Wilson's disease Cerebral anoxia Neurosyphilis
have s y m p t o m a t i c p a r k i n s o n i s m , r a t h e t t h a n P a r k i n s o n ' s disease. T h e gait of patients with h y d r o c e p h a l u s a n d Binswanger's disease caused by periventricular w h i t e m a t t e t ischemia is characterized by s h o r t shuffling steps, often of variable length, with a wide-based stance (and stride w i d t h ) a n d a degree of i m b a l a n c e . T h e truncal p o s t u r e is upright with exaggetated a r m swing d u r i n g w a l k i n g , giving t h e gait a military a p p e a r a n c e . E x a m i n a t i o n also teveals preservation of upper b o d y m o v e m e n t in c o n t r a s t to P a r k i n s o n ' s disease. These stance and stepping chatactctisties h a v e also been demonstrated by kinematic studies of gait in h y d r o c e p h a l u s and Binswanger's disease (Ebcrsbach et al. 1 9 9 9 ; Stolze et al. 2 0 0 1 ) . Finally, the d r a m a t i c response to L-dopa t h a t is typical of idiopathic P a t k i n s o n ' s disease d o e s n o t occur in symptomatic p a r k i n s o n i s m , a l t h o u g h sonic patients with
multiple period.
system
atrophy
respond
partially
for a
331 short
Dystonic G a i t Of all gait d i s t u r b a n c e s , dystonic s y n d r o m e s m a y p r o d u c e the most bizarre a n d often the most difficult diagnostic p r o b l c m s . T h e classic p r e s e n t a t i o n of c h i l d h o o d - o n s e t p r i m a r y torsion dystonia (dystonia m u s c u l o r u m deform a n s ) is an action d y s t o n i a of a leg with a sustained a b n o r m a l p o s t u r e of the foot (typically, p l a n t a t flexion a n d inversion) on a t t e m p t i n g to r u n . In c o n t r a s t , walking f o r w a r d o r b a c k w a r d o r even r u n n i n g b a c k w a r d may b e entirely n o r m a l at an early stage. An easily o v c t l o o k e d sign in t h e early stages is tonic e x t e n s i o n of the great toe (the striatal toe) w h e n w a l k i n g . This m a y be a subtle finding but occasionally is so p r o n o u n c e d t h a t a hole is w o r n in che roe of the s h o e . W i t h time, dystonia m a y progress to involve the w h o l e leg and then b e c o m e generalized. M o r e difficult to identify a r e those dystonic s y n d r o m e s t h a t p t e s e n t w i t h bizarre, seemingly inexplicable postures of the legs a n d t r u n k w h e n w a l k i n g . A characteristic featute c o m m o n to all these dystonic p o s t u r e s is excessive flexion of t h e hip w h e n w a l k i n g . These patients m a y h o p or walk s i d e w a y s in a crablike fashion with hypcrflexion of the hips, p r o d u c i n g an attitude of general b o d y flexion in a simian p o s t u r e , or with a birdlikc (peacock) gait with excessive flexion of the hip a n d knee a n d p l a n t a r flexion of t h e foot d u r i n g t h e s w i n g p h a s e of each step. M a n y of these patients h a v e been t h o u g h t to be hysterical because of the bizarre n a t u r e of their gait d i s t u r b a n c e a n d because formal neurological e x a m i n a t i o n s h o w s no a b n o r m a l i t i e s if the patient is e x a m i n e d w h e n lying supine. Each of these gait p a t t e r n s has been described in association with identifiable s e c o n d a r y dystonic s y n d r o m e s , including postencephalitic m o v e m e n t disorders, m a n g a n e s e p o i s o n i n g , and Wilson's
Table 25.5; Summary of the clinical features that help differentiate between Parkinson's disease and symptomatic or secondary parkinsonism in patients with an akinetic-rigid gait syndrome Feature
Parkinson's
Posture Stance Initiation of walking Steps Stride length Freezing Leg movement
Stooped (trunk flexion) Narrow Start hesitation Small, shuffling Short Common Stiff, rigid Slow Common Minimal or absent Normal Preserved in early stages Late (forward, tripping)
Spi-cd
Festi nation Arm swing Heel-to-toe walking Postural reflexes Falls
disease
Symptomatic
parkinsonism
Stooped or upright (trunk flexion or extension) Often wide based Start hesitation, magnetic feet Small, shuffling Short Common Stiff, rigid Slow Rare Reduced or excessive Poor (truncal ataxia) Absent at early stage Early and severe (backward, tripping or without apparent reason)
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
disease. Finally, tardive dystonia after the ingestion of neuroleptic drugs also may produce similar bizarre abnormalities of gait, It is always important to look for asymmetry in the assessment of childhood-onset dystonia, because a hemidystonic syndrome should be investigated to exclude symptomatic causes. Similarly, an isolated dystonic leg also should point toward symptomatic causes in an adult, though not in childhood, Should there be an early loss of postural responses and righting reflexes in association with a dystonic gait disturbance, attention also should be directed toward excluding underlying secondary causes. Dystonia with diurnal fluctuation (dopa-rcsponsive dystonia) characteristically presents with walking difficulties in childhood. Typically, the child walks normally in the early morning but develops increasing rigidity and dystonic posturing of the legs with difficulty walking as the day progresses. These dystonic leg postures usually become evident or worsen after exercise. Examination reveals a dystonic foot posture of plantar flexion and inversion, with the additional feature of brisk tendon reflexes. Some of these patients respond dramatically to L-dopa-containing preparations, and early recognition is important. Indeed, all children presenting with a dystonic foot or leg should have a therapeutic trial of L-dopa before other therapies, such as anticholinergic drugs, are commenced. Paroxysmal dyskinesias also may present with difficulty walking. Paroxysmal kincsigenic choreoathetosis may present with the sudden onset of difficulty walking as a result of dystonic postures and involuntary movements of the legs that often appear after standing from a seated position. Similarly, dystonia of the legs, cither paroxysmal or exercise induced, may interfere with walking.
are variable in length and timing. Spontaneous knee flexion and leg raising are also common. Haloperidol reduces the chorea but does not improve gait in Huntington's disease. Balance and equilibrium usually are maintained until the terminal stages of Huntington's disease, when an akinetic rigid syndrome may supervene.
Mixed Movement Disorders and Gait Many conditions, notably athetoid cerebral palsy, produce :.i range of motor signs that refleci abnormalities at many levels of the nervous system. All interfere with and disrupt normal patterns of walking. These include spasticity of the legs, truncal and gait ataxia, and dystonic spasms and postures affecting the trunk and limbs. Difficulties may arise in distinguishing such patients from those with primary torsion dystonia, which may begin at a similar age in childhood. The patient with cerebral palsy usually has a history of hypotonia and delayed achievement of developmental motor milestones. Often, there is a history of perinatal injury or birth asphyxia, but in a substantial proportion of patients, such an event cannot be identified. A major distinguishing feature is poor balance at an early age, which may be a contributing factor to the delay in sitting and later walking. As the child begins to walk, the first signs of dystonia and athetosis appear. The presence of spasticity and ataxia also helps distinguish this condition from primary dystonia. Childhood neurodegenerative diseases also may first manifest as a disorder of walking with a combination of motor syndromes. A progressive course should raise the possibility that the syndrome is symptomatic and secondary to an underlying cause.
Choreic Gait The random movements of chorea are accentuated and often most noticeable during walking. The gait is often described as having a dancing quality because of the supcrimposition of chorea on the trunk and leg movements of the walking cycle. Chorea may be incorporated into the stepping and truncal movements of the walking cycle, resulting in exaggerated motion of the legs when stepping and excessive associated arm swing. Chorea may interrupt the normal movements of walking, leading to a hesitant gait, and there may be additional voluntary compensatory movements in response to perturbations from the chorea. Choreic movements in Sydenham's chorea or chorea gravidarum may be sufficiently violent to throw patients off their feet or be unable to walk at all. Chorea of this severity is uncommon in Huntington's disease and usually causes a lurching or occasionally stumbling gait with frequent additional steps cither forward, backward, or to one side. In Huntington's disease, walking is slow, the stance is wide based, the trunk sways excessively, and steps
ACTION MYOCLONUS AND TREMOR OF THE LEGS Some causes of involuntary movements of the legs when standing or walking are listed in Table 25.6.
Action Myoclonus Action myoclonus and reflex myoclonus affecting the legs are rare but striking disorders. Postanoxic action myoclonus of the legs is often accompanied by negative myoclonus (or astcrixis) and severely disrupts normal postural control and any attempts to use the legs to stand or walk. Repetitive action myoclonus produces jerky movements of the legs, throwing the patient off balance, and lapses of muscle activity between the jerks (negative myoclonus) cause the patient to sag toward the ground. This sequence of events gives rise to an exaggerated bouncing appearance, which the patient is able to sustain for only a few seconds
GAIT DISORDERS Table 25.6: Differential diagnosis of involuntary movements of the legs when standing Action myoclonus of legs (as in postanoxic myoclonus) Benign essential tremor Orthostatic tremor Cerebellar truncal tremor Clonus in spasticity Spastic ataxia
before falling or seeking relief by sitting down. Difficulty walking is one of the major residual disabilities of postanoxic myoclonus, and many patients remain wheelchair bound. The stance is wide based, and there is often an element of cerebellar ataxia, although this may be difficult to distinguish from the severe action myoclonus. Stimulussensitive cortical reflex myoclonus also may produce a similar disorder of stance and gait, with reflex myoclonic jerking of leg muscles, particularly the quadriceps, resulting in a bouncing posture.
Tremor of the Trunk and Legs An action tremor of the legs may produce a similar though less severe bouncing standing posture and gait. Leg tremor in benign essential tremor is occasionally symptomatic. Trunk and leg tremor may be a cause of unsteadiness in cerebellar disease. Orthostatic tremor has a unique frequency of 16 Hz and distribution, affecting trunk and leg muscles while standing. It produces an intense sensation of unsteadiness, rather than shaking, which is relieved by walking or sitting down. Patients avoid standing still, for example, in a queue, and may shuffle on the spot or pace about in an effort to avoid the unsteadiness experienced when standing still. Falls are rare. Examination may reveal only a rippling of the quadriceps muscles during standing, and the rapid tremor is often only appreciated by palpation of leg muscles. The differentiation among leg tremors and the diagnosis of orthostatic tremor is best made by recording the clectromyographical activity of leg muscles during standing and measuring tremor frequency.
GAIT IN THE ELDERLY Healthy, neurologically normal elderly people tend to walk at slower speeds than their younger counterparts (Murray, Kory, and Clarkson 1969). The slower speed of walking is related to shorter and shallower steps with reduced excursion at lower limb joints. In addition, stance width may be slightly wider than usual, and synergistic arm and trunk movements are less vigorous. The rhythmiciry of stepping is preserved. These changes give the normal elderly gait a cautious or guarded appearance. Factors contributing
333
to this general decline in mobility of the elderly include degenerative joint disease, reduced range of limb movement, and dcctcascd cardiovascular fitness, limiting exercise capacity. The reduced speed of walking and associated changes in gait pattern in the elderly also may represent one method of providing a more secure base to compensate for a subtle age-rein red deterioration in balance. In imsclccicd elderly populations, a more pronounced deterioration in gait is evident (Imms and F.dholm 1981). Steps are shorter, stride length is reduced, and the stance phase of walking is increased, leading to a reduction in walking speed, particularly in those who fall. Neurological causes of walking difficulty in the elderly, such as myelopathy, parkinsonism, cerebellar disease, and imbalance caused by sensory loss, are common etiologies, as are frontal gait disorders and gait apraxias (Sudarsky and Ronthal 1983). The etiology of imbalance and an insecure gait in the elderly is often multifactorial. The cumulative effects of lesions at many sites can interfere with walking without any one lesion being severe enough to explain the difficulty. Multiple sensory deficits affecting vision, vestibular, and proprioceptive function cause imbalance and an insecure gait. Multiple mild sensory deficits of peripheral nerve or posterior column origin, combined with modest leg weakness of peripheral nerve or corticospinal tract origin, as in cervical and lumbar spondylosis, are also common causes of this clinical picture. Loss of confidence, especially after falls, adds to the multifactorial age-related gait disturbance. A formal program of gait retraining may correct this loss of confidence and improve the ability to walk. In some patients, difficulty walking and even standing is related to dysequilibrium because of impaired postural reflexes and a tendency to fall, often with injury. Acute vascular lesions of the thalamus (thalamic astasia) or basal ganglia produce this clinical picture with falls away from the side of the lesion without corrective postural adjustments. Similar dysequilibrium with impaired postural reflexes occurs in progressive supranuclear palsy and multiple system atrophy, with falls forward or backward. Impaired central vestibular function may also account for isolated dysequilibrium in some elderly patients and correlate with increased body sway (Fife and Baloh 1993). The mechanisms responsible for the disturbances of gait that accompany lesions of the frontal lobes are poorly understood {Thompson 2001). Frontal lobe tumors (glioma or meningioma), anterior cerebral artery infarction, obstructive or communicating hydrocephalus (especially normal pressure hydrocephalus), and diffuse cerebrovascular disease (multiple lacunar infarcts and Binswanger's disease) all produce a similar disturbance of gait. The clinical appearance of the gait of patients with such lesions vanes from a predominantly wide-based ataxic gait to an akinetic-rigid gait with slow short steps and a tendency to shuffle. It is common for a patient to present with a combination of these features. In the early stages, the stance
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
base is wide with an upright posture of the trunk and short shuffling steps. This may be most noticeable on starting to walk or turning corners. There may be episodes of freezing. Arm swing is often normal or even exaggerated when walking, but the normal fluidity of trunk and limb motion is lost, giving the appearance of a "military two-step" gait. Examination often reveals normal voluntary upper limb and hand movements and a lively facial expression. This lower half parkinsonism is commonly seen in diffuse cerebrovascular disease. The marchc a petits pas of Dejerine and Critchley's atherosclerotic parkinsonism refers to a similar clinical picture. Patients with this clinical syndrome commonly are often misdiagnosed as having Patkinson's disease. The normal motor function of the upper limbs, the upright truncal posture, UMN signs, including a pseudobulbar palsy, and the absence ot a resting tremor distinguish this syndrome from Parkinson's disease. In addition, the lower half parkinsonism of diffuse cerebrovascular disease does not respond to i.-dopa treatment, further distinguishing it from Parkinson's disease (see Table 25.4). The slowness of movement and the lack of heel-shin ataxia distinguish the wide-stance base of this syndrome from cerebellar gait ataxia. As the underlying condition progresses, the elements of ataxia and parkinsonism become more pronounced. There may be great difficulty initiating a step, as if the feet were glued to the floor (the magnetic foot response). Attempts to take a step require assistance with the patient clutching for the support of neatby objects or persons. There may be excessive upper body movement as the patient tries to ftee the feet to initiate walking, and when undetway, shuffling becomes even more pronounced. Such patients rarely exhibit the festination of Parkinson's disease, but a few steps of propulsion or retropulsion may be taken. Postural and righting reactions are impaired and eventually lost, and falls are common at the slightest perturbation. By contrast, these patients often can move their legs with greater facility when seated or lying supine. They may be able to make stepping, walking, or bicycling leg movements when lying but be quite unable to do so when standing. A severe loss of truncal mobility and truncal balance may develop in the advanced stages of a frontal gait disorder, so patients are unable to stand or turn over when lying in bed. Walking then becomes impossible, and even simple leg movements ate slow and clumsy when lying down. Paratonic rigidity (gegcnhalten) of the arms and legs is common. Tendon reflexes may be brisk with extensor plantar responses. Gtasp reflexes in the hands and feet may be elicited and urinary incontinence and dementia commonly occut. Investigation by MRI or computed tomography of the brain reveal the majority of conditions causing this syndrome. Some patients display fragments of this clinical picture. Those with gait-ignition failure exhibit profound start hesitation without disturbance of stepping once walking is
underway. Balance while standing or walking is normal. Initiation of the first step is hampered by shuffling, and walking may be interrupted by freezing (Atchison ct al. 1993). Sensory cues may facilitate stepping. These findings are similar to walking in Parkinson's disease, but speech and upper limb function are normal and there is no response to i.-dopa. Results of imaging of the brain are normal. The cause of this syndrome is not known, but the slowly progressive evolution of symptoms suggests a degenerative condition. Occasionally, isolated episodic festination with truncal flexion is encountered. Others complain of a loss of the normal fluency of stepping when walking and a conscious effort is required to maintain a normal stepping rhythm and step size. These symptoms may be associated with subtle dysequilibrium manifesting as a few brief staggering steps to one side or a few steps of retropulsion after standing up, turning quickly, or other rapid changes in body position. Finally, there remain elderly patients with severe walking difficulties that resemble those described in frontal lobe disease. The history in these syndromes is one of gradual onset, without strokclike episodes or identifiable structural or vascular lesions of the frontal lobes or cerebral white matter on imaging. The cause of these syndromes is not known. The criteria fot normal pressure hydrocephalus are not fulfilled, there are no signs of parkinsonism, L-dopa is ineffective, and thcte is no evidence of more generalized cerebral dysfunction, as occurs in Alzheimer's disease. Indeed, it is rare for patients with Alzheimer's disease to develop difficulty walking until the later stages of the disease.
Nomenclature of Gait in the Elderly Early descriptions of frontal gait syndromes emphasized the imbalance and ataxic components. The term frontal ataxia was used to reflect the perceived involvement of the frontopontocerebellar pathway as the most likely mechanism. Indeed, the gait ataxia of many midline cerebellar lesions associated with obstructive hydrocephalus can be out of ptoportion to the degree of lower limb heel-shin ataxia and may be largely relieved by the insertion of a ventricular drain or shunt. This observation confirms the importance ot hydrocephalus in the gait ataxia associated with these lesions. Others were impressed by the slowness of movement and the discrepancy between the pronounced disability when attempting to walk and the preservation of leg movements when lying or sitting. This combination of signs was considered a form of limb-kinetic apraxia and referred to as frontal apraxia and later gait apraxia. Gait apraxia is defined as an inability to properly use the lower limbs in the act of walking that cannot be accounted for by demonstrable sensory impairment or motor weakness (Meyer and Barron 1960). Meyer and Barron (1960) emphasized that gait apraxia included ataxia plus
GAIT DISORDERS hypokinesia, rigidity (gegenhalten), and brisk reflexes, the latter signs distinguishing apraxia of gait from cerebellar ataxia. The combination of bradykinesia and ataxia in frontal lobe or diffuse cerebral white matter disease is explained by interruption of the connections between motor, premoror, and supplementary motor cortex and other subcortical motor areas, such as the cerebellum and basal ganglia. Use of the term apraxia in this context remains controversial because these gaits probably encompass a spectrum of higher motor syndromes (Nutt, Marsden, and Thompson 1993). Discussions concerning the classification of higher gait syndromes have variously emphasized the presumed anatomical or physiological basis of the problem (Nutt, Marsden, and Thompson 1993; Jankovic, Nutt, and Sudarsky 2001). For example, a frontal gait disorder refers to a combination of elements of dyseciuilibrium, marche a petits pas, and gait-ignition failure. Subcortical dysequilibrium refers to a predominant disorder of equilibrium with a loss of postural reflexes and severe falls as seen in thalamic and basal ganglia astasia and progressive supranuclear palsy.
MYOPATHIC WEAKNESS AND GAIT Weakness of proximal leg and hip-girdle muscles interferes with the stabilization of the pelvis and legs on the trunk during all phases of the gait cycle. Failure to stabilize the pelvis produces exaggerated rotation of the pelvis with each step (waddling or Trendelenburg gait), the hips are slightly flexed as a result of weakness of hip extension, and an exaggerated lumbar lordosis occurs. Weakness of hip extension interferes with the ability to stand from a squatting or lying position and patients may use their arms to push themselves up from a squatting position (Gowers' sign). The classic descriptions of this gait were of patients with Duchenne's muscular dystrophy, but any myopathy affecting these muscles results in such a picture. Similarly, neurogenic weakness of proximal muscles, for example, spinal muscular atrophy and, occasionally the Guillain-Barre syndrome, may mimic this waddling gait.
NEUROGENIC WEAKNESS AND GAIT Muscle weakness of peripheral nerve origin, as in a peripheral neuropathy, typically affects distal muscles of the legs and results in a steppage gait. The patient lifts the leg and foot high above the ground with each step because of weakness or paralysis of ankle dorsiflexion and a foordrop (steppage gait). When this clinical picture is confined to only one leg (unilateral footdrop), a common peroneal or sciatic nerve palsy or an L5 radiculopathy is the usual cause. Less common is footdrop caused by
335
myopathic weakness, for instance, in the scapuloperoneal syndromes. A femoral neuropathy, such as in diabetes mellitus, is another example of a strategic mononeuropathy that may disable walking. Weakness of knee extension allows the knee to buckle when walking or standing. This may first be evident when walking down stairs. Such focal weakness also may be the presenting feature of the progressive muscular atrophy in motor neuron disease or be an early feature of quadriceps myopathy, for instance, caused by inclusion body myositis.
HYSTERICAL AND PSYCHOGENIC GAIT DISORDERS The wide range of abnormalities of gait seen in lesions of different parts of the nervous system make hysterical and psychogenic gaits among the most difficult to diagnose. In a hysterical paralysis, there may be complete inability to use a leg when walking, but normal synergistic movements of the affected leg may be observed when the patient is examined while lying down or when changing position. This discrepancy is further illustrated by Hoover's sign. The patient with an apparently paralyzed leg or legs is examined when supine. As the patient lifts the normal leg, the examiner places his or her hand under the "paralyzed" leg and feels the presence (and strength) of synergistic hip extension. The apparent severe weakness of hysterical paresis often presents little disability or inconvenience. In contrast, other patients with hysterical paraplegia may he totally confined to bed and may even develop contractures from lack of leg movements. A gait disorder is one of the more common manifestations of a psychogenic or hysterical movement disorder and various gait patterns are encountered. These include transient fluctuations in posture while walking, knee buckling without falls, excessive slowness and hesitancy, a crouched, stooped, or other abnormal posture of the trunk, complex postural adjustments with each step, exaggerated body sway or excessive body motion, and trembling weak legs. Suggestibility and improvement with distraction are common features, as is the case with other psychogenic movement disorders. The more acrobatic hysterical disorders of gait indicate the extent to which the nervous system is functioning normally. These patients are able to take advantage of high-level motor skills and coordination to perform various complex maneuvers. This is an important observation in the assessment of suspected hysterical gait disorders, as is a rapid, dramatic, and complete recovery. One must be cautious in accepting a diagnosis of hysteria though, because a bizarre gait may be a presenting feature of primary torsion dystonia and unusual truncal and leg postures may be encountered in truncal and leg tremors.
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
MISCELLANEOUS GAIT DISORDERS Space Phobia and Gait A syndrome of space phobia is described in which middleaged people develop an inability to walk and a fear of falling in open spaces. These patients seek the support of nearby fences or walls and may even crawl about on all fours. Falls may occur in the course of the illness. Other neurological symptoms and cardiovascular disease are common accompaniments. Some patients may experience symptoms while driving or simply standing, suggesting the condition is related to the perception of visuospatial information and is distinct from simple agoraphobia.
Painful (Antalgic) Gaits At one time or another, most people experience a limp caused by a painful or injured leg. Limps and gait difficulties that are caused by joint disease or by local bony or soft tissue injury are not usually accompanied by muscle weakness or by reflex or sensory change. Limitation of the range of movement at the hip, knee, or ankle joinrs may lead ro short steps with a fixed leg posture. Pain in the leg caused by intermittent claudication of the cauda equina is most commonly caused by spinal stenosis with lumbar spondylosis and, rarely, by a spinal tumor. Diagnosis is confirmed by spinal imaging. Occasionally, it may be difficult to distinguish this syndrome from claudication of the calf muscles caused by peripheral vascular disease, although the duration of the pain after rest (see earlier discussion) is usually characteristically different in the two syndromes. Examination of the patient after inducing the symptoms by exercise may resolve rhe issue by revealing a depressed ankle jerk or radicular sensory loss, with preservation of arterial pulses in the leg.
Skeletal Deformity and Joint Disease Degenerative osteoarthritis of the hip may produce leg shortening, in addition to mechanical limitation of leg movement at the hip, giving rise to a waddling gait or a limp. Leg shortening with limping in childhood may be the presenting feature of hemiatrophy caused by a cerebral or spinal lesion. Such walking difficulties between the ages of 1 and 5 years are the most common mode of presentation of spinal dysraphism. On examination, various additional abnormalities may be detected, including lower motor neuron signs in the legs and sensory loss with trophic ulcers of the feet. Occasionally, UMN signs, such as a brisk knee reflex, are present in the same limb. Lumbosacral vertebra] abnormalities (spina bifida), bony foot deformities, and a cutaneous hairy patch over the lumbosacral region are clues to the diagnosis. In adult life, spinal dysraphism
(diastcmatomyelia with a tethered cord) may first become symptomatic after a back injury, with the development of walking difficulties, leg and lower back pain, neurogenic bladder disturbances, and sensory loss in a leg. Imaging of the spinal canal reveals the abnormality.
Epileptic Falls in Childhood Seizure disorders of the myoclonic or akinetic-atonic type typically produce falls but may present as an unsteady or uncoordinated gait in childhood. Tonic seizures or flexor spasms also may produce this clinical picture. Simultaneous video, electroencephalographical, and electromyographic recordings arc helpful in diagnosing and identifying these various seimre patterns.
REFERENCES Atchison, P. R., Thompson, P. D., Fraekowiak, R. S. j . , tk Marsden, C. D. 1993, "The syndrome of isolated gait ignition failure: A report of six cases," Mov Disord, vol. 8, pp. 285-292 lUvrskich, (.., Soj.-r, M., Valldmiml.i. 1-.. i-[ ,il. Dl>'). "Comparative analysis of gait in Parkinson's disease, cerebellar ataxia and subcortical arteriosclerotic encephalopathy," Brum, vol. 122, pp. 1349-1355 Elble, R. J„ Moody, C, Leffler, K., Sc Sinha, R. 1994, "The initiation of normal walking," Mov Disord, vol. 9, pp. 139-146 Fife, T. D. 8c Baloh, R. W. 1993, "Dysequilibrium of unknown cause in older people," Ann Neurol, vol. 34, pp. 694-702 Imms, F. J. &c Edholm, D. G. 1981, "Studies of gait and mobility in the elderly," Age Ageing, vol. 10, pp. 147-156 Jankovic, J., Nun, J. G., &C Sudarsky, L. 2001, "Classification, diagnosis and etiology of gait disorders," in Gait Disorders, eds E. Ruzicka, J. Jankovic, & M. Hallett, Lippincott, Williams flc Wilkins, Philadelphia Labadie, E. L., Awerbuch, G. I., Hamilton, R. H., Sc Rapcsak, S. Z. 1989, "Falling and postural deficits due to acute basal ganglia lesions," Arch Neurol, vol. 45, pp. 492-496 Masdeu, J. C. & Gorelick, P. B. 1988, "Thalamic astasia: Inability to stand after unilateral thalamic lesions," Ann Neurol, vol. 23, pp. 596-603 Meyer, J. S. & Barron, D. 1960, "Apraxia of gait: A clinicopathologlcal study," Brain, vol. 83, pp. 61-84 Murray, M. P., Kory, R. C, & Clarkson, B. H. 1969, "Walking patterns in healthy old men,"/ Gerontol, vol. 24, pp. 169-178 Nutt, J. G., Marsden, C. D., & Thompson, P. D. 1993, "Human walking and higher level gait disorders, particularly in the elderly," Neurology, vol. 43, pp. 268-279 Siul/e. H.. kuhtz-lii'ischheck, J. P., Druke. I!., el ,il. 2001, "Comparative analysis of the gait disorder of normal pressure hydrocephalus and Parkinson's disease," } Neurol Neurosurg Psychiatry, vol. 70, pp. 289-297 Sudarsky, L. 5c Ronthal, M. 1983, "Gait disorders among elderly patients: A survey of 50 patients," Arch Neurol, vol. 40, pp. 740-743 Thompson, P. D. 2001, 2001, "Gait disorders accompanying diseases of the frontal lobes," in Classification, Diagnosis and Etiology of Gait Disorders, eds E. Ruzicka, J. Jankovic, &c M. Hallett, Lippincott, Williams & Wilkins, Philadelphia
Chapter 26 Hemiplegia and Monoplegia Karl E. Misulis Anatomy Hemiplegia Cerebral Lesions Brainstem Lesions Spinal Lesions Peripheral Lesions Functional Hemiplegia Monoplegia Cerebral Lesions Brainstem Lesions
337 337 337 340 341 342 342 343 343 343
ANATOMY Accurate neurological diagnosis begins with anatomical localization. Many disorders have diffuse localizations, but hemiplegia and monoplegia arc more likely to be due to focal structural lesions and are therefore easier to localize. Imaging studies are often confirmatory of the structural lesion, but clinical localization must precede imaging studies. Hemiplegia and monoplegia are motor symptoms and signs, but associated sensory abnormalities are discussed along with the motor findings because they are commonlypresent and helpful for accurate localization. Sensory deficit syndromes are discussed in more depth in Chapter 3 1 . Motor power begins with initiative or volition, lack of which does not produce weakness, but akinesia. Projections from the premotor regions of the frontal lobes to the motor strip result in activation of corticospinal tract (CST) neurons. The descending fibers pass through the internal capsule and the cerebral peduncles, and then remain in the ventral brainstem before crossing in the medulla at the pyramidal decussation. Most of the CST crosses at this point. Descending CST axons project to the spinal cord segments where the fibers exit the CST and enter the spinal gray. Here, motoneurons are activated, which then conduct action potentials in the motor axons to the muscle. Transmission at the neuromuscular junction provides for one action potential in the muscle fiber for each action potential in the motor axon. Depolarization of the muscle fiber results in release of calcium, which then promotes the repeated cross-linking and release of actin and myosin filaments, which results in contraction. The contraction is terminated when the calcium is sequestered and prepared for reuse.
Spinal Lesions • Peripheral Lesions Pitfalls in the Diagnosis of Hemiplegia and Monoplegia Weakness in Intrinsic Muscles of the Hand: Median, Ulnar, Plexus, or Small Cerebral Cortical Lesion? Radial Neuropathy or Small Cerebral Cortical Infarcts? Leg Weakness: Peroneal Nerve Palsy or Paramedian Cerebral Cortical Lesion? Leg Weakness: Cauda Equina Lesion, Myelopathy, or Paramedian Cerebral Cortical Lesion?
343 343 348 348 348 348 349
Localization begins with identification of weakness. Differentiation is made between the following distributions: • • • •
Generalized weakness Monoplegia Hemiplegia Paraplegia
Only hemiplegia and monoplegia are discussed here.
HEMIPLEGIA Cerebral Lesions Cerebral lesions arc the most common causes of hemiplegia with lesions in either conical or subcortical structures (Table 26.1). Cortical
Lesions
Cortical lesions produce weakness, which is more focal than the weakness seen with subcortical lesions. Figure 26.1 shows a diagrammatic representation of the surface of the brain, showing how the body is mapped on the surface of the motor sensory cortex. This is the homunculus. In this representation, the face and arm are laterally represented on the hemisphere, whereas the leg is draped over the top of the hemisphere and into the interhemispheric fissure. Small lesions of the cortex can produce prominent focal weakness of one area, such as the leg or the face and hand, but hemiplegia—prominent involvement of both the leg and arm—is not expected unless there is a stroke involving the whole territory of the internal carotid artery. V%7
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 26.1;
Cerebral lesions
Lesion
Symptoms
Signs
.Motor cortex
Weakness and poor control of the affected extremity, which may involve face, arm, and leg to different degrees
Internal capsule
Weakness rhar usually affects the face, arm, and leg almost equally Weakness and incoordination on the contralateral side Sensory loss
Incoordination and weakness that depends on the location of the lesion within the cortical homunculus; often associated with neglect, apraxia, aphasia, or other signs of cortical dysfunction Often associated with sensory impairment in same distribution Weakness, often without sensory loss; no neglect or aphasia Sensory loss with tittle or no weakness
Basal ganglia Thalamus
Infarction. Cortical infarctions are more likely to be associated with sensory abnormalities than subcortical infarctions. Also, cortical infarctions are associated with a so-called cortical sign—neglect with non-dominant hemisphere lesions and aphasia with dominant hemisphere lesions. Unfortunately, this distinction is not absolute, because rarely subcortical lesions can produce these signs. Diagnosis of infarction is usually made on clinical grounds, especially early in the course. The abrupt onset of the deficit is typical. Weakness that progresses over several days is unlikely to be caused by infarction, although some infarcts can show worsening for a few days after onset. Progression over days suggests demyelinating disease. Progression over weeks suggests a mass lesion, such as a tumor or an abscess. Progression over seconds to minutes
Media! surface
Lateral surface
in a marching fashion suggests cither epilepsy (which usually produces convulsions and not weakness) or migraine; remember that not all migraine-associated deficits are associated with subsequent headache. Computed tomography (CT) scans often do not show infarction for up to 3 days after the event, and magnetic resonance imaging (MRI) is not available on an urgent basis in most hospitals. Confirmation of the ischemia can be made by MRI or follow-up CT scan 2 - 3 days after the onset of symptoms. Infarcts show particularly well on flair images of the MRI. Recent infarction can be distinguished from remore infarction on diffusion-weighted imaging. Middle Cerebral Artery. The middle cerebral artery (MCA) supplies rhe lateral aspect of the motor sensory cortex, which controls the face and arm. In addition, on the
FIGURE 26.1 Representation of the body on the motor cortex. The face and arms are represented laterally, and the legs are represented medially, with the distal legs of the cortex bordering on the central sulcus.
HEMIPLEGIA AND MONOPLEGIA
dominant side, speech centers are also supplied—Broca's area in the posterior frontal region and Wernicke's area on the superior aspect of the temporal lobe. Cortical infarction in the territory of the MCA produces contralateral hemiparesis, usually associated with other signs of cortical dysfunction such as aphasia with left hemisphere lesions, or neglect with right hemisphere lesions. The arm, hand, and face are affected much more than the leg. Diagnosis is suspected with hemiparesis, which affects predominantly the face and arm. Aphasia or neglect is confirmatory of the cortical localization. Anterior Cerebral Artery. The anterior cerebral artery (ACA) supplies the inferior frontal and parasagittal regions of the frontal and anterior parietal lobes. This region is responsible for leg movement and is important for bowel and bladder control. Infarction in the ACA distribution produces contralateral leg weakness. The arm may be slightly affected, especially the proximal arm, with sparing of hand and face. Diagnosis is suspected when a patient presents with leg weakness and CST signs. The leg weakness can be bilateral if both ACAs arise from the same trunk; this situation can he mistaken for myelopathy. Posterior Cerebral Artery, The posterior cerebral arteries (PCAs) are the terminal branches of the basilar artery. They supply most of the occipital regions and the medial temporal regions. PCA infarction is not expected to produce weakness but produces contralateral hemianopia, often with memory deficits. Diagnosis may be missed, because the examiner may not look for hemianopia in a patient who otherwise may present only with confusion. The visual complaints may be vague or nonexistent. Subcortical
Lesions
Subcortical lesions are more likely to produce equal weakness of the face, arm, and leg on the contralateral side, because the descending axons that project to the brainstem and spinal cord converge into a small volume in the internal capsule to ultimately form the CST, Lesions of sudden onset are most likely to be stroke, usually lacunar infarction, but hemorrhage can occur. Demyelinating disease has a subacute onset. Tumors have a slower onset and can get quite large in subcortical regions before reaching medical attention. Infarction, Infarction is usually a clinical diagnosis but can be confirmed by CT or MRI scans, as discussed (see Cortical Lesions, Infarction, earlier in this chapter). Lenticulostriate Arteries. These small penetrating arteries arise from the proximal MCA and supply the basal ganglia and internal capsule. Infarction commonly produces contralateral hemiparesis with little or no sensory involvement ("pure motor hemiplegia," which can also be due to a brainstem lacuna).
339
Thaiamoperforate Arteries. These small penetrating arteries arise from the PCAs and supply mainly the thalamus. Infarction in this distribution produces contralateral sensory disturbance but can also cause movement disorders such as chorcoathetosis or hemiballismus; hemi paresis is not expected. Demyelinating Disease. Demyelinating disease is a group of conditions whose pathophysiology implicates the immune system. Diagnosis is based on clinical grounds for most patients but is suggested by finding areas of increased signal intensity on T2-weighted images of the MRI. Active demyelinating lesions often show enhancement on Tl-weighted gadolinium-enhanced images. Cerebrospinal fluid (CSF) examination is usually performed and can be normal or show elevated protein, a mild lymphocytic pleocytosis, and/ or oligoclonal bands of immunoglobulin G (IgG) in the CSF.
Multiple Sclerosis. Multiple sclerosis (MS) presents with any combination of white matter dysfunction, Hemiparesis can develop especially if there are large plaques affecting the CST fibers in the hemispheres. However, hemiparesis is even more likely with brainstem or spinal demyelinating lesions, because smaller lesions can produce more profound deficits in these areas. The diagnosis is suspected by the progression over days and a history of episodes of relapsing and remitting neurological deficits. Episodes of weakness that last for only minutes are likely not to be due to demyelinating disease, but to be vascular or a migraine equivalent. Parainfectious Encephalomyelitis, Parainfectious encephalomyelitis (acute disseminated encephalomyelitis) is a demyelinating illness that is monophasic but in other respects presents like a first attack of MS. Symptoms and signs at all levels of the central nervous system (CNS) are common, including hemiparesis, paraplegia, ataxia, and brainstem signs. Diagnosis is based on clinical grounds because MRI scans cannot distinguish between MS and parainfectious encephalomyelitis. CSF may show a mononuclear pleocytosis and elevation in protein, but these findings arc neither always present nor specific. Even the presence or absence of oligoclonal IgG in the CSF cannot differentiate between this and MS, When a patient presents clinically with this, the patient should be warned of the possibility of recurrent events. Progressive Multifocal Leukocnccphalopathy. Progressive multifocal leukocnccphalopathy (PML) is a demyelinating disease caused by reactivation of the JC virus, especially seen in immunodeficiency. Patients with acquired immunodeficiency syndrome, leukemia, lymphoma, tuberculosis, and sarcoidosis are predisposed to develop PML. Visual loss is the most common symptom and weakness is the second most common. MRI scan shows multiple
340
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
white matter lesions. CSF is either normal or shows a lymphocytic pleocytosis and/or elevated protein. Brain biopsy is required for specific diagnosis. Migraine. Migraine is often associated with an aura of visual symptoms (classic migraine), but motor and sensory symptoms can also develop (complicated or hcmiplegic migraine). Sensory symptoms may include loss of sensation or paresthesias. Motor symptoms can include hemiparesis. The deficit progresses across the extremities in a manner that looks like the spreading of cortical localization. Headache does not always follow the neurological deficit, making the diagnosis even more difficult. Diagnosis is suspected when the patient is young, has few risk factors, and the deficit marches in a manner that can be visualized as a migration of spreading electrical depression across the cerebral cortex. Imaging is often necessary to rule out hemorrhage, infarction, and demyelinating disease. Tumors. Tumors affecting the cerebral hemispheres commonly present with progressive deficits including hemiparesis. Cortical dysfunction is also commonly present, such as aphasia with dominant hemisphere lesions. Other signs of expanding tumors may include headache, seizures, confusion, and visual field defects. The hemiparesis often is manifest as a disorder of coordination developing before the weakness. Diagnosis is suspected in a patient with progressive motor deficit over weeks, especially if there are coexistent seizures and/or headache. MRI with contrast enhancement is more sensitive for identification of tumors than CT
Brainstem Lesions Brainstem lesions producing hemiplegia are among the easiest to localize, because associated signs of brainstem dysfunction are almost always present. Brainstem
Motor
Organization
Figure 26.2 shows the anatomical organization of the motor systems of the brainstem. Discussion of the complex anatomical organization of the brainstem can be simplified by concentrating on some important functions: • • • • •
Appendicular motor and sensory function Facial motor and sensory function Appendicular coordination Ocular motor function Descending sympathetic tracts
Motor pathways descend to the pyramidal decussation in the medulla, when they cross to innervate the
Alternating Hemiplegia of Childhood. Alternating hemiplegia of childhood is characterized by attacks of unilateral weakness, often with signs of other motor deficits (e.g., dyskinesias or stiffness) and oculomotor abnormalities (e.g., nystagmus). Attacks begin in young childhood, usually before age 18 months; they last hours, and deficits accumulate. Initially, patients are normal, but with time, neurological deficits, including motor deficits and cognitive decline, become obvious. Diagnostic studies show no abnormalities, including MRI, electroencephalography, and angiography. Hemiconvulsion-Hemiplegia Syndrome. Young children with this rare condition develop unilateral weakness after the sudden onset of focal seizures. The seizures are often incompletely controlled. Neurological deficits ate not confined to the motor system and may include cognitive, language, and visual deficits. Unlike alternating hemiplegia, the seizures and motor deficits are consistently unilateral, although eventually the unilateral seizures may become generalized. Imaging may be normal initially but eventually shows atrophy of the affected hemisphere. CSF analysis is not specific, but a mild mononuclear pleocytosis may develop because of the CNS damage and seizures.
FIGURE 26.2 Brainstem motor organization, beginning with the internal capsule. The corticospinal tract remains topographically organized throughout the brainstem and spinal cord, although isolated lesions below the cerebral cortex are unlikely to produce topographically specific damage.
HEMIPLEGIA AND MONOPLEGIA contralateral body. Lesions of the pons and midbrain above this level produce contralateral hemiparesis, which may involve the contralateral face. Rostral lesions of the medulla produce contralateral weakness, whereas more caudal medullary lesions produce ipsilateral cranial nerve signs with a contralateral hemiparesis and sensory deficit. Sensory pathways from the nucleus gracilis and nucleus cuneatus cross at about the same level as the motor fibers of the CST, so deficits m light touch and position sense tend to parallel the distribution of the motor deficit. In contrast, the spinothalamic tracts have already crossed in the spinal cord and ascend laterally in the brainstem. Therefore lesions of the lower medulla may produce contralateral loss of pain and temperature sensation and ipsilateral loss of touch and position sense. Lesions above the mid medulla produce a contralateral sensory defect of all modalities indistinguishable from cerebral lesions, yet the clues to brainstem localization can include the following: • Ipsilateral facial sensory deficit from a trigeminal lesion • Ipsilateral hemiataxia from damage to the cerebellar hemispheres or nuclei • Ocular motor weakness, resulting in diplopia • Ipsilateral Horner's syndrome from damage of the descending sympathetic tracts Tabic 26.2:
Common
341
Lesions
Table 26.2 shows some of the important lesions of the brainstem and their associated motor deficits. Brainstem lesions are usually due to damage to the penetrating branches of the basilar artery. Patients present with contralateral weakness along with other findings that help localize the lesion. Hemiataxia often develops and can be mistaken for hemiparesis, so careful examination is essential; the implications for localization of the differentiation of hemiataxia and hemiparesis are tremendous. Demyelinating disease and tumors are the other most common causes of brainstem dysfunction.
Spinal Lesions Spinal lesions can produce hemiplegia sparing the face, although they mostly will cause bilateral findings typical of myelopathy. Diagnosis of a spinal cord lesion is suspected in a patient if there is bilateral weakness, bowel- and/or bladder-control deficits, or back pain. Spinal
Hemisection
(Brown-Sequard's)
Syndrome
Spinal hemisection is seldom seen in clinical practice. However, components of the syndrome are occasionally identified. This is usually seen in intradural tumors, trauma,
brainstem lesions
Named disorder Midbrain Weber's syndrome Benedikr's syndrome
Top-of-the-basilar syndrome
Location
Signs
Cranial nerve III, ventral midbrain, corticospinal tract Cranial nerve HI, ventral midbrain, corticospinal tract, red nucleus
Contralateral hemiparesis, third nerve palsy Contralateral hemiparesis, third nerve palsy, intention tremor, cerebellar ataxia Contralateral hemiparesis, cortical blindness, oculomotor deficits, memory difficulty, contralateral sensory deficit
Occipital lobes, midhrain oculomotor nuclei, cerebral peduncle, medial temporal lobe, thalamus
Pons Millard-Gubler syndrome Clumsy-hand syndrome Pure motor hemiparesis with lesion in the pons Ataxic hemiparesis with lesion in the pons Fovilie's syndrome Medulla Media! medullary syndrome
Cranial nerve VI, cranial nerve VII, ventral pons Corticospinal tract, facial nerve Ventral pons Corticospinal and cerebellar tracts Cranial nerve VII, vcnrral pons, paramedian pontine reticular formation Corticospinal tract, medial lemniscus, hypoglossal nerve
Contralateral hemiparesis, sixth nerve and seventh nerve palsies Contralateral hemiparesis; dysarthria, often with facial weakness Contralateral hemiparesis with corticospinal tract signs Contra lateral hemiparesis with impaired coordination Contralateral hemiparesis, seventh-nerve palsy, gaze palsy to side of lesion Contralateral hemiparesis, loss of position and vibratory sensation, ipsilateral tongue paresis
342
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
and inflammatory conditions. Spondylitic myelopathy, discdisease, and most extradural tumors usually produce symmetrical findings. Patients with the spinal hcmisection syndrome present with weakness ipsilateral to and below the lesion. In addition, segmental motor loss may be seen wirh involvement of the motoneurons at the level of the lesion. Sensory findings include loss of pain and temperature contralateral to and below the lesion. Position sense may be affected ipsilateral to the lesion. Transverse
Myelitis
Transverse myelitis is an acute myelopathic process that is presumed to be autoimmune in origin. Patients present with motor and sensory deficits below the lesion. Findings are typically bilateral yet may be asymmetrical.
with progression over months or even years. Usually the combined presence of upper motor neuron (UMN) and LMN involvement, without sensory changes, assists in making the diagnosis. If the predominant involvement is UMN in type, the picture can look like a progressive hemiparesis. Conditions that predispose to separate lesions affecting one arm and leg are disorders producing mononeuropathy multiplex. Diabetes is the most common cause, hut other causes include leprosy, vasculitis, and predisposition to pressure palsies. Diagnosis is by electromyography (EMG), which can differentiate mononeuropathy from polyneuropathy. Radiculopathy would not give hemiparesis but is in the differential diagnosis of monoplegia (see Radiculopathies, later in this chapter).
Functional Hemiplegia Spinal Cord Compression Spinal cord compression is usually due to disc protrusion or spondylosis. Neoplastic and infectious causes should always be considered. Disc disease and spondylosis are typically in the midline, so unilateral findings are not expected. Extradural tumors are less likely than intradural tumors to produce unilateral symptoms. Lastly, lesions below the cervical spinal cord would not produce hemiplegia, hut monoplegia of the lower limb or paraplegia. Spondylosis with cord compression produces lower motor neuron (LMN) weakness at the level of the lesion and CST signs below the level of the lesion. Spinal cord compression resulting in paralysis should be evaluated as quickly as possible with MRI if available. Myelography should be considered if MRI is not urgently available. Spinal Cord Infarction Anterior spinal artery infarction usually causes paraparesis and spinothalamic sensory loss below the level of the lesion. Rarely, one segmental branch of the anterior spinal artery can be involved with unilateral spinal cord damage and monoparesis or hemiparesis.
Peripheral Lesions Peripheral lesions are not expected to produce hemiplegia. However, a pair of peripheral lesions affecting both the arm and the leg oil the same side may occasionally masquerade as hemiplegia. Differentiation depends on identification of the individual lesions as being within the distribution of one nerve, nerve root, or plexus. The tendon reflexes are likely to be depressed in patients with CST lesions. Amyotrophic lateral sclerosis can produce weakness of one limb, followed by weakness of the other limb on the same side,
Functional or psychogenic weakness includes both conversion reaction and malingering. In conversion reaction, the patient is not conscious of the nonorganic nature of the deficit, whereas in malingering the patient is making a conscious effort to fool the examiner. In both circumstances, there is some secondary gain for the patient, whether psychological or economic. In malingering, the secondary gain is usually more obvious and includes disability payments, litigation, family attention, and avoidance of stressors or tasks. Clues to functional weakness include the following: • Improvement in strength with coaching • Give-way weakness • Inconsistencies in examination, for example, inability to extend the foot but able to walk on toes • Hoover's sign: The patient lies supine on the bed and lifts one leg at a time. If the leg is truly paralyzed, the examiner should feel effort to press down with the opposite heel. Failure to do so is a positive Hoover's sign. • Paralysis in the absence of other signs of motor system dysfunction, including tone and reflex changes Diagnosis of functional weakness is based on consistencies on examination and elimination of the possibility of organic disease. Functional weakness should be diagnosed with caution. It is easy to dismiss the patient's complaints after an inconsistent feature is seen, especially if some secondary gain is obvious. Unfortunately, the diagnosis of functional weakness is difficult, because a patient with organic problems may have a functional overlay, which may exaggerate an otherwise subtle clinical finding. For example, weakness and incoordination of the hand may seem subtle on examination and may be missed completely if the patient gives incomplete effort with the extremity.
HEMIPLEGIA AND MONOPLEGIA Some diagnostic testing is often required to rule out neurological disease, although this should be kept to a minimum. Prescription of multiple tests and treatments may serve to reinforce the presumed presence of illness, and thereby augment illness behavior. Psychological evaluation and treatment can be key.
343
consciousness associated with the episodes. Seizures are usually more frequent and have a shorter duration than TIAs. Multiple
Sclerosis
MS can produce monoplegia through a discrete white matter plaque, but hemiparesis is more common. MONOPLEGIA
Tumors
Cerebral Lesions Cerebral lesions more commonly produce hemiplegia than monoplegia, but isolated limb involvement can occasionally occur, especially with cortical involvement. The arm segment of the motor sensory cortex lies on the lateral part of the hemisphere, adjacent to the sylvian fissure. Subcortical infarction is less likely to produce monoplegia than cortical lesions because of the dense packing of the fibers of the CST in the internal capsule. The internal capsule is generally organized with the arm segments represented anteriorly in the capsule relative to the leg sections. Infarction in the distribution of the lenticulostriate arteries, however, usually affects both divisions. Infarction The arm region of the cerebral motor cortex is supplied by the MCA. Infarction of a branch of the MCA can produce isolated arm weakness, although facial involvement and cortical signs are expected—language deficit with left hemisphere lesions and neglect with right hemisphere lesions. With more extensive lesions, visual fields can be abnormal because of infarction of the optic radiations. Mild leg weakness can also occur. The leg segment lies in the parasagittal region and is supplied by the ACA. ACA infarction produces weakness of the contralateral leg,
Tumors deep to the cortex rarely produce monoplegia because the involvement is not sufficiently discrete to affect only one limb. Cortical involvement makes single limb involvement more likely. Parasagittal lesions often produce leg involvement, which can be initially unilateral. Meningiomas often arise from one side of the falx, so they predominantly affect one leg. The presentation is of CST findings referable to only one leg. The single leg weakness could be mistaken for a thoracic spinal lesion, although paraparesis is more common in such a situation. Metastatic tumors are often found at the gray-white junction and as such are in position to produce focal cortical damage. Early on, the lesion may be too small to produce definite neurological symptoms, but with increasing growth, the lesion is more likely to produce focal seizures or loss of function.
Brainstem Lesions Brainsrem lesions seldom produce monoplegia because of the tight packing of the fibers of the CSTs in the brainstem. Unilateral cerebellar hemisphere lesions may produce appendicular ataxia, which is most obvious in the arm, although this should be distinguished from monoparesis by the absence of weakness and the presence of ataxia.
Migraine
Spinal Lesions
Migraine can produce sensation that marches along one limb, usually the arm. The progression through the limb differs from the abrupt onset of stroke. Involvement of only the leg is unusual. The headache phase typically begins as the neurological deficit is resolving. Weakness can develop as part of the migraine aura, but this is much less likely than sensory disturbance.
Spinal lesions can produce weakness from segmental damage to nerve roots, or CSTs. CST signs below the level of the lesion are expected. Weakness in one leg can develop from damage ro the spinal nerve roots, and in this case, the weakness is associated with muscle wasting and lost reflexes in a radicular distribution.
Seizure and Transient Ischemic Attacks
Peripheral Lesions
Seizure can rarely produce negative motor symptoms rather than positive symptoms. Episodic paralysis can seem like a transient ischemic attack (TIA), and evaluation for vascular disease is often indicated. Focal seizure activity may be suggested by subtle twitching or disturbance of
Peripheral lesions usually produce monoparctic weakness in the distribution of a single nerve, nerve root, or plexus. A few conditions, such as amyotrophic lateral sclerosis and focal spinal muscular atrophy, may produce weakness in a monomelic (monopk'j;ic) distribution.
344 Pressure
APPROACH TO COMMON NEUROLOGICAL PROBLEMS Mononeuropathies
Palsies
Intermittent compression of a peripheral nerve can p r o d u c e transient paresis of p a r t of a limb. T h e patient m a y think the entire limb is paralyzed, b u t detailed e x a m i n a t i o n shows that the paresis is limited. T h e w e a k n e s s usually improves so quickly t h a t e x a m i n a t i o n is often n o t possible before the improvement. Predisposition to pressure palsies can be seen in t w o main circumstances: on a hereditary basis and in the presence of peripheral p o l y n e u r o p a t h y . Hereditary N e u r o p a t h y Ptcd is position to Pressure Palsies. Hereditary n e u r o p a t h y with predisposition to pressure palsies is associated with episodic w e a k n e s s and sensory loss associated with c o m p r e s s i o n of isolated nerves. N e r v e conduction studies may s h o w distal slowing of c o n d u c t i o n velocities. Pressure Palsies in P o l y n e u r o p a t h y . Patients with polyn e u r o p a t h y may have an increased susceptibility to pressure palsies. Areas of demyelination a r e m o r e likely to have a depolarizing block produced by even mild pressure,
Table 26.3:
T a b l e 2 6 . 3 s h o w s some i m p o r t a n t peripheral nerve lesions of the a r m . T a b l e 26.4 s h o w s some i m p o r t a n t peripheral n e r v e lesions of the leg. Median Nerve Carpal Tunnel Syndrome. C a r p a l tunnel s y n d r o m e is t h e m o s t c o m m o n m o n o n e u r o p a t h y . T h e median nerve is compressed as it passes u n d e r the flexor retinaculum at the wrist. Patients present w i t h n u m b n e s s o n t h e p a l m a r aspects of t h e first t h r o u g h third digits. F o t c c d flexion or extension of the wtist c o m m o n l y e x a c e r b a t e s the sensory s y m p t o m s . W e a k n e s s of t h e a b d u c t o r poilicis brevis may develop in a d v a n c e d cases. T h i s c o n d i t i o n w o u l d n o t n o r m a l l y be considered in the differential diagnosis of m o n o p a r e s i s , but because the patient can c o m p l a i n of w e a k n e s s t h a t is m o r e extensive t h a n t h e actual deficit, it is considered here. N e r v e c o n d u c t i o n studies s h o w slow m o t o r a n d sensory velocities t h r o u g h the carpal tunnel. K M G s h o w s d e n e r v a t i o n in the a b d u c t o r poilicis brevis muscle with severe disease.
Peripheral nerve lesions of the arm
Lesion Median neuropathy Carpal runnel syndrome
Anterior interosseous syndrome
Pronator teres syndrome
Compression at the ligament of Strurhers Ulnar neuropathy Palmar branch damage
Entrapment at Guyon's canal Entrapment at or near the elbow
Radial neuropathy Posterior interosseous syndrome
Compression at the spiral groove
NCY = nerve conduction velocity.
Clinical findings
EM.G findings
Abductor poilicis brevis wasting and weakness when severe. Sensory loss on palmar aspect of the first through third dibits Weakness of flexor digitorum profundus, pronator titiadratus, flexor poilicis longus Weakness of distal median-innervated muscles; tenderness of pronator teres
Slow motor and sensory NCV through carpal tunnel; abductor poilicis brevis denervation if severe
Weakness of distal median-innervated muscles
Weakness of dorsal interossei; no sensory loss Weakness of numbness Weakness of numbness
ulnar intrinsic muscles; over fourth and fifth digits ulnar intrinsic muscles; over fourth and fifth digits
Weakness of ringer and wrist extensors; no sensory loss Weakness of finger and wrist extensors; triceps spared; sensory loss on dorsal aspect of first digit
Denervation in flexor digitorum profundus, flexor poilicis longus, pronator quadratus Slow median motor NCV through proximal forearm; denervation of distal median-innervated muscles As for pronator teres syndrome, with the addition of denervation of pronator teres Normal ulnar NCV; denervation of first dorsal intcrosseus but not abductor digiti minimi Slow ulnar motor and sensory NCV through wrist Slow ulnar motor NCV across elbow, denervation in abductor digiti minimi and ulnar half of flexor digitorum profundus Denervation in wrist and finger extensors; supinator and extensor carpi radialis spared Slow radial motor NCV across spiral groove; denervation in distal radialinnervated muscles; triceps may be affected with proximal lesions
HEMIPLEGIA AND MONOPLEGIA Table 26.4:
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Peripheral nerve lesions of the leg
Lesion
Clinical findings
EMG findings
Sciatic neuropathy
Weakness of tibial- and peroneal-innervated muscles with sensory loss on posterior leg and foot Weakness of foot extension and eversion and of toe extension Weakness of foot plantar flexion Weakness of knee extension; weakness of hip
Denervation distally in tibial- and peroneal-innervated muscles; contralateral muscles normal
Peroneal neuropathy Tibial neuropathy Femoral neuropathy
Denervation in peroneal-innervated muscles; conduction across fibular neck may be slowed Denervation in gastrocnemius and soieus Denervation in quadriceps, and sometimes psoas
flexion if psoas involved
Anterior Interossetts Syndrome. The anterior interosseous nerve is a branch of the median nerve in the forearm that supplies some of the forearm muscles. Damage can occur distal to the elbow, producing a syndrome that is essentially purely motor. Weakness of finger flexion is prominent. Affected muscles include the flexor digitorum profundus to the second and third digits (the portion to the fourth and fifth digits is innervated by the ulnar nerve). The distal median nerve entering the hand is unaffected, because the anterior interosseous nerve arises from the main trunk of the median nerve. Diagnosis is suspected by weakness of the medianjj-mervared finger flexors with sparing of the abductor pollicis brevis and ulnar-innervated flexors. EMG can confirm the diagnosis, but because this entrapment is not commonly looked for by many electromyographers, study of the appropriate muscles must be specifically requested. Pronator Teres Syndrome. The median nerve distal to the elbow can be damaged as it passes through the pronator teres muscle. All median-innetvated muscles of the arm are affected except for the pronator teres itself. The clinical picture looks like an anterior interosseous syndrome plus distal median neuropathy. The pronator teres may be tender, and palpation may exacerbate some of the distal pain. Ulnar Nerve. Ulnar entrapment is most common near the elbow and at the wrist, Entrapment at the elbow produces weakness of the ulnar-innervated intrinsic muscles. Weakness of long flexors of the fourth and fifth digits also can develop. When the entrapment is at the wrist, the weakness is isolated to the intrinsic muscles of the hand, and more proximal muscles are unaffected. Although most of the intrinsic muscles of the hand are ulnar innervated, a few arc median innervated and arc unaffected in ulnar neuropathy. Diagnosis of ulnar neuropathy is suspected when a patient complains of pain or numbness on the ulnar aspect of the hand. The diagnosis is reinforced when the patient has weakness and wasting of the intrinsic muscles of the hand, which is especially easy to see in the first dorsal interosseous.
Radial Nerve Palsy. Radial neuropathy is most commonly seen above the elbow, such that wrist and finger extensors are mainly affected. The triceps can also be affected. This is most commonly a pressure palsy seen in alcoholic intoxication. Peripheral neuropathy makes the development of pressure neuropathy of the radial nerve more likely. Femoral Neuropathy. Femoral neuropathy can occur from compression by intra-abdominal contents (fetus or neoplasm), but we have also seen it from damage around the time of angiography or surgery. Patients present with pain in the thigh and weakness of knee extension. The complaint is usually not so specific but is of the leg "giving out" during walking or of the patient being unable to get out of a chair without using the arms. Examination may show quadriceps weakness, but this muscle group is so strong that the examiner may not be able to detect the weakness. Lower leg muscles must be examined to ensure that muscles in the sciatic distribution arc normal. Diagnosis is confirmed by EMG, showing denervation confined to the femoral nerve distribution. Unfortunately, electrical signs of denervation may not be obvious for up to 4 weeks after the injury. Sciatic Neuropathy. Sciatic neuropathy can have multiple causes, including acute trauma and chronic compressive lesions. The term sciatica describes pain in the distribution of the sciatic nerve in the back of the leg. It is usually due to radiculopathy (see Radiculopathies, later in this chapter). An intramuscular injection into the sciatic nerve rather than the gluteus is an occasional cause of sciatic neuropathy and is characterized by initial severe pain followed by a lesser degree of pain and weakness. Pyriformis syndrome is an uncommon condition in which the sciatic nerve is compressed by the pyriformis muscle. This is a difficult diagnosis to make, requiring demonstration of increased pain on tensing the pyriformis muscle by flexing and adducting the hip. Diagnosis of sciatic neuropathy is considered when a patient presents with pain and/or weakness of the lower leg muscles. EMG can confirm the distribution of denervation. Nerve conduction studies are usually normal. MRI of the lumbosacral plexus is occasionally needed to look for
346
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
tumors and other causes of sciatic nerve or plexus compression. Peroneal Neuropathy. Peroneal neuropathy can develop from a lesion at the fibular neck, the popliteal fossa, or even ihi1 sciatic nerve in the thigh. The peroneal division of rhe sciatic nerve is more susceptible to injury than the tibial division, so incomplete sciatic injury affects predominantly the peroneal innervated muscles. The peroneal nerve innervates the tibialis anterior, extensor digitorum brcvis, and pcronei muscles. In addition, the peroneal division innervates the short head of the biceps femoris in the distal posterior thigh. This is an important muscle to remember, because distal peroneal neuropathy spares this muscle, whereas a proximal sciatic neuropathy, a peroneal division lesion, or a radiculopathy is expected to cause denervation not only in the tibialis anterior but also the short head of the biceps femoris. Radiculopathies Radiculopathy produces weakness of one portion of a limb. Common radiculopathies are summarized in Table 26.5. Complete paralysis of all of the muscles of an arm or leg is not caused by radiculopathy, other than traumatic avulsion of the nerve roots, which may occur in the upper limbs with distraction injuries of the arm from the neck. Roots serving arm power include chiefly C5 to T l . Roots serving leg power are chiefly L2 to SI. A lesion at the L5 level often elicits a complaint of the entire limb being weak because of the footdrop, which interferes with gait. Reflex abnormalities are often present early in a radiculopathy and are a manifestation of the sensory component. Motor deficits develop with increasingly severe radiculopathy. Diagnosis of radiculopathy can be facilitated by EMG, which is an aid to localization and helps determine whether acute changes are developing. V1RI shows the structural cause of a definite radiculopathy in most patients, although
Table 26,5:
Plexopathies Brachial and Lumbar Plexitis (or Piexopathy). Brachial plexitis is an acute neuropathic syndrome of presumed autoimmune etiology. Patients present with shoulder and arm pain followed by weakness as the pain abates. Eventually the weakness improves, although this takes months and is occasionally incomplete. Brachial plexitis is somewhat more common than lumbar plexitis. The upper plexus, C5-C6, is most commonly affected, although the lower plexus can be involved. Lumbar plexitis has a similar clinical course to brachial plexitis. Diagnosis of plexitis is considered when a patient presents with single limb pain and weakness, which docs not follow a single root or nerve distribution. MRI of the region is normal, unless there is neoplastic infiltration, Nerve conduction studies may be normal distally in the limbs, but F waves will be slowed or absent. EMG may be normal initially but eventually shows denervation in the distribution of the affected portion of the plexus. Differentiation of plexitis from radiculopathy is made on the basis of not only the more extensive deficits in patients with plexitis, but also the time course of pain followed by weakness as the pain abates; this pattern is not expected in patients with radiculopathy. Neoplastic Plexus Infiltration, The brachial and lumbar plexuses are in proximity to the areas that can be infiltrated by tumors, including those involving the lymph nodes, lungs, kidneys, and other abdominal organs. The first symptom of tumor infiltration is usually pain. Weakness and sensory loss are less common symptoms. Neoplastic plexus compression or infiltration presents as a progressive
Radiculopathies
Level Cervical radiculopathy C5 C6 C7 C8 Lumbar radiculopathy L2 L3 L4 L5 SI
the diagnostic yield in patients with back pain without clear radicular symptoms is far less (see Chapter 34). Myelography with post-myelographic CT scanning is still more sensitive for structural imaging, although it is not performed as a first-line investigation because of the invasive nature of the procedure.
Motor findings
Sensory findings
Deltoid, biceps Biceps, brachioradialis Wrist extensors, triceps Intrinsic hand muscles
Lateral upper arm Radial forearm and first and second digits Third and fourth digits Fifth digit and ulnar forearm
Psoas, quadriceps Psoas, quadriceps Tibialis anterior, quadriceps Peroneus longus, gluteus medius, tibialis anterior, extensor ballucis longus Gastrocnemius, gluteus maximus
Lateral and anterior upper thigh Lower medial rhigh Medial lower leg Lateral lower kg Lateral foot and fourth and fifth digits
HEMIPLEGIA AND MONOPLEGIA
painful monoparesis. Limb movements that stretch the plexus elicit pain, and the patient tends to hold the limb immobile to avoid exacerbating the pain. Neoplastic infiltration of the brachial plexus usually involves the lower plexus, C8-T1. Lung cancer and lymphoma are the most common tumors to cause this, Horner's syndrome can develop with lower brachial plexus involvement. The main differential diagnosis is radiation plexopathy. Diagnosis is suspected as a result of the severe pain and weakness. EMG often shows denervation that spans single nerve and root distributions. Detailed knowledge of the plexus anatomy is essential during examination and EMG. MRI usually shows the infiltration or compression of the plexus. Radiation Plexopathy, Radiation therapy in the region of the plexus can produce progressive dysfunction. The upper brachial plexus is especially susceptible because of the lesser amount of surrounding tissues to attenuate the radiation. Symptoms are dysesthesias and weakness. The dysesthesias may be uncomfortable but are seldom described as painful. This is one key to differentiation from neoplastic plexus infiltration, which is typically quite painful. Diagnosis is suspected in the clinical setting of progressive painless weakness in a patient with cancer who has received radiation to the region, MRI is essential to rule out tumor infiltration. EMG shows denervation, which is not a differentiating feature, but myokymia is more commonly seen in patients with radiation plexopathy than in those with neoplastic infiltration. Plexus Hematomas. Hematomas can develop adjacent to and compress the brachial and lumbosacral plexuses producing motor and sensory findings. Brachial plexus hematomas are usually from bleeding disorders or instrumentation such as central line placement. Lumbosacral plexus hematomas can also develop from coagulopathies including anticoagulant treatment, and after procedures such as abdominal surgeries or after femoral arterial catheterization. In the latter circumstance, blood leaking from the puncture site can flow proximally, and a substantial amount of blood may be lost without a clinically obvious hematoma. Hematomas interfere with the function of the peripheral nerves and plexus by blocking conduction. The prognosis is generally good as long as the plexus or nerve has not been directly injured, because the condition is usually neurapraxia rather than neurotmesis, and conduction is usually restored when the blood is resorbed. Large hematomas should be evacuated if severe plexopathic damage is present. Plexus Trauma. A history of trauma makes the etiology of the plexopathy quite obvious. The main difficulty is
347
differentiating plexopathy from radiculopathy (nerve root avulsion) or peripheral nerve damage. Also, spinal cord damage must be considered, because cord contusion and hemaromyelia may present with weakness that is more prominent in one extremity. Motor vehicle accidents, deliveries, and occupational injuries arc the most common causes of traumatic plexopathy. In many cases of plexus stretch, the mechanism is forced extension of the arm over the head or forced downward movement of the shoulder. Forced extension of the arm over the head damages the lower plexus, with the intrinsic muscles of the hand being especially affected (Klumpke's palsy). Forced depression of the shoulder produces damage to the upper plexus, giving prominent weakness of the deltoid, biceps, and other proximal muscles (Erb's palsy). Diagnostic studies should include imaging not only of the plexus but also of the proximate spinal cord, looking for disc herniation, spondylosis, subluxation, or other anatomic deformity. Plain radiograph should always be performed. MRI and/or CT of the region is also helpful. Trauma includes not only stretch injury, but also penetrating injury, such as knife and bullet wounds. Knife wounds are less likely to affect the lumbar plexus, but downward strike with a knife can easily affect the brachial plexus and nearby vessels. Gunshot wounds may directly affect the plexus, and the shock waves of high-velocity bullets may damage the plexus without direct involvement. Unfortunately, the speed and effectiveness of recovery from these types of injuries is poor. Thoracic Outlet Syndromes, Thotacic outlet syndrome is an overdiagnosed condition characterized by weakness of muscles innervated by the lower trunk of the brachial plexus. The motor axons in the lower trunk supply both the median- and ulnar-innervated intrinsic muscles of the hand, Finger and wrist flexors may occasionally be affected, causing marked impairments in use of the hand, which is not restricted to a single nerve distribution. This must be differentiated from a cortical lesion. Sensory loss is mainly in an ulnar distribution because the sensory fibers of the median nerve ascend through the middle trunk rather than the lower trunk. Diagnosis of thoracic outlet syndrome depends on demonstration of low-amplitude median and ulnar nerve compound motor action potentials and ulnar sensory nerve action potentials. Median sensory nerve action potentials are normal. Cervical ribs are usually asymptomatic, so their presence does not confirm the diagnosis of thoracic outlet syndrome. MRI of the plexus may be necessary to rule out infiltration by nearby tumor. Diabetic Amyotrophy. Diabetic amyotrophy is the term given to the syndrome of damage to the proximal lumbar plexus, serving mainly the femoral nerve, seen in diabetics. Patients present with weakness and pain in a femoral nerve distribution. Although there may bq an additional
348
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
length-dependent diabetic peripheral neuropathy, the femoral distribution symptoms and signs overshadow the other findings. Patients eventually improve, although the recovery is often prolonged and incomplete. It is difficult to study the nerve conduction of the femoral nerve. EMG usually shows denervation with chronic lesions, although up to 4 weeks may pass before electrical signs of denervation are seen. Neuronnpathies Neuronal degenerations usually affect multiple individual nerve distributions and more than one limb. However, a few focal motor neuropathies can produce single limb defects. Monomelic amyotrophy is a condition in which motoneurons of one limb degenerate; often the distribution suggests involvement of specific motoneuron columns in the spinal cord. Monomelic Amyotrophy. Monomelic amyotrophy is a degenerative condition that affects only one limb, usually an arm. The opposite limb can be affected to a much lesser extent. There is no pain or sensory loss. Progressive weakness develops over months to years and may eventually produce weakness that plateaus. Onset is usually in young adult life, about the age of 20 years, and men are predominantly affected. Diagnosis is confirmed by clinical presentation and EMG findings of active and chronic denervation without sensory abnormalities. Poliomyelitis. Poliomyelitis is now uncommon but still occurs in some parts of the world. A poliomyelitis-like syndrome can result from viruses other than the poliovirus itself. The illness usually presents with acute asymmetrical weakness after an initial phase of encephalitic symptoms, including headache, meningeal signs, and possibly confusion or seizures. The paralysis may involve only one limb but is more commonly generalized. After recovery, only one limb may remain weak (monoparesis).
PITFALLS IN THE DIAGNOSIS OF HEMIPLEGIA AND MONOPLEGIA Diagnosis of hemiplegia and monoplegia can always be a challenge, but some diagnoses can be especially difficult.
Weakness in Intrinsic Muscles of the Hand: Median, Ulnar, Plexus, or Small Cerebral Cortical Lesion? Most of the intrinsic muscles of the hand arc innervated by the ulnar nerve, so an isolated distal ulnar lesion produces profound loss of use of the hand. This lesion must be
differentiated from a lateral frontocentral cerebral lesion, which if located in the hand region produces prominent loss of independent digit use. A median nerve lesion produces impaired hand function because of loss of function of the finger and wrist flexors more than of the intrinsic muscles of the hand. With stabilization of the hand, intact function of ulnar- and radial-innervated muscles can be demonstrated to rule out lesions at or above the plexus. Lower brachial plexus lesions produce dysfunction of the median- and ulnar-innervated intrinsic muscles of the hand and may also affect the long finger flexors. This dramatic loss of function can be mistaken for central weakness, because the deficit spans peripheral nerve distributions. EMG usually documents the axonal damage. A small cerebral cortical lesion can produce disuse of the hand without signs of other deficit. Reflexes should be exaggerated, although acutely they may not be. Cupping of the outstretched hand and pronator drift strongly suggests a central lesion. EMG cannot rule out a peripheral nerve lesion, because several weeks may be required before signs of axonal damage are evident on needle study. MRI of the brain is the most sensitive imaging study for a small cerebral lesion.
Radial Neuropathy or Small Cerebral Cortical Infarcts? Radial neuropathy presents with weakness of the wrist extensors, which if severe can result in destabilization of the intrinsic muscles of the hand and long finger flexors, because opposition from the radial-innervated extensors is required for these median- and ulnar-innervated muscles to work well. Therefore the deficit seems more extensive than would be expected on the basis of a radial lesion alone. A cerebral lesion is suggested. Although cerebral lesions span neural distributions, wrist extension may be more obviously affected than grip and/or finger flexion. Differential diagnosis of radial neuropathy from cerebral lesion depends on the examiner stabilizing the finger flexors and wrist to demonstrate intact median and ulnar nerve function. Also, CST signs and other signs of cortical damage (aphasia or neglect) should be looked for in a patient with a possible cerebral infarct.
Leg Weakness: Peroneal Nerve Palsy or Paramedian Cerebral Cortical Lesion? Peroneal nerve palsy results in weakness of foot dorsiflcxion and eversion with relative preservation of other motor functions. Small lesions of the leg region of the homunculus on the medial aspect of cerebral hemispheres cause weakness that is most prominent in the same distribution as a peroneal nerve palsy. Differentiation is by absence of inverter weakness with peroneal palsy. EMG signs of
HEMIPLEGIA ANl> MONOPLEGIA denervation do not develop with cerebral lesions. Cerebral causes of lower leg weakness also cause upgoing plantar response and hyperactivity of the Achilles tendon reflex, despite little clinical evidence of gastrocnemius muscle involvement.
Leg Weakness: Cauda Equina Lesion, Myelopathy, or Paramedian Cerebral Cortical Lesion? This chapter discusses monoplegia rather than paraplegia (Chapter 27), but it is important to differentiate between lower spinal cord dysfunction and cauda equina compression; between upper spinal cord involvement and cervical spondylotic myelopathy; and between these problems and midline cerebral lesions producing leg weakness. Cauda equina lesions are usually due to acute disc herniations, spondylosis, or tumors in the lumbosacral spinal canal. The lumbar and sacral nerve roots are compressed, resulting initially in a depolarizing block but later axonal degeneration, which produces motor and sensory loss. With the syndromes of intermittent claudication of the cauda equina, repetitive nerve action potentials result in severe pain that is relieved by rest only after a few minutes and that may be accompanied by neurological dysfunction. Pain, sensory loss, and weakness are typically worsened by standing and relieved by flexing the lumbar spun-. Spondylotic myelopathy is compression of the spinal cord by degenerative spondylosis above the cauda equina.
349
Compression of the CSTs produces weakness of the legs. Pain is usually near the level of the lesion, although the localizing value is not precise. Midline cerebral lesions produce unilateral or bilateral leg weakness, depending on the cause and exact location, with CST signs. Spine pain is not expected. Differentiation between these three lesion locations (cauda equina, spinal cord, and cortical) can be tricky, but in general the following apply: • Bowel and bladder incontinence can develop with all three locations but is more common with cauda equina lesions. • Cauda equina lesions are associated with depressed reflexes, whereas spinal cord and cerebral lesions have hyperactive reflexes and upgoing plantar responses. • Sensory loss is more prominent with cauda equina lesions than higher lesions. • Pain in the spine is approximately at the level of the lesion, although the localization is not exact.
FURTHER READING Misulis, K. E. 1996, Neurological Localization and Diagnosis, Bu tte rwort h-He i nem a nn, Rosto n Misulis, K. E, 200.1, Essentials of Clinical Neurophysiology, 3rd ed, Elsevier, Philadelphia Patten, J. 1995, Neurological Differential Diagnosis, SpringerVerlag, New York
Chapter 27 Paraplegia and Spinal Cord Syndromes Thomas N. Byrne and Stephen G. Waxman Segmental Innervation Ventral Root Dysfunction Dorsal Root Dysfunction Sensory Disturbances Dermatomes Deep Tendon Reflexes Nerve Root Versus Peripheral Nerve Lesion Localization of Lesions in the Transverse Plane Motor Disorders Sensory Disturbances Autonomic and Respiratory Disturbances Common Spinal Cord Syndromes Spinal Shock
351 351 352 355 355 355 356 357 357 357 359 359 359
The clinical presentations of spinal cord disease are diverse, The protean manifestations of spinal cord disease may mislead even the most astute clinician. Patients may present with vague numbness or weakness. Alternatively, their first complaint may be pain without neurological signs, which may he incorrectly attributed to musculoskeletal disease or visceral pathology. Because it is essential to evaluate and treat such patients with spinal cord compression expeditiously, a thorough understanding of the clinical manifestations of spinal cord diseases and those of the n on-neurological diseases that may mimic spinal disease is necessary. The purpose of this chapter is to provide an understanding of the clinical pathophysiology of the spinal cord and to demonstrate the methods of history taking and physical examination that are helpful in assessing the patient suspected of suffering from spinal cord disease. The localization of spinal cord pathology is described by the following three coordinates. The first two are anatomical: (1) the level in the rostrocaudal axis and (2) the extent in the transverse plane of spinal cord involvement, These coordinates are determined by clinically assessing neurological functions served by both nerve roots and spinal cord tracts. The third coordinate is the time course of evolution of spinal cord dysfunction, which is often important in predicting the etiology, the physiological response of the cord to the disease, and the prognosis (Byrne, Benzel, and Waxman 2000),
Incomplete Lesions of the Spinal Cord Characteristic Clinical Features of Lesions at Dittercm Levels Foramen Magnum Upper Cervical Spine Lower Cervical and Upper Thoracic Spine Thoracic Levels Conus Medullaris and Cauda Equina Distinguishing Intramedullary from Extra medullary Lesions Classification of Diseases Affecting the Spinal Cord Metastatic Epidural Spinal Cord Compression
360 361 361 362 362 362 363 363 363 365
SEGMENTAL INNERVATION Ventral Root Dysfunction Ventral root dysfunction is manifested by characteristic motor disturbances that are usually quite distinct from those arising from corticospinal tract disease or from plexus or peripheral nerve disease. Important aspects of the physical examination are the assessment of the distribution of abnormalities of muscle strength, tone, and bulk. The pattern of weakness is often the most important physical finding that distinguishes root disease from peripheral nerve disease. Muscle strength or power may be determined by individual muscle testing or by functional assessment. Because each muscle usually is innervated by several nerve roots, complete lower motor neuron (LMN) paralysis of a muscle or muscle group typically signifies plexus or peripheral nerve disease, rather than a monoradiculopathy. The lattet usually produces partial weakness of a muscle. Despite this fact, with a monoradiculopathy, a single muscle often suffers greater dysfunction than others. Such muscles have been termed segment-pointer muscles. Table 27,1 lists a group of muscles that may point the examiner to a specific nerve root. This listing, however, should not be considered infallible, because some individuals have prefixed or postfixed plexuses (i.e., are one nerve root higher or lower than the usually described anatomical localization). Hi
352
APPROACH TO COMMON NEUROLOGICAL PROBLEMS Table 27.1:
S eg me nr-pointer muscles
Root
Muscle
Primary
CA CA
Diaphragm Diaphragm Deltoid Biceps Brachioradialis Triceps Intrinsic hand muscles Intrinsic hand muscles Iliopsoas Quadriceps femoris Quadriceps reiuoris Tibialis anterior Extensor hallucis longus Gastrocnemius
Respiration Respiration Arm abduction Forearm flexion Forearm flexion Forearm extension Finger adduction/abduction Finger adduction/abduction Hip flexion Knee extension Knee extension Foot dorsiflexion Great toe dorsiflexion Plantar flexion
cs
CA C6 C7 C8 Tl LI L3 14 1.4 L5 SI
function
Source: Modified with permission from Schliack, H. 1969, "Segmental innervation and the clinical aspects of spinal nerve root syndromes," in Handbook of Clinical Neurology, vol. 2, eds P. J. Vinken, G. 8c W. Rruyn, North! lolhuul Publishing, Amsterdam.
Denervation of a muscle causes muscular atrophy (neurogenic atrophy). Other common causes of muscular atrophy are disuse, endocrinological disturbance, and malnutrition. Neurogenic atrophy develops in cases of radiculopathy. With a monoradiculopathy, however, the atrophy is not as prominent as that occurring with peripheral nerve injury because most muscles receive innervation from several nerve roots. In cases of chronic radiculopathy, such as that caused by cervical spondylosis, atrophy may precede weakness. Alternatively, in cases of acute radiculopathy, for instance, caused by acute disc herniation, weakness may ptecedc atrophy. Neurogenic atrophy may be associated with fasciculations, which represent spontaneous contraction of a group of muscle fibers innervated by a single motor neuron (a motor unit). Usually, they are seen as a twitching or rippling movement just beneath the skin. Exercise, cold, medications, and metabolic derangements often cause similar movements. Fasciculations are seen commonly in motor neuron disease but are widesptead in this case. In cases of compressive root lesions, fasciculations may be tcstricted to the myotomal distribution of the compressed root. These fasciculations are different from those seen in antctiot horn cell disease in that they occur tepetitively in the same fasciculus during minimal contraction and are usually absent during complete test. The syndtome of benign fasciculations is more diffuse and is not associated with weakness or atrophy. Muscle tone is often a valuable sign in distinguishing the site of a lesion causing weakness. When measuring muscle tone, the clinician must ensure that the patient's muscles are relaxed, and it is often helpful to distract the patient's attention. In cases of radiculopathy, either muscle tone is not affected ot tone is decteased unless there is muscle spasm, as often occurs if there is severe pain. Alternatively, spasticity and rigidity refer to common fotms of incteased
muscle tone caused by central nervous system disease. In spasticity, the increased rone is caused by an exaggeration of the sttetch reflex and accordingly is dependent on stretch rate. Thus if the muscle is slowly stretched, tone may be normal; however, if the muscle is stretched more rapidly, increasing amounts of resistance occur. Spasticity has been referred to as rate sensitive for this teason. The weakness of upper motor neuron (UMN) damage preferentially involves the deltoid, triceps and wrist extensors in the upper limbs, and the iliopsoas, hamsttings, and tibialis anterior muscles in the lower extremities, whether caused by cortical or corticospinal tract disease. Spasticity usually results from dysfunction of the descending spinal tracts, including but not limited to the corticospinal ttact (Ditunno and Formal 1994). Rigidity refers to increased muscle tone, which does not depend on the fate of movement. Unlike spasticity, it is found equally in both extensors and flexors. Rigidity is commonly caused by extrapyramidal disease or is a side effect of antidopamincrgic drugs (e.g., halopcridol).
Dorsal Root Dysfunction Disturbance of dorsal root function most commonly produces pain and to a lesser extent sensory impairment. The pain may be local or projected elsewhere in a tadiculat or nonradicular distribution (referred pain). Local Pain Local or regional back or neck pain is usually secondary to irritation or damage of innervated structures of the spine. The periosteum, ligaments, dura, and apophyseal joints are innervated structures. The clinical characteristics of local pain are that it is appreciated in the local tcgion of the spine
PARAPLEGIA AND SPINAL CORD SYNDROMES and that it is deep, aching, and exacerbated by activity that places an increased load on the diseased structures. Patients suffering from pain caused by an epidural tumor often report that their pain is made worse by the supine position, wiu-RMs those sntiering from spondylosis and musculoligamentous strain generally favor bed rest. Palpation or percussion of the spinal column may exacerbate the local pain regardless of the cause. Irritation of local innervated structures also causes secondary muscle spasm and local or somewhat diffuse pain. Projected Pain Projected pain is pain that arises from one anatomical site but is projected to a site some distance from the location of the pathology. When the spine is the source, the projected pain may be either radicular or nonradicular. Projected pain that arises from irritation of posterior nerve roots is of a radicular type, whereas that caused by irritation of other spinal structures is usually of a nonradicular type, herein termed referred pain. Although these forms of pain are not always easy to differentiate, it is important to distinguish between them because radicular pain has strong localizing value and nonradicular pain does not. Referred Pain. The pain in normal volunteers after injection of 6% saline into the facet joints of L1-L2 and L4-L5 is cramping and aching in quality. As shown in Figure 27.1, there is overlap in the regions of pain referral from upper and lower lumbar injections, with most of the pain being referred to the flanks, buttocks, groins, and thighs. It is of clinical interest that referred pain in normal volunteers does
353
not project below the knee despite rhe fact that the L4-L5 level is stimulated, whereas it can radiate below the knee in symptomatic individuals. It appears that unlike tadicular pain, referred pain does not follow segmental dermatomes and is not usually helpful in localization. Although there may be paresthesias in the cutaneous area of pain referral, as well as tenderness to deep palpation of the muscles, no neurological abnormalities are found in cases of referred pain of nonradicular origin. This situation is in contrast to cases of radicular pain, in which disturbance of the nerve root often may be present in the form of sensory loss, hyporcflexia, ventral root dysfunction, or a combination of these. Referred pain generally is aggravated and relieved by the same maneuvers that alter local pain. Radicular Pain. Radicular pain, which has great localizing value, arises from irritation of dorsal roots, with pain being projected to the dermatome of the nerve root. Tables 27.2 and 27.3 list the differential diagnoses of lesions of the cervical and lumbosacral nerve roots and the common sites to which pain of radicular origin is projected. Radicular pain often has a sharp, stabbing quality. Maneuvers that stretch or further compress the nerve root, such as Valsalva maneuver, coughing, straight-leg raising, and neck flexion, generally aggravare the pain. The patient may avoid certain activities and postures that place further strerch on the nerve. For example, in the case of sciatica (pain in the distribution of the sciatic nerve) caused by a compressive SI radiculopathy (Figure 27,2), the patient may maintain the leg in a flexed posture at the hip and knee and plantar flex the foot. Such a posture may result in
FIGURE 27.1 Patterns of referred pain. The distributions of pain referral from L1-L2 (diagonal Shies) and L4-L5 (crosshatching) are superimposed following (A) intracapsular and (B) pericapsular injections of 6% saline into the apophyseal joints. Overlap of the patterns is shown in the region of the iliac crest and groin. (Reprinted with permission from Mccall, J. W,, Park, W.M., & O'Brien, J, P. 1979, "Induced pain referral from posterior lumbar elements in normal subjects," Spine, vol. 4, pp. 441-446.)
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 27.2;
Differential diagnosis of lesions of the cervical nerve roots
Roots
C5
C6
C7
C8
Tl
Sensory supply
Lateral border upper arm
Lateral forearm including thumb
As above As above, and thumb and index finger Biceps jerk Deltoid
As above As above, especially thumb and index finger Supinator jerk Biceps
Medial forearm to include little finger As above As above
Axilla down to the olecranon
Sensory loss Area of pain
Over triceps, mid forearm, and middle finger Middle fingers As above, and medial scapula border Triceps jerk Latissimus dorsi
Finger jerk Finger flexors
Supraspinatus Infraspinatus
Rrachioradialis Brachial is (pronators and supinators of forearm)
Pectoralis major Triceps
Finger extensors Flexor carpi ulnaris (thenar muscles in some patients)
Reflex arc Motor deficit
Rhomboids Some causative lesions
Brachial neuritis
Acute disc lesions
Cervical spondylosis
Cervical spondylosis
Wrist extensors Wrist flexors Acute disc lesions
As above Deep aching in shoulder and axilla to olecranon None All small hand muscles in some via C8
Rare in disc lesions or spondylosis
Cervical rib
Cervical spondylosis
Thoracic outlet syndromes Pan coast's tumor Metasta ticca rci noma in deep cervical nodes
Upper plexus avulsion
Source: Adapted from Patten, J. 1977, Neurological Differential Diagnosis, Springer-Verlag, New York.
Table 27.3:
Differential diagnosis of lesions of the lumbosacral nerve roots
Roots
L2
I >'
IA
U
SI
Sensory supply
Across upper thigh
Across lower thigh
Across knee to medial malleolus
Sensory loss
Often none
Often none
Medial leg
Side of leg to dorsum and sole of foot Dorsum of foot
Area of pain
Across thigh
Across thigh
Down to medial malleolus
Reflex arc
None
Knee jerk
Motor deficit
Hip flexion
Adductor and knee reflex Knee extension
Back of thigh, lateral calf, dorsum of foot None
Behind lateral malleolus to lateral foot Behind lateral malleolus Back of thigh, back of calf, lateral foot Ankle jerk
Do rsi flex ion of toes and foot (latter L4 also) Disc prolapse
Plantar flexion and eversion of foot Disc prolapse
Metastases Neurofibroma Meningioma
Metastases Neurofibroma Meningioma
Some causative lesions
Neurofibroma Meningioma Metastasis Intervertebral disc prolapse (infrequent)
Inversion of the foot
Source: Adapted from Patten, J. 1977, Neurological Differential Diagnosis, Springer-Verlag, New York.
PARAPLEGIA AND SPINAL CORD SYNDROMES
355
FIGURE 27.2 MRI (axial image) of the lumbar spine demonstrating a right-sided herniated L5-S1 disc (Note: The herniated disc is on rhe left side of the figure). The patient had right-sided sciatica and an absent ankle reflex and sensory loss ot 111 L- lateral foot.
a characteristic gait. As with referred pain, cutaneous paresthesias and tenderness of tissues in the region of pain projection are common. However, in radicular pain, unlike referred pain, there may be sensory disturbances and at times reflex and motor abnormalities corresponding to the injured nerve root.
Finally, it should be recognized that there arc variations in dermatomal innervation between individuals that may make it difficult to base clinical conclusions on sensory testing alone.
DEEP TENDON REFLEXES
SENSORY DISTURBANCES Dermatomes A knowledge of the dermatomal map is valuable in recognizing and localizing radicular syndromes, A currently recognized dermatomal map is shown in Chapter 31 {see Figure 31.4). A few points deserve emphasis: • On the trunk, the C4 and T2 dermatomes are contiguous. • The thumb, middle finger, and fifth finger are innervated by C6, C7, and C8, respectively. • The nipple is at the level of T4. • The umbilicus is at the T10 level. • In the posterior axial line of the leg {medial thigh), the lumbar and sacral dermatomes arc contiguous.
In addition to motor and sensory disturbances, deep tendon reflex abnormalities can be of precise localizing value. When deep tendon reflexes are segmentally hypoactive, they can be sensitive indicators of specific root disturbance. When they arc hyperactive below a specific spina! level, they may indicate a myelopathy at or above that level. The combination of hypoactive tendon reflexes at a segmental level with hyperactive reflexes caudal to that level is found commonly with cervical spine disease. For example, cervical spondylosis may cause hyporcflcxia of the biceps, brachioradialis, or triceps because of impingement on C5, C6, or C7 roots, respectively, and hyperreflexia below this level secondary to an associated myelopathy. At times, attempts to elicit the brachioradialis reflex produce no direct response but paradoxically cause contraction of the finger flexors rather than flexion and supination of the hand. Such a response is called inversion of the radial reflex.
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
NERVE R O O T VERSUS PERIPHERAL NERVE LESION Monoradiculopathies rarely cause complete paralysis of a single muscle or muscle group. In contrast, with peripheral nerve disease, it is common for paralysis of such muscle groups to occur. A knowledge of innervation of muscle groups is important in making the distinction between peripheral nerve, plexus, or nerve root lesions. The sensory examination may be helpful in distinguishing peripheral nerve lesions from radiculopathies. Autonomic disturbances may also be valuable in distinguishing peripheral nerve lesions from root disturbances. Tabic 27.4:
Ordinarily, mo no radiculopathies are not associated with autonomic disturbances such as sweat loss, whereas peripheral nerve injuries often arc associated with autonomic complaints. Tables 27.2, 27.3, 27,4, and 27.5 review the locations of sensory loss, projected pain, reflex loss, motor deficit, and some causative lesions of the more common radiculopathies and peripheral neuropathies. Electrodiagnostic studies are often helpful in differentiating radiculopathies from peripheral neuropathies. With radiculopathies, the sensory action potentials are unaffected, whereas they are typically decreased in amplitude or absent in petiphcral nerve disease. Motor conduction
Differential diagnosis of lesions of upper limb peripheral nerves
Nerves
Axillary
Musculocutaneous
Radial
Median
Ulnar
Sensory supply
Over deltoid
Lateral forearm
Lateral palm, thumb, and lateral two fingers
Sensory loss
Over deltoid
Lateral forearm
Medial palm, fifth finger, and medial one half of ring finger As above
Area of pain
Across shoulder tip
Lateral forearm
Lateral dorsal forearm and back of thumb and index finger Dorsum of thumb and index finger Dorsum of thumb and index finger
Reflex arc
Nil
Biceps jerk
Triceps jerk and supinator jerk
Motor deficit
Deltoid
Biceps
Triceps
Brachial is
Wrist extensors
Finger extensors
Brachioradialis
Some causative lesions
I'lMCUllVtl llec'k
Rarely damaged
Supinator of forearm Crutch palsy
of humerus
Dislocated shoulder
Saturday night palsy
Deep intramuscular
Fractured humerus
As above
Thumb, index, finger(s) and middle fingers Often spreads up forearm Finger jerks {flexor digitorum sublimis) Wrist flexors
Long finger flexors (thumb, index fingers, and middle fingers) Pronator* of forearm
Ulnar-supplied fingers and palm distal to wrist Pain occasionally along course of nerve Nil
All small hand muscles, excluding abductor pollicis brevis Flexor carpi ulnaris
Long flexors of ring and little fingers
Abductor pollicis b rev is Carpal tunnel syndrome
Direct trauma to wrist
injections
Entrapment in supinator muscle Source: Adapted from Patten, J. I 977, Neurological Differential Diagnosis, Springer—Verlag, New York.
Elbow: trauma, bed rest, fractured olecranon Wrist: local trauma, ganglion of wrist joint
PARAPLEGIA AND SPINAI, CORD SYNDROMES Tabic 27,5:
357
Differential diagnosis of lesions of lower limb peripheral nerves Sciatic nerve
Nerves
Obturator
Femoral
Peroneal division
Tibial divisio?t
Sensory supply
Medial surface of thigh
Sensory loss
Often none
Anteromedia! surface of thigh and leg to medial malleolus As above
Posterior leg, sole, and lateral border of foot As above
Area of pain
Medial thigh
Reflex arc Motor defieir
Adductor reflex Adduction of thigh
Anterior thigh and medial kg Knee jerk Extension of knee
Anterior leg, dorsum of ankle and foot Often just dorsum of foot Often painless
Some causative lesions
Pelvic neoplasm
Diabetes
Pregnancy
IVmoral hernia
None Dorsiflexion and eversion of the foot (plus lateral ham strings) Pressure palsy at fibula neck Hip fracture or dislocation Penetrating trauma to buttock Misplaced injection
Ankle reflex Plantar flexion and inversion of foot (plus medial ham strings) Rarely injured, even in buttock Peroneal division more sensitive to damage
Pregnancy Pelvic hematoma Posterior abdominal neoplasm Psoas abscess
Often painless
Source: Adapted from Patten, J. 1977, Neurological Differential Diagnosis, Springer-Vcrlag, New York. studies and patterns of denervation also may be helpful (see Chapter 36B). In dorsal root ganglionopathics, the sensory axons degenerate, often causing loss of sensory nerve action potentials in the affected segment.
LOCALIZATION OF LESIONS IN THE TRANSVERSE PLANE Motor Disorders As mentioned previously, the abnormalities on neurological examination of LMN dysfunction are weakness associated with atrophy, hypotonia, fasciculations, and depressed reflexes. In contrast, corticospinal tract disease often manifests with spasticity, hyper-reflexia, and Babinski's sign (except during the early phase of spinal shock), as well as weakness that usually involves more than a single extremity. In cervical spine disease, one may find a combination ot IAIN disturbance involving the upper extremity and UMN findings in one or both lower extremities. U M N disease usually affects the distal extremity more prominently than the proximal. For example, hand and foot dexterity are usually more impaired with UMN lesions than are shoulder and hip strength. Perhaps the most important clue suggesting a spinal origin to weakness is the pattern of weakness. Hemiparesis involving the face, arm, and leg usually localizes the problem to the brain. Proximal muscle weakness of the arms and legs with intact sensation and notmal deep tendon reflexes directs the examiner to myopathic
disorders. When the pattern is distal and associated with stocking-glove sensory loss and decreased deep tendon reflexes, peripheral neuropathies are considered. In patients with paraparesis or quadriparcsis, the examiner usually is directed to the spinal cord. Monoparesis creates the greatest diagnostic confusion. Early in the development of spinal cord disease, the patient may present with unilateral leg weakness, and examination may not reveal findings in the contralateral leg or the arms. Lesions of the cranioccrvical junction and cervical spine often present with a pattern of unilateral arm weakness before progressing to ipsilateral leg weakness, and then contralateral involvement. However, although weakness involving an ipsilateral arm and leg with sparing of the face suggests a high cervical lesion, it should be recognized that cerebral disturbances or lacunar infarction in the internal capsule or medullary pyramidal may cause this pattern of involvement. Babinski's response is a sign of corticospinal tract disease. Plantar stimulation therefore helps differentiate U M N causes from othet etiologies in patients with leg weakness.
Sensory Disturbances Subjective sensory complaints generally precede objective sensory signs, and therefore sensory complaints without abnormal sensory signs may be the first sign of serious underlying neurological disease. One corollary is that in the absence of sensory complaints, the sensory examination is usually normal.
358
Al'l'ROACH TO COMMON NEUROLOGICAL PROBLEMS
Dysfunction of the dorsal (or posterior) columns and of the lateral spinothalamic pathways usually causes characteristically different symptoms. Tingling paresthesias, which may be vibratory in nature, are sometimes reported below the level of a dorsal column lesion. Subjective reports of the skin being "too tight" or an extremity or trunk being "wrapped in bandages" also may be caused by dorsal column disturbances. Spinothalamic tract disturbance is often first manifested by pain that is poorly characterized and localized. It should be recognized that many of the complaints of patients with imiMinediiihii'v lesions are nutassociated with any abnormal signs early in their course, so the complaints may be dismissed inappropriately after a negative sensory examination. Pain sensation, usually measured by pinprick, and temperature sensation are conveyed via the lateral spinothalamic tract. These pathways are somatotopically organized so that the sacral fibers are most peripheral and the cervical fibers are most central. Because a laterally placed extramedullary lesion compresses the peripheral fibers before the more centrally located fibers, a compressive lesion in the rostral spine may give rise to an apparency ascending loss of pain and temperature sensation (Adams et al. 1996). These findings underscore the importance of recognizing that
a rostral lesion may give rise to a sensory level far below the site of the compression. In practical terms therefore when spinal cord compression is suspected, one may need to image the entire spine rostral to the sensory level to exclude a lesion above the sensory level. Position and vibration sensation classically arc thought to be transmitted through the posterior columns. However, both modalities of sensation also probably travel in other pathways (Glendinning and Vierck 1993). Spinal cord impairment of position and vibration sensation generally arc easily evaluated. Ataxia caused by spinal lesions is not as readily recognized. Disturbances of posterior columns or possibly the spinocerebellar tracts may result in an ataxic gait. This may be particularly evident in vitamin B 1 2 deficiency. Light touch is conveyed by both lateral and posterior columns and usually is not impaired as early in spinal cord disease as the more specific modalities described previously. Several incomplete lesions of the spinal cord result in characteristic sensory signs. A hemisection of the spinal cord results in a Brown-Sequard syndrome, in which there is loss of appreciation of pain and temperature contralateral to the lesion, loss of sensation for position and vibration, and UMN paralysis ipsilateral to the lesion (Figure 27.3).
ES3 Analgesia IZZ) Loss of vibratory and position sense ^M Combined loss
Complete transection of thoracic cord (lesion at T10)
Anterior spinal artery syndrome (lesion at T4)
FIGURE 27.3
Right hemisection of thoracic cord
(lesion at T3)
Cauda equina lesion
Early intra-axial lesion of thoracic cord at T3-T6 (syringomyelic suspended pattern)
Advanced intra-axial lesion of thoracic cord at T3-T6 (sacral sparing)
Right S1 radiculopathy
Peripheral neuropathy (glove stocking sensory loss)
Characteristic sensory disturbances found in various spinal cord lesions in comparison with peripheral neuropathy.
PARAPLEGIA AND SPINAL CORD SYNDROMES
An early intramedullary lesion such as a syrinx, intramedullary tumor, or contusion may give rise to a dissociated sensory loss in which damage to the decussating fibers at the level result in sensation of pain and temperature being lost or decreased, whereas the position and vibratory sensibilities remain unimpaired. Central cord lesions also may result in a suspended sensory level (see Figure 27.3). In such cases, sacral sensation is preserved until late in the course because these fibers are most peripheral in the lateral spinothalamic tracts and they tend to be involved later.
AUTONOMIC AND RESPIRATORY DISTURBANCES Dysfunction of the spinal cord and cauda equina is often manifested as symptoms and signs of bladder, bowel, and sexual dysfunction (see Chapter 42). A high cervical cord lesion may cause respiratory compromise. Although the diaphragm, intercostal muscles, and abdominal muscles are used for normal respiration, individuals may ventilate adequately with only the diaphragm intact (see Tabic 27.1). In cases of complete cord transection above the C3 level, respiration cannot be maintained. Trauma, foramen magnum tumors, atlantoaxial dislocation, and congenital disturbances of the craniocervical junction are common causes of upper cervical spine injury, The urinary bladder and its sphincters are innervated by (1) sympathetic nerves beginning in the intermediolateral cell column at the lumbar level (primarily LI and L2); (2) parasympathetic nerves exiting at S2-S4; and (3) somatic efferent nerves to the skeletal muscles of the external urethral sphincter exiting at S2-S4 to form the pudendal nerves. In complete transverse lesions of the cord, the bladder immediately becomes flaccid. In unilateral lesions, voluntary control of micturition is not lost. This corresponds to the clinical observation in spinal cord compression in which it is unusual to have sphincter function disturbed early when there is only unilateral or equivocal bilateral lower extremity weakness or sensory disturbance. The most common exception is when the conus medullars or sacral nerve roots arc compressed. Immediately after acute spinal cord injury, there is often an initial period of spinal shock, which is often accompanied by urinary retention and overflow incontinence (as well as flaccid areflexia); Liter, a reflex (neurogenic or spastic) bladder typically develops (see Chapter 42). If the disturbance of UMN function evolves slowly, then the reflex bladder may develop without a preceding period of spinal shock and flaccid bladder. The reflex bladder is characterized by overactivity of both the detrusor muscle and the external sphincter. This causes incontinence of urine. In addition, the bladder capacity is diminished because of the detrusor contraction. The sensation of bladder distention may be lost if ascending tracts are involved. The anal reflex
359
is often intact in cases of reflex bladder. On cystometry, the detrusor muscle demonstrates excessive contraction to small increments of fluid volume. In contrast to the reflex bladder, when the damage occurs in the region of the conus medullaris or the cauda equina, a decentralized or autonomous flaccid bladder develops (see Chapter 42), Voluntary control over bladder function is impaired or abolished entirely. In such cases, detrusor tone is lost and the bladder distends to the point that overflow incontinence occurs. Bladder sensation is impaired. Control over the anal sphincter and the anal reflex usually is lost. A region of saddle anesthesia may be present (see Figure 27.3). Unlike the situation in the reflex bladder, cystometrography usually demonstrates diminished or absent contractions of the detrusor muscle. The anatomical pathways subserving bowel function are similar to those controlling the urinary bladder. Spinal shock generally is associated with ileus, and a neurogenic megacolon may develop. The anal reflex usually is lost in cases of spinal shock. In lesions above the sacral level that evolve slowly, voluntary control of the sphincter ani may be lost, but in such cases, the anal reflex remains intact unless complete cord transection occurs, in which case it may be absent. In disturbances of the conus medullaris and cauda equina {nerve roots S3-S5), fecal incontinence and a flaccid anal sphincter with loss of the anal reflex may be a presenting manifestation of neurological disease. Saddle anesthesia (i.e., loss of sensation in the perianal area) is often seen in such cases. Partial impairment may be present in any of these syndromes before frank paralysis and a flaccid sphincter ensue, Disturbances of sexual function arc common in spinal cord disease, especially in men. The descending pathways from the neocortex, limbic system, and hypothalamus course adjacent to the corticospinal tracts in the lateral funiculi. Penile erection occurs via the sacral parasympathetics {S3 and S4), the pudendal nerves, and nervi erigenres, and via inhibition of the sympathetic vasoconstrictor center located in the intermediolateral cell column at L1-L2, and then through the superior hypogastric plexus. Ejaculation is performed via the reflex arc beginning with the afferent limb arising in the genital epithelium and passing centrally via the dorsal nerve of the penis and pudendal nerve to the S3 and S4 dorsal roots. The perineal branch of the pudendal nerve is an important peripheral efferent pathway.
C O M M O N SPINAL CORD SYNDROMES Spinal Shock A complete transverse lesion of the spinal cord results in total loss of motor and sensory functions below the level of the lesion. If the lesion is slow in development, such as may occur with a benign tumor or cervical spondylosis, or if it is
360
APPROACH TO COMMON NKUROl OCTCAL PROBI.FMS
incomplete, then spinal reflexes such as hyperactive deep tendon reflexes and Eabinski's signs genetally arc present. Alternatively, if the lesion is acute, a condition known as spinal shock ensues, in which there is temporary loss of all spinal reflex activity below the level of the lesion along with motor paralysis and sensory loss. Spinal shock is characterized by flaccid, areflexic paralysis of skeletal and smooth muscles. A complete loss of autonomic functions occurs below the level of the lesion, which results in a loss of urinary bladder tone and paralytic ileus. Sweating and piloerection also are diminished or absent below the level of the lesion. Because vasomotor tone is lost, dependent lower extremities may become edematous and temperature regulation may be a major problem. Genital reflexes such as penile erection, the cremasteric reflex, and bulbocavernosus reflexes are losr. Sensation below the level of the lesion is completely absent.
Incomplete Lesions of the Spinal Cord Unilateral Transverse Lesion A unilateral lesion or hemisection of the spinal cord produces a Brown-Scquard syndrome. In reality, pure unilateral lesions are rare, and therefore most clinical cases are described as a modified or partial BrownSequard syndrome. The clinical presentation of pure Brown-Sequard's syndrome is that of ipsilatcral weakness and loss of position and vibration below the level of the lesion, as well as contralateral loss of pain and temperature caudal to the lesion. The loss of pain and temperature usually is manifest a few segments below the level of the lesion because the decussating fibers enter the spinothalamic tract a few segments rostral to the level of entry of the nerve root. At the level of the insult, there may be a small ipsilateral area of anesthesia, analgesia, and LMN weakness because the segmental afferent and efferent pathways arc disrupted (see Figure 27.3). Trauma such as a bullet or stab wound is probably the most common cause of a Brown-Scquard syndrome. Spinal metastases rarely present with a Brown-Sequard syndrome. In the large series of spinal metastases, fewer than 2% of patients with signs of myelopathy have a pure Brown-Sequard syndrome. Approximately 8% have greater weakness ipsilateral to the lesion and more marked pain and temperature loss contralateral to the lesion, without dorsal column signs (modified Brown-Sequard's syndrome). Radiation necrosis also has been reported to presenr with Brown-Sequard's syndrome.
are either acute, in which case they are usually caused by hemorrhage or contusion following trauma (see Chapter 56C), or chronic, in which case they may be caused by tumor or syringomyelia. A demyelinating process occasionally may cause a similar syndrome, but it usually is not confused with the other more typical causes. Though clinically distinct, the presentations of these disorders share some common features. Contusions following trauma and syringomyelia often occur in the cervical spine and cervicotboracic junction. Spontaneous hematomyelia generally presents with the acute onset of severe back or neck pain followed by paralysis. When the cervical spine or cervicothoracic junction is the site of a central cord syndrome, the upper extremities show weakness of an LMN type. Characteristically, there is loss of sensation in the upper extremities of a dissociated type, with loss of pain and temperature sensation and preservation of position and vibration sensation. This is caused by the decussating fibers destined for the spinothalamic tracts being interrupted, whereas those projecting within the dorsal columns are spared (see Figure 27.3). As a result of the laminated structure of the spinothalamic tract, sensation from the more caudal regions is preserved, with a capelike distribution of sensory loss in some patients with sacral sparing of pain and temperature sensation being the rule (Figure 27.4). Anterior
Spinal Artery
Syndrome
Spinal cord infarction has been seen more frequent!) in recent years, in part because of an increased number of invasive procedures such as vascular and thoracoabdominal surgery and improved survival after cardiac arrest and hypotension. The anterior horns and anterolateral tracts are involved in this syndrome (see Chapter 57F). The thoracic vascular watershed zone at about T6 is especially susceptible. Corticospinal deficits develop below the level of the infarction; dysfunction of autonomic pathways occurs, causing loss of bowel, bladder, and sexual functions; and a sensory disturbance develops in which posterior column function remains intact and the spinothalamic tracts arc disrupted. Initially spinal shock with areflexia is expected, followed later by spasticity. Anterior spinal artery syndrome is differentiated from acute central cord syndrome, as occurs in traumatic contusions and hematomyelia, by the sacral sensory sparing that tends to occur in the latter. Moreover, the anterior spinal artery syndrome can be differentiated from that of acute complete transverse myelopathy caused by the loss of posterior column function in the latter.
Central Cord Syndrome
Anterior Horn and Pyramidal Tract Syndromes
The central cord syndrome is caused by an jntra-axial lesion disturbing the normal structures of the central or paracentral region of the spinal cord. Such disturbances
Disturbances of the anterior horns and pyramidal tracts alone with sparing of the sensory functions and autonomic nervous system are seen in motor neuron disease. Clinically,
PARAPLEGIA AND SPINAL CORD SYNDROMES
361
Combined Posterior and Lateral Column Disease The clinical presentation of loss of posterior column and lateral column (pyramidal! (unction is that ot spastic ataxic gait. The ataxia is of a sensory type and may be bizarre in appearance. Although Friedreich's ataxia may cause such a syndrome, the classic cause for this is subacute combined degeneration associated with vitamin BL2 deficiency.
CHARACTERISTIC CLINICAL FEATURES OF LESIONS AT DIFFERENT LEVELS Spinal lesions at different levels often present with characteristic symptoms and signs referable to the segmental levels involved. In cases of extramedullar compression, disturbances at the segmental level (i.e., nerve root signs) usually herald the presentation. Conversely, intramedullary diseases frequently do not present with segmental disturbances but rather with tract dysfunction.
Foramen Magnum
FIGURE 27.4 Magnetic resonance imaging scan of the cervical spine showing a contrast-enhancing mass. The patient presented with a capclike sensory loss to pain and temperature. Resection of the mass revealed a glioma. one typically finds a combination of both LMN weakness with its attendant atrophy and fasciculations (and fibrillations and dcncrvation/reinnervatlon on electromyography) and upper motor weakness with spasticity, hyperrcflcxia, and Babinski's signs. Virtually diagnostic is the presence of LMN and UMN signs in the same muscle group. Alternatively, either the LMN or the UMN disturbance may predominate for months or years. Ultimately, as the LMN disease progresses, increasingly severe atrophy and evolution from hyperreflexia to hyporeflexia occur.
Lesions of the foramen magnum, which include trauma, tumors, syringomyelia, multiple sclerosis, Arnold-Chiari malformation, atlantoaxial dislocation, and other bony abnormalities of the craniocervical junction, present a most challenging diagnostic problem for the clinician because symptoms are often vague or may be distant from the foramen magnum. Occipital or neck pain, often increased by neck movement, is a common initial manifestation. The pain may radiate also into the shoulders or the ipsilateral arm. In the latter situation, the pain may be similar to that of cervical spondylosis. The neurological signs associated with foramen magnum tumors also may be perplexing. Cranial nerve symptoms and signs are inconstant; nystagmus, often downbeating, impaired sensation over the upper face (caused by involvement of the descending tract of cranial nerve V), and dysarthria, dysphonia, and dysphagia arc present in some patients. Motor system involvement characteristically presents as spastic weakness. The corticospinal tract compression causes weakness that typically begins in the ipsilateral arm and is loll owed by weakness of the ipsilateral leg, spreading to the contralateral leg and then the arm, Alternatively, foramen magnum tumors may cause signs of LMN weakness, atrophy, and depressed reflexes in the arms and hands. The mechanism of this LMN disturbance well below the level of the tumor is uncertain but possibly is secondary to circulatory disturbances affecting the (descending) distribution of the anterior spinal artery. Sensory disturbances consisting of pain and numbness are early manifestations of foramen magnum tumors. Pain and paresthesias affecting the same upper extremity first
362
APPROACH TO COMMON NEUROLOGICAL PROBLfcMS
involved by spastic weakness is an early finding. The sensory disturbances in these patients are often of the dissociated type so patients suffer from loss of pain and temperature sensation but have preserved tactile sensation. In addition, a suspended sensory loss also has been reported in some cases and vibratory sensory loss over the clavicles in others. This pattern of sensory loss may be caused by a secondary syrinx, which may direct attention away from the causative lesion at the cervicomedullary junction. Magnetic resonance imaging (MRI) has become the test of choice for imaging the craniocervical junction.
Upper Cervical Spine Compressive lesions of the upper cervical spine have similar clinical characteristics to those arising at the foramen magnum. Pain in the neck, occipital region, or shoulder is a common presenting complaint. The second cervical root innervates the posterior aspect of the scalp, which explains the pattern of radicular pain. If the compression is at the third or fourth cervical level, radicular pain may be projected to the neck or top of the shoulder. When pain does occur, it is usually provoked by neck movements, resulting in marked limitation of head turning and nodding. With progressive compression, upper extremity weakness usually becomes apparent on the side of pain. The weakness may be of a UMN or LMN type. Some patients therefore may have spasticity and hyper-reflexia and others may have atrophy and hyporeflexia of a portion or the entire upper extremity including the hand. When UMN findings develop in the ipsilateral leg, a spinal hemiplegia is present. Weakness may then progress to the contralateral lower extremity and then the contralateral upper extremity.
Lower Cervical and Upper Thoracic Spine Spinal cord and root compressions at the levels of C5-T1 most frequently betray their presence by radicular symptoms at the affected level in the shoulder or upper extremity in the form of pain and later reflex, motor, and sensory disturbances. With lesions at the C4-C6 level, pain and sensory disturbances are frequently reported along the radial aspect of the arm, forearm, and thumb (see Table 27.2). With intramedullary neoplasms, pain is also common at these levels, but the localization is usually more diffuse and less typically radicular. At the C7-T1 level, pain and sensory symptoms often are localized to the ulnar aspect of the arm, forearm, and hand. Tumors at the Tl and T2 levels often cause pain to radiate into the elbow and hand, together with sensory complaints along the ulnar border of the hand. As at other locations, intramedullary neoplasms usually give rise to more
diffuse symptoms, which are often bilateral. Conversely, extramedullar)' compression often presents with exquisite localizing symptoms. Weakness usually follows pain, particularly at the affected segmental level. As might be expected based on the myotomal map of the upper extremity, intramedullary and extra medullary lesions at the C4-C6 level show a predilection to involve the muscles in the shoulder and upper arm (see Table 27,2), Atrophy and weakness of the hand can rarely occur with lesions at the C4-C6 level. This may be caused by vascular factors affecting the lower cervical segments. Such a pattern of weakness and atrophy is usually caused by a lesion at the C7-T2 level. The pattern of extremity weakness may be a guide in distinguishing intramedullary from extramcdullary disorders. Although exceptions are encountered, extramedullary lesions tend to affect the ipsilateral upper and lower extremity before involving the contralateral side. In contrast, intramedullary lesions may involve both upper extremities before the lower extremities are affected or show bilateral arm and leg involvement from the onset. The deep tendon reflexes are helpful in localizing the segmental level of involvement in the cervical spine. Disease at the C5-C6 level is often associated with depressed biceps (C5), brachioradialis reflex (C6), or both (see Table 27.2). Alternatively, one may encounter depressed biceps and brachioradialis reflexes associated with a hyperactive triceps reflex if there is a compressive myelopathy at the C5-C6 level. Suggestive of cervical spondylosis is a depressed brachioradialis (C6) reflex with hyperactive finger flexors (C8-T1), indicaring a C6 radiculoneuropathy with myelopathy; neoplasms or other diseases at the C6 level may cause a similar clinical presentation. When the lesion is at the C7 level, the triceps reflex may be depressed. With lesions at C8 and T l , the finger flexor response may be impaired. Hoffmann's sign is performed by dorsiflexing the patient's wrist and then flicking the distal phalanx of the middle finger with the examiner's thumb. The patient's middle finger is thus flexed and suddenly extended. When Hoffmann's sign is present, this maneuver is followed by reflex flexion of the patient's thumb and other fingers. When present bilaterally, Hoffmann's sign is usually an indication of hyperactive deep tendon reflexes. Although disease of the pyramidal pathways may be responsible, healthy individuals with hyperactive reflexes may have bilateral Hoffmann's signs such as in the case of anxiety, hyperthyroidism, and stimulatory drugs. When Hoffmann's sign is present unilaterally, it usually signifies disease of the nervous system.
Thoracic Levels The thoracic dcrmatomal landmarks that guide the examiner ro the level of involvement are the nipple (T4),
PARAPLEGIA AND SPTNAI. CORD SYNDROMES Table 27.6:
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Differentiation of con us lesions from cauda equina lesions
Spontaneous pain Motor findings
Sensory findings
Rdk'\ dump's Sphincter disturbance Male sexual function Onset
Cotius medullar is
Cauda equina
Unusual and not severe; bilateral and symmetrical in perineum or thighs Not severe, symmetrical
Often very prominent and severe, asymmetrical, radicular May be severe, asymmetrical, fibrillary twitches of paralyzed muscles arc common
Fibrillary twitches are rare Saddle distribution, bilateral, symmetrical, dissociated sensory loss (impaired pain and temperature sensibility with sparing of tactile sensibility) Lpiconus: only Achilles reflex absent Conns: Achilles and patellar present Early and marked (both urinary and fecal incontinence) Impaired early Sudden and bilateral
Saddle distribution, may be asymmetrical, no dissociation of sensor; loss
Patellar and Achilles reflexes may be absent Late and less severe Impairment less severe Gradual and unilateral
Source: Modified with permission from Dejong, R. N. 1979, The Neurologic Examination, 4th ed, Harper & Row, Hagerstown, Md; Haymaker, W. 1969, Bmg's Local Diagnosis in Neurological Disease, 15th ed, Mosby, St. Louis.
the umbilicus (T10), and the inguinal ligament (LI). Pain or sensory alterations in a radicular distribution are localized to a specific dermatome using these levels as points of reference. The relatively small vertebral canal and the vascular watershed area of the spinal cord at about T6 in the thoracic region make the thoracic spinal cord extremely vulnerable to injury from compression. Consequently, the temporal course of symptoms of cord compression is often shorter in this region than elsewhere in the spine. Thus pain often evolves rapidly into weakness, sensory loss, and reflex abnormalities caudal to the lesion. Sphincter disturbances ultimately develop.
Conus Medullaris and Cauda Equina Lesions of the cauda equina and conus medullaris (Table 27.6) cause similar symptoms and signs including local, referred, and radicular pain, sphincter disturbances, loss of buttock and leg sensation, and leg weakness. Although it may be relatively easy to establish the level of a single radiculopathy based on sensory, motor, and reflex changes, it is much more difficult to assign the cause and localization when several lumbosacral levels are involved. In such situations, one must consider the possibility of a lower spinal cord lesion or a cauda equina syndrome. Although there has been a long effort to differentiate conus medullaris lesions from those of the cauda equina, it is not always possible to accurately discriminate between them. Although rare in its pure form, the conus medullaris syndrome presents with sphincter disturbances, saddle anesthesia (S3-S5), impotence, and absence of lower extremity abnormalities. If the cauda equina is involved, patients may experience difficulty with external rotation and extension of the thigh at the hip,
flexion of the knee, and weakness of all muscles below the knee.
DISTINGUISHING INTRAMEDULLARY FROM EXTRAMEDULLARY LESIONS The earlier sections of this chapter describe several features that help distinguish between intramedullary lesions and extra medullary compressive lesions of the spinal cord. However, as stressed earlier, this may be a vexing clinical problem that ultimately requires elucidation by imaging techniques. The explanation for this clinical experience has been provided by clinicopathological studies of extramedullary spinal neoplasms. It has been demonstrated that extramedullary compression can cause ischemia and demyelination in the posterior and lateral column, with relative sparing of the anterior columns regardless of the location of the extramedullary tumor. Both coup and contrccoup injuries occur in the spinal cord. The areas of infarction and demyelination are often deep and do not follow a specific pattern. In some instances, the pathological findings are more marked ipsilatcral to the tumor, and in other cases, they are primarily contralateral to the mass. It follows therefore that stereotypical clinical patterns of evolution cannot be expected.
CLASSIFICATION OF DISEASES AFFECTING THE SPINAL C O R D This chapter emphasizes the clinical pathophysiology of spinal cord disorders. Table 27.7 lists a classification of disorders that may cause a spinal cord syndrome; discussion of specific diseases can he found elsewhere in
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 27.7:
Differential diagnosis of diseases affecting the spinal cord
Compressive lesions No n-neoplastic Trauma Spondylosis Intervertebral disc herniation Spinal stenosis Infectious disorders (e.g., abscess, tuberculosis) Inflammatory (e.g., rheumatoid arthritis, ankylosing spondylitis, sarcoid) Spinal hemorrhage Syringomyelia
Congenital disorders Arachnoid cysts Paget's disease Osteoporosis Neoplastic Epidural Intradural extramedullar (e.g., meningioma, neurofibroma, and leptomeningeal metastasis) Intramedullary Noncompressive myelopathies Demyelinating (e.g., multiple sclerosis, acute disseminated encephalomyelitis) Viral myelitis (e.g., roster, acquired immunodeficiency syndrome-related myelopathy, human T-lymphotropic virus type 1) Vitamin B12 deficiency and other nutritional deficiencies Infarction
Ischemia and hemorrhage resulting from vascular malformations Spirochetal diseases (syphilis and Lyme disease) Toxic myelopathies (e.g., radiation induced) Autoimmune diseases (e.g., lupus, Sjogren's syndrome) Paraneoplastic Neuronal degenerations Acute and subacute transverse myelitis of unknown cause
Subarachnoid space
Lamina Vertebral body
Nerve root Intervertebral foramen
FIGURE 27.5 Anatomical locations of spine metastases. (A) Intramedullary metastasis is located within the spinal cord. (B) Leptomeningeal metastasis is in the subarachnoid space and is extra medullary and intradural. Epidural metastases arise from the extension of metastases located in one of the adjacent structures: (C) vertebral column; (D) paravertebral spaces via the intervertebral foramina; or rarely, (E) the epidural space itself. As these epidural metastases grow, they compress adjacent blood vessels, nerve roots, and the spinal cord, resulting in local and referred pain, radiculopathy, and myelopathy. (Reprinted with permission from Byrne, T. N. 1992, "Spinal cord compression from epidural metastases," N Engl J Med, vol. 327, pp. 615.)
PARAPLEGIA AND SPINAL CORD SYNDROMES this book. Diseases arc classified according to their etiology and location. With the availability of MRI, this classification permits the clinician to consider the differential diagnosis before and after the imaging has been obtained. Furthermore, because compressive lesions may be surgical emergencies, this classification considers the therapeutic nature of many of the diseases that must be considered.
METASTATIC EPIDURAL SPINAL CORD COMPRESSION Metastatic epidural spinal cord compression (MESCC) deserves special comment because it affects approximately 20,000 patients with cancer in the United Stares annually. Figure 27.5 demonstrates the location of tumors of the spine, distinguishing among intramedullary, extramedull a r , intradural, and extradural tumors. As with other causes of spinal cord compression, the major presenting clinical signs and symptoms of MESCC are pain, weakness, sensory loss, and autonomic disturbance. In approximately 9 5 % of adults and 8 0 % of children, progressive axial, referred, radicular, or all three kinds of pain are the most common initial complaint of both vertebral metastasis and MESCC, Because the neurological prognosis depends directly on the level of neurological function at the time of initiation of therapy, there is a great incentive to make an early diagnosis while the patient is still ambulatory.
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The imaging test of choice in evaluating patients for MESCC is MRI when available in a timely fashion. Alternatively, myelography should be performed when management is delayed by inability to obtain an MRI, in patients unable to undergo MRI (e.g., those with pacemakers and pain precluding recumbency) or when a technically adequate MRI cannot be obtained. The mainstays of treatment include corticosteroids, radiotherapy, and, in selected patients, surgical decompression of the cord. Approximately 8 0 % of patients who arc ambulatory at the initiation of radiotherapy remain so at the end of treatment, whereas fewer than 10% who are paraplegic at the beginning of radiotherapy recover ambulation.
REFERENCES Adams, K. K., Jackson, C, E., Rauch, R. A., et al. 1996, "Cervical myelopathy with false localizing sensory levels," Arch Neurol, vol. 53, pp. 1155-1158 Ryrne, T. N. 1992. "Spinal cord compression from epidural metastases," N Engl J Med, vol. 327, pp. 614-619 Byrne, T. N., Benzel, E. C, & Waxman, S. G. 2000, Diseases of the Spine and Spinal Cord, Oxford University Press, Oxford Ditunno, J. Sc Formal, C. 1994, "Chronic spinal cord injury," N Engl] Med, vol. 330, pp. 550-556 Glcndinning, D. S. & Vierck, C. J. Jr. 1993, "Lack of a proprioceptive defect after dorsal column lesions in monkeys," Neurology, vol. 43, pp. 363-366 Patten, J. 1977, Neurological Differential Diagnosis, SpringerVerlag, New York
Chapter 28 Proximal, Distal, and Generalized Weakness David C. Preston, Barbara E. Shapiro, and Michael H. Brooke Symptoms of Weakness Ocular Muscles Facial and Bulbar Muscles Neck, Diaphragm, and Axial Muscles Proximal Upper Extremity Distal Upper Extremity Proximal Lower Extremity Distal Lower Extremity Bedside Examination of the Weak Patient Observation Muscle Bulk and Deformities Muscle Palpation, Percussion, and Range of Motion Strength Fatigue Reflexes Sensory Disturbances Peripheral Nerve Enlargement Faseiculations, Cramps, and Other Abnormal Muscle Movements
367 368 368 368 369 369 369 369 369 370 370 372 372 373 373 373 374
Functional Evaluation of the Weak Patient Investigating the Weak Patient Serum Creatine Kinase Electromyography Muscle Biopsy Genetic Testing Exercise Testing Approach to the Patient with Weakness Disorders with Prominent Ocular Weakness Disorders with Distinctive Facial or Bulbar Weakness Disorders with Distinctive Shoulder-Girdle or Arm Weakness Disorders with Prominent Hip-Girdle or Leg Weakness Disorders with Fluctuating Weakness Disorders Exacerbated by Exercise Disorders with Constant Weakness Other Conditions
374 376 376 376 377 377 377 378 378 378 379 381 382 382 383 386
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Muscle weakness may be due to disorders of the central or peripheral nervous system (CNS and PNS, respectively), the neuromuscular junction, or the muscle. The neurological examination allows separation of weakness arising from these different locations. If the pattern of weakness is characteristic of upper motor neuron (UMN) weakness {i.e., weakness of the extensors of the upper limbs and the flexors of the lower limbs), together with hyper-reflexia and an extensor plantar response, weakness is clearly of CNS origin. If there is clear sensory impairment, the weakness is likely to arise from dysfunction of the peripheral nerves, nerve roots, or CNS. If there is marked fatigue and weakness involves the extraocular, bulbar, and proximal upper limb muscles, the diagnosis is likely to be myasthenia gravis.
these patterns is the first step in the differential diagnosis of weakness, as certain disorders have a predilection for certain muscle groups. This chapter begins with a discussion of symptoms of muscular weakness, depending on which muscle groups are affected. This is followed by a discussion of the bedside and functional physical examinations and comments on laboratory tests often employed in patients with muscle weakness. The chapter concludes with an approach to the diagnosis of muscle weakness, based on which muscle groups are weak, whether the muscle weakness is constant or fluctuating, and whether the disorder is acquired or inherited.
If weakness is not accompanied by sensory loss, marked fatigue, or signs of CNS involvement, then it is likely to be due to a disorder of the motor unit. The motor unit includes the anterior horn cell, the motor nerve, rhe neuromuscular junction, and the muscle itself. This chapter concentrates on disorders of the motor unit, discussing disorders of the neuromuscular junction and PNS as they enter into the differential diagnosis. The clinical features of motor unit disorders arc determined mostly by which muscles are weak. Muscle weakness changes functional abilities that are more or less specific to the muscle groups affected. Recognizable patterns of symptoms and signs often allow a reasonable estimation of the anatomical involvement. Recognizing
SYMPTOMS OF WEAKNESS As muscles begin to weaken, symptoms depend more on which muscles are involved than on the cause of involvement. A complicating factor in evaluating weakness is the difference in the patient's interpretation of the word weak. Although physicians use the word to denote a loss of muscle power, the patient may use the word more loosely. Even more confusing, many people use the words numb and weak interchangeably. Thus the complaint of weakness should not be taken at face value but should be questioned until it is clearly shown to mean a loss of muscle strength. If the patient has no objective weakness when examined, the clinician must rely on the history. Patients with weak 367
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
muscles have a fairly stereotypical set of symptoms depending on which muscle groups are weak (see the following sections). The patient whose weakness is caused by depression or malingering will have much more vague symptoms, and if leading questions are avoided, the stereotypical symptoms of weakness are seldom volunteered. Instead, patients make statements such as, "I have no strength to do the housework,1" "I just can't do the task," and "I can't climb the stairs because I get so tired and have to rest." When ptcsscd regarding these symptoms, it soon becomes apparent that specific details are lacking. Patients who cannot get out of a low chair because of real weakness explain exactly how they have to maneuver themselves into an upright position (e.g., pushing on the chair arms, leaning forward in the seat, and bracing their hands against the furniture). The examiner should avoid providing patients with the details for which they are searching. Asking patients whether they have to push on the arms of the chair to stand up provides patients with information that can be used later in response to the questions of baffled successive examiners. In addition, it is often difficult to differentiate true muscle weakness from apparent weakness that accompanies tendon or joint contractures or that occurs secondary to pain. For example, patients with primary orthopedic conditions often complain of weakness. However, in these situations, pain with passive or active motion is often a prominent part of the symptoms. In evaluating weakness, the first key task is to discern which muscle groups are affected. In this regard, it is helpful to divide the symptoms of weakness into the following body regions: ocular; facial and bulbar; neck, diaphragm, and axial; proximal upper extremity; distal uppet extremity; proximal lower extremity; and distal lower extremity.
Ocular Muscles Extraocular muscle weakness results in ptosis and/or diplopia. Drooping of the eyelids may be noticed by the patient when looking in the mirror or may be pointed out by family and friends. It is important to keep in mind that older patients occasionally develop ptosis as a consequence of aging (i.e., partial dehiscence of the levator muscles) or as a consequence of ocular surgery (e.g., lens implanrs for cataracts). To differentiate between acute and chronic ptosis, it is often helpful to look at prior photographs or because the ocular myopathies are often familial to look at family photographs. Bilateral ptosis may result in compensatory backward tilting of the neck to look ahead or upward. Rarely, this may lead to neck pain and fatigue as the prominent symptoms. In addition, true ptosis often results in compensatory contraction of the frontalis muscles to lessen the ptosis, resulting in a characteristic pattern of a droopy eyelid with prominent contraction and furrowing of
the frontalis muscle above. Weakness of extraocular muscles may result in diplopia. However, mild diplopia may cause only blurring of vision, sending the patient to the ophthalmologist for new eyeglasses. It is also worth asking the patient if closing one eye corrects the diplopia, because neuromuscular weakness is not among the causes of monocular diplopia.
Facial and Bulbar Muscles Facial weakness is usually experienced by the patient as a feeling of stiffness or sometimes as a twisting or altered perception in the face (note that patients often use the word numbness in describing facial weakness). Drinking through a straw, whistling, and blowing up balloons are particularly difficult tasks and may be sensitive tests for facial weakness, parricularly when such weakness dates from childhood. Acquaintances may notice that the patient's expression is somehow changed. A pleasant smile may turn into a snarl because of weakness of the levator anguli oris muscles in myasthenia gravis. In lower facial weakness, patients may have difficulty with drooling and retaining their saliva, often requiring them to carry a tissue in their hand (socalled "napkin sign," which often accompanies bulbar involvement in amyotrophic lateral sclerosis |ALS|). A common observation in mild long-standing facial weakness, for instance, in facioscapulohumeral (FSH) muscular dystrophy, is a tendency for the patient to sleep with the eyes open from weakness of the orbicularis oculi. Weakness of masticatory muscles may result in difficulty chewing, sometimes with a sensation of fatigue and discomfort, as may occur in myasthenia gravis. Pharyngeal, palatal, and tongue weakness disturbs speech and swallowing. A flaccid palate is associated with nasal tegurgitation, choking spells, and aspiration of liquids. Speech may become slurred, nasal, or hoarse. In contrast to central lesions, there is no problem with fluency or language function.
Neck, Diaphragm, and Axial Muscles Neck muscle weakness is first noticed in situations in which the patient is called on to stabilize the head. Riding as a passenger in a car when the brake or the accelerator is used, particularly in an emergency situation, may be disconcerting for the patient with neck weakness because the head tocks forward or backward. Similarly, when the patient is stooping or bending forward, weakness of the posterior muscles may cause the chin to fall on the chest. A patient with neck flexion weakness often notices difficulty lifting the head off the pillow in the morning. As neck weakness progresses, patients may develop the L 'dtopped head" syndrome, in which they can no longer extend the neck and their chin rests against the chest (Figure 28.1).
PROXIMAL, DISTAL, AND GENERALIZED WEAKNESS
369
Difficulty with activities that require dextetity is often noticed first, such as buttoning and using a zipper. With further decreased hand strength, other activities are affected, especially opening a jat, turning on a faucet or the car ignition, using a key, holding silvetware, writing, or opening a car door.
Proximal Lower Extremity
FIGURE 28.1 Dropped head syndrome. In severe weakness of the neck extensor muscles, patients can no longer extend the neck and their chin rests against the chest.
This posture leads to several secondary difficulties, especially with vision and swallowing. When diaphragm muscles weaken, patients often develop shortness of breath, especially when lying flat or with exertion, and these symptoms can be mistaken for lung or heart disease. Severe diaphragmatic weakness leads to hypoventilation and carbon dioxide retention. This may first manifest as morning headaches and/or vivid nightmares. Latet, hypercapnia results in sedation and a depressed mental state. Rarely, axial and trunk muscles can be involved early in the course ol a neuromuscular disorder. Weakness ol the abdominal muscles may make sit-ups impossible. Focal weakness of the lower abdominal muscles results in an obvious protuberance that superficially mimics an abdominal hernia. Patients with weakness of the paraspinal muscles are unable to maintain a straight posture when sitting or standing as compared to lying on the bed (socalled "bent spine" syndtome).
Proximal Upper Extremity A feeling of tiredness is often the first expression of shoulder weakness. The weight of the arms is sufficient to cause fatigue. Eatly on, the patient expetiences fatigue on performing sustained tasks with the hands held up, especially over the head. The most problematic activities include painting the ceiling, shampooing ot combing the hair, shaving, or simply trying to lift an object off a high shelf.
Weakness of the proximal lower extremity is often responsible for the earliest symptoms experienced by patients who develop weakness. Patients notice that they have difficulty arising from the floor or horn a low chair and have to use the support of the hands ot knees. Getting out of a bath or a toilet without handrails is particularly difficult. Older patients may interpret this as arthritis or some similar minor problem. Walking becomes clumsy, and the patient may stumble. In descending stairs, people with quadriceps weakness tend to keep the knee locked and stiff. If the knee bends slightly as the weight of the body is transferred to the lower stair, the knee may collapse. Greater problems coming down staits than going up suggest quadriceps weakness, whereas the reverse is true for hip extensor weakness. Once patients with hip-girdle weakness are up and on level ground, they feel more secure. Howevct, others will often notice an obvious change in their gait. Patients with hip-girdle weakness often develop a waddling gait, because weakness of the hip abductors of the weight-bearing leg results in the hip falling as the patient walks (a Trendelenburg gait).
Distal Lower Extremity Weakness of the distal lower extremity is most often manifested by symptoms of the antetiot compartment (i.e., peroneal) muscles. Weakness of the anterior tibial and ankle evertor muscles often results in tripping, even over small obstacles, and an increased tendency to sprain the ankle repeatedly. If the weakness becomes severe, a footdrop is noted, and the gait assumes a slapping quality. To compensate for a dropped foot, patients must raise their knee higher when they walk, so the dropped ankle and toes cleat the floor (i.e., steppage gait). Weakness of both anterior and postetiot muscles of the lower leg often makes the stance unstable, which causes the patient to complain of poor balance. Isolated weakness of the posterior calf makes standing on tiptoes impossible.
Distal Upper Extremity
BEDSIDE EXAMINATION OF THE WEAK PATIENT
Hand and forearm weakness is easily noticed because it interferes with so many common activities of daily living.
The neurological examination of patients with muscle weakness is the same as that used for patients with other
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neurological problems. However, special attention to the observation and functional evaluation of the patient are particularly rewarding in the patient with weakness.
Observation It is useful to spend a few moments observing the patient and noting natural posture and motion. When patients, particularly children, are aware that they arc being examined, they often concentrate on performing as normally as possible. When unaware of scrutiny, their posture and movements may be more natural. At one time or ::.n(>iikT, wc ha\e heard the parents' exasperated cry, "He never does it that way at home." For example, ptosis may be obvious on inspection of the head and neck. The more severe the ptosis, the greater is the patient's tendency to throw the head backward. The eyebrows are elevated and the forehead is wrinkled in an attempt to raise the upper lids. This is sometimes so successful that ptosis is apparent only when the examiner smooths out the wrinkled forehead and allows the eyebrows to assume a more normal position, Psychogenic ptosis is easy ro detect because raising of the lower lid (due to contraction of both parts of the orbicularis oculi muscle, i.e., blepharospasm) accompanies the lowered upper lid. Weakness of the face that has been present since childhood may give a smooth, unlined appearance to the adult face. In addition, facial expression is diminished or altered. A smile may become a grimace or snarl, with eversion of the upper lip. The normal blink may be slowed or eyelid closure may be incomplete so the sclera is always visible. The normal preservation of the arch of the upper lip may be lost, and the mouth may assume either a tented or a straight-line configuration. Actual wasting of the facial muscles is difficult to see, but temporal and massctcr atrophy produces a characteristic scalloped appearance above and below the cheekbone. Because the hairstyle may be rearranged to cover the wasting, the examiner should make a conscious effort to check the upper portion of the face. The tongue should be inspected for atrophy and fasciculations. This is best accomplished by inspecting the tongue at rest with the mouth open looking for random, irregular twitching movements of fasciculations. When the tongue is fully protruded, many patients will have some normal quivering movements. It is wise to diagnose fasciculations of the tongue only when atrophy is associated, Facial weakness causes the normal labial sounds (that of p and b) to be softened. The examiner with a practiced car can detect other alterations of speech. Lower motor neuron (LMN) involvement of the palate and tongue gives the speech a hollow, nasal, echoing timbre, whereas U M N dysfunction causes the speech to be monotonous, forced, and strained. Laryngeal weakness may also be noticed in speech when the voice becomes harsh or brassy, often
associated with the loss of the glottal stop {the small sound made by the larynx closing, as at the start of a cough). Weakness of the shoulder muscles causes a characteristic change in posture. Normally, the shoulders are braced back by the tone of the muscles, so the thumbs tend to face forward when the arms are held by the side. As the shoulder muscles lose their tone, the point of the shoulder rotates forward. This forward rotation of the shoulder is associated with a rotation of the arm, so that the backs of the hands now face forward. Additionally, the loss of tone causes a rather loose swinging movement of the arms in normal walking. When shoulder weakness is severe, the patient may fling the arms by using a movement of the trunk, rather than lifting the arms in the normal fashion. In the most extreme example, the only way the patient can get the hand above the head is to use a truncal movement to throw the whole arm upward and forward so the hand rests on the wall, and then to creep the hand up the wall using finger movements. Atrophy of the pectoral muscles leads to the development of a horizontal or upward sloping of the anterior axillary fold. This is particularly seen in FSH muscular dystrophy, The examiner may observe winging of the scapula, a characteristic finding in weakness of muscles that normally fix the scapula to the thorax {i.e., the serratus anterior, rhomboid, or trapezius). As these muscles become weak, any attempted movement of the arm causes the scapula to rise off the back of the rib cage and protrude like a small wing. The arm and shoulder may be thought of as a crane: The boom of the crane is the arm and the base is the scapula. Obviously, if the base is not fixed, any attempt to use the crane results in the whole structure falling over. This is how it is with attempts to elevate the arm; the scapula simply pops off the back of the chest wall in a characteristic fashion. In the most usual type of winging, the entire medial border of the scapula protrudes backward. In some diseases, particularly FSH muscular dystrophy, the inferomedial angle juts out first, and the entire scapula rotates and rides up over the back. This is often associated with a trapezius hump, in which the middle part of the trapezius muscle, in the web of the neck, is mounded over the upper border of the scapula (Figure 28.2). A word of caution pertains to the examination of the slender person or a child, in whom a prominent shoulder blade is often seen. The shoulder configuration returns to normal, however, when the individual attempts to use the arm forcibly, as in a push-up.
Muscle Bulk and Deformities The examination of muscle bulk, looking both for atrophy and hypertrophy, is an important part of the neuromuscular examination. Prominent muscle wasting usually accompanies neurogenic disorders associated with axonal loss. However, severe wasting can also be seen in chronic
PROXIMAL, DISTAL, AND GENERALIZED WEAKNESS
371
FIGURE 28.2 The scapular winging of facioscapulohumeral muscular dystrophy is distinguished by the prominent protrusion of the inferior medial border of the scapula. When viewed from the front, the elevation of the scapula under the trapezius muscle produces the trapezius hump. myopathic conditions. Wasting is most often best appreciated in the distal hand and foot muscles and around bony prominences. In the upper extremity, wasting of the intrinsic hand muscles produces the characteristic claw hand, in which the thumb rotates outward so that it lies in the same plane as the fingers; the interphalangeal joints are slightly flexed and the metacarpophalangeal joints are slightly extended (the simian hand). Wasting of the small muscles leaves the bones easily visible through the skin, resulting in the characteristic guttered appearance of the back of the hand. In the foot, one of the easier muscles to inspect is the extensor digitorum brevis, a small muscle on the lateral dorsum of the foot that helps to dorsiflex the toes (Figure 28.3). It often wastes early in neuropathies and anterior horn cell disorders. In myopathic conditions in which proximal muscles are affected more than distal muscles, the extensor liis'jtoiuni brevis may actually hypertrophy to try to compensate for weakness of the long toe dorsiflexors above. Muscle mass of the leg is so variable among people that it is sometimes difficult to decide whether the muscles are wasted. Any marked asymmetry indicates an abnormality, but distinguishing a slender thigh from quadriceps muscle atrophy is often difficult. One way to try to distinguish these conditions is to ask the patient to tighten the knee as firmly as possible. The firm medial and lateral bellies of the normal quadriceps that bunch up in the distal part of the thigh just above the knee fail to appear in the wasted muscle. The same technique may be used to evaluate anterior tibial wasting. In a severely wasted muscle, a groove on the latetal side of the tibia (which should be filled by the anterior tibial muscles) is apparent. A moderate
degree of wasting is difficult to distinguish from a thin leg, but if the patient is asked to dotsiflcx the foot, the wasted muscle fails to develop the prominent belly seen in a normal muscle. Abnormal muscle hypertrophy is uncommon but may be a key finding when present. Beyond the expected increase in muscle bulk that accompanies exercise, generalized muscle hypertrophy is seen in patients with myotonia congenita
FIGURE 28.3 Extensor digitorum brevis (EDB) muscle {arrow) is a small muscle on the lateral dorsum of the foot, which helps dorsiflex the toes. It often wastes early in neuropathic conditions but may become hypcrtrophicd in proximal myopathic conditions.
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and paramyotonia congenita, giving them the appearance of weight lifters. Hypertrophy is a common finding in the rare syndrome of acquired ncuromyotonia, in which the continuous discharge of motor axons results in the muscle effectively exercising itself. Exceptionally, hypertrophy can be seen in chronic denervating disorders, especially in the posterior calf muscle in SI radiculopathies. Electromyography (EMG) of these patients often reveals spontaneous discharges in these muscles (usually complex repetitive discharges) as a consequence of the chronic denervation. In contrast, there are conditions in which muscle hypertrophy is not from true muscle enlargement but from infiltration of fat, connective tissue, and other material (i.e., pseudohypertrophy). Focal hypertrophy may be seen in calf muscles of patients with Duchenne's and Becker's muscular dystrophy, as well as in patients with the limb-girdle muscular dystrophies, spinal muscular atrophies (SMA), and in some glycogen storage disorders. Similarly, hypertrophy may also be seen rarely in sarcoidosis, cysticercosis, amyloidosis, hypothyroid myopathy, and focal myositis. Palpable masses in muscles may be seen with muscle tumors, ruptured tendons, or muscle hernias. Several bony deformities are often important clues in neuromuscular conditions. Proximal and axial muscle weakness often leads to scoliosis. Intrinsic foot muscle weakness, present from childhood, often leads to the characteristic foot deformity of pes cavus, in which the arch is high, the foot is foreshortened, and hammer toes, where the toes are cocked up (Figure 28.4). Pes cavus is a sign that weakness has been present at least since early
childhood and implies a genetic disorder in most patients. Likewise, a high-arched palate often develops from chronic neuromuscular weakness present from childhood,
Muscle Palpation, Percussion, and Range of Motion Palpation and percussion of muscle provide additional information. Fibrotic muscle may feel rubbery and hard, whereas denervated muscle may separate into separate strands that can be rolled under the fingers. Muscle in inflammatory myopathies or rheumatologic conditions may be tender to palpation, but severe muscle pain on palpation is unusual. An exception to this is the patient experiencing an acute phase of viral myositis or rhabdomyolysis, whose muscles may be very sensitive to either movement or touch. Percussion of muscle may produce the phenomenon of myotonia, in which a localized contraction of the muscle persists for some seconds after percussion. This is best noted percussing the thenar eminence and watching for a delayed relaxation of the thumb abductors. This phenomenon, which is characteristic of myotonic dystrophy and myotonia congenita, is to be distinguished from myoedema, which is found occasionally in patients with thyroid disorders and other metabolic problems. In myoedema, the percussion is followed by the development of a dimple in the muscle, which then mounds to form a small hillock. In addition to its diagnostic value, the presence of muscle contracture across a joint may cause disability, even in the absence of weakness. Thus an evaluation of range of morion at major joints is an important part of the cluneal examination. In a standard examination, contractures are evaluated at the fingers, elbows, wrists, hips, knees, and ankles. Wrist and finger flexor contractures can be evaluated only with the fingers extended; otherwise, the dorsiflcxion of the wrist is compensated for by flexion of the fingers. At the hips, both flexion and iliotibial band contractures should be evaluated.
Strength
FIGURE 28.4 Pes cavus is caused by intrinsic foot muscle weakness present as a child develops. It is recognized as a high arch, foreshortened foot, and hammer toes. It is often a sign that weakness has been present since early childhood and implies an inherited disorder in most patients.
Evaluation of individual muscle strength is an important part of the clinical examination. Many methods are available. Fixed myomctry has become popular with the research community. This uses a strain gauge attached to a rigid supporting structure, often integrated into the examining couch on which the patient lies. The patient then uses maximum voluntary contraction, which can be quantitated in Newtons. The merits of this method are debated, and for the average clinician, the expense of the machinery is prohibitive. In an office situation, and in many clinical drug trials, manual muscle testing gives perfectly adequate results and is preferable to fixed myometry in young children. It is based on the Medical Research Council grading system with some modification (Table 28.1).
PROXIMAL, DISTAL, AND GENERALIZED WEAKNESS Table 28.1: The Medical Research Council scale for grading muscle strength 0 1 2 3 4 5
No contraction Flicker or trace of contraction Active movement, with gravity eliminated Active movement against gravity Active movement against gravity and resistance Normal power
This is adequate for use in an office situation, particularly if it is supplemented by the functional evaluation. A scale of 0-5 is used. Grade 5 is normal strength. A grade 5 is used only if the examiner is certain that a muscle is normal and should not be used for muscles that are slightly weak. Muscles that can move the joint against resistance may vary quite widely in strength; grades of 4 + , 4, and 4— are often used to indicate differences, particularly between one side of the body and the other. Grade 4 represents a wide range of strength, from slight weakness to moderate weakness, which is a disadvantage. For this reason, the scale has been more useful in following the average strength of many muscles during the course of a disease, rather than the course of a single muscle. Averaging the scores of many muscles smooths out the stepwise progression noted in a single muscle and may demonstrate a steadily progressive decline in an illness. Grade 3+ is used when the muscle can move the joint against gravity and can exert a tiny amount of resistance but then collapses under the pressure of the examiner's hand. It is not used to denote the phenomenon of sudden give way, which occurs in conversion disorders and in patients limited by pain. Grade 3 indicates that the muscle can move the joint throughout its full range against gravity, but not against any added resistance. Sometimes, particularly in muscles acting across large joints like the knee, the muscle is capable of moving the limb partially against gravity, but not through the full range of movement. A muscle that cannot extend the knee horizontally when in a sitting position but can extend the knee to within 30-40 degrees of horizontal is graded 3—. Grades 2, 1, and 0 are as defined in Table 28.1. Although it is commendable and sometimes essential to examine each muscle separately, most of us test muscle groups rather than individual muscles. In our clinic, we test neck flexion, neck extension, shoulder abduction, internal rotation, external rotation, elbow flexion and extension, wrist flexion and extension, finger abduction and adduction, thumb abduction, hip flexion and extension, knee flexion and extension, ankle dorsiflexion and plantar flexion, and dorsiflexion of the great toe.
Fatigue Fatigue is a common symptom in many neuromuscular disorders and in many medical conditions. Anemia, heart
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disease, lung disease, cancer, poor nutrition, and depression are among the many disorders that can result in fatigue. However, in certain neuromuscular conditions, strength is normal at rest but progressively worsens with use. This most often occurs in the postsynaptic neuromuscular transmission disorders, especially myasthenia gravis. Repetitive or sustained muscle resting brings out true muscle fatigue. In patients with a suspected neuromuscular transmission disorder, fatigue should be formally tested. Ptosis may be provoked by sustained upgaze for 2-3 minutes. Counting out loud from 1-100 may result in the voice becoming slurred, nasal, or hoarse. Repetitively testing the strength of shoulder abduction or hip flexion may result in progressive weakness in patients with myasthenia gravis.
Reflexes In disorders of the motor unit, reflexes are either normal, reduced, or absent. ALS is the exception because both UMN and LMN dysfunction coexist and hyperreflexia and spasticity often accompany signs of LMN loss. In neurogenic disorders, demyelinating conditions tend to lose reflexes early, as occurs in Guillain-Barre syndrome from blocking and desynchronization of muscle spindle afferents and motor efferents. Disorders resulting in axonal loss depress reflexes in proportion to the amount of axonal loss. As most axonal neuropathies predominantly affect distal axons, the distal reflexes (ankle reflexes) are depressed or lost early and the more proximal ones remain normal. In myopathies, reflexes tend to be diminished in proportion to the amount of muscle weakness. The same is true for postsynaptic neuromuscular transmission disorders. Presynaptic neuromuscular transmission disorders (e.g., Lambert-Eaton myasthenic syndrome) tend to have depressed or absent reflexes at rest that can be elicited after brief (10 seconds) periods of exercise.
Sensory Disturbances Disorders of the motor unit are generally not associated with disturbances of sensation unless there is a second superimposed condition. Motor neuron disorders, neuromuscular transmission disorders, and myopathies generally follow this rule. Among the few exceptions is the minor sensory loss in patients with X-linked spinobulbar muscular atrophy (Kennedy's disease) and inclusion body myositis, in which some coexistent degeneration of the peripheral nerves and dorsal root ganglion cells may occur. In the paraneoplastic Lambert-Fa ton myasthenic syndrome, patients often have minor sensory signs reflecting a more widespread paraneoplastic process. Sensory findings often accompany peripheral neuropathies that are predominantly motor and usually thought of
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as motor ncuroparhies. These include the Guillain-Barre syndrome, multifocal motor neuropathy with conduction block, Charcot-Maric-Tooth disease, and some toxic neuropathies (e.g., lead). In these conditions, sensory abnormalities on examination and/or electrophysiological testing help identify the disorder as a neuropathy and thus limit the differential diagnosis.
Peripheral Nerve Enlargement
cle relieves the cramp. Superficially, a muscle contracture that occurs in a metabolic myopathy may resemble a cramp, although it is completely different on electrophysiological testing. Electrical silence occurs during a contracture and numerous motor units fire at high frequencies during a cramp.
Functional Evaluation of the Weak Patient Walking
Palpation of peripheral nerves may yield important information in several neuromuscular conditions. Diffusely enlarged nerves occur in some patients with chronic demyclinating peripheral neuropathies, especially Charcot-MarieTooth disease type 1, Dejerine-Sottas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), and Refsum's disease. In addition, nerves may be focally enlarged in the presence of a nerve sheath tumor (neurofibromatosis) or with infiltrative lesions (e.g., amyloidosis, leprosy). Nerves that are often easily palpated include the greater auricular nerve in the neck, the ulnar nerve at the elbow, 111L- superficial radial sensory nerve ;i\ il crosses the extensors to the thumb distal to the wrist, and the peroneal nerve at the fibular head at the knee.
Fascicurations, Cramps, and Other Abnormal Muscle Movements All limbs should be examined to determine the presence or absence of fascicular ions. Fasciculations are brief twitches caused by the spontaneous firing of one motor unit. Fasciculations may be difficult or impossible to see in infants or obese individuals. They can be present in normal people, so their presence in the absence of wasting or weakness is probably of no significance (benign fasciculations). Fasciculations that are widespread and seen on every examination may indicate denervating disease, particularly anterior horn cell disease. Mental or physical fatigue, caffeine, cigarette smoking, or drugs such as amphetamines exacerbate fasciculations. Patients whose fasciculations appear benign should be re-evaluated after avoiding exposure to exacerbating factors. Abundant fasciculations may be difficult to differentiate from myokymia, which is a more writhing, bag of worms-like motion of muscle. Myokymia is caused by repetitive bursting of a motor unit (i.e., grouped fasciculations) and is characteristically associated with certain neuromuscular conditions (e.g., radiation injury and GuillainBarre syndrome). Similar to fasciculations, cramps may be a benign phenomenon or accompany a variety of neuropathic conditions. Cramps are painful and occur when a muscle is contracting in a shortened position. During a cramp, the muscle becomes hard and well defined. Stretching the mus-
Gait is altered by weakness of muscles of the hip and back, leg, and shoulder. In normal walking, when the heel hits the ground, the shock is taken up by the action of the hip abductors, which stabilize the pelvis. In a sense, the hip abductors act as shock absorbers; their weakness disturbs the normal fluid movement of the pelvis during walking so when the heel hits the ground, the pelvis dips to the other side; when the weakness is bilateral, this results in a waddle. Additionally, weakness of the hip extensors and back extensors makes it difficult for the patient to maintain a normal posture. Ordinarily the body is carried so the center of gravity is slightly forward of the hip joint. To maintain an erect posture, the hip and back extensors are in continual activity. If these muscles become weak, the patient often throws the shoulders back so the weight of the body falls behind the hip joints. This accentuates the lumbar lordosis. Alternatively, if there is much weakness of the quadriceps muscles, the patient stabilizes the knee by throwing it backward. When the knee is hyperextended, it is locked; it derives its stability from the anatomy of the joint, not from the support of the muscles. Finally, weakness of the muscles of the lower log may result in a steppage gait, in which dorsiflexion of the foot is affected by a short throw at the ankle midswing. The foot is then brought rapidly to the ground before the toes fall back into plantar flexion. Shoulder weakness may be noted as the patient walks; the arms hang loosely by the sides and tend to swing in a pcndular fashion, rather than with a normal conrrolled swing. Arising from the Floor The normal method for arising from the floor depends, to a certain extent, on the age of the patient. The young child can spring rapidly ro his or her feet without the averageobserver being able to dissect the movements. The elderly patient may turn to one side, place a hand on the floor, and rise to a standing position with a deliberate slowness. In spite of this vatiability, abnormalities caused by muscle weakness are easily detected. The patient with hip muscle weakness will turn to one side or the other to put the hand on the floor for support. The degree of turning is proportional to the severity of the weakness. Some patients have to turn all the way around until they are in a prone
PROXIMAL, DISTAL, AND GENERALIZED WEAKNESS position before they draw their feet under them to begin the standing process. Most people arise to a standing position from a squatting position, but the patient with hip extensor and quadriceps muscle weakness finds it easier to keep the hands on the floor and raise the hips high in the air. This has been termed the butt-first maneuver; the patient forms a triangle, with the hips at the apex and the base of support provided by both hands and feet on the floor, and then laboriously rises from this position, usually by pushing on the thighs with both hands to brace the body upward. The progress of recovery or progression of weakness can be documented by noting whether the initial turn is greater than 90 degrees, whether unilateral or bilateral hand support is used on the floor and thighs, whether this support is sustained or transitory, and whether there is a butt-first maneuver. The entire process is known as
Gower's maneuver, but it is useful to break it up into its component parts (Figure 28.5).
Stepping onto a Stool For a patient with hip and leg weakness, stepping onto an 8inch-high footstool is equivalent in difficulty to a normal person's stepping onto a table. This analogy is apt because similar maneuvers are performed in both cases. Whereas the patient with normal strength readily approaches a footstool and easily steps onto it, the patient with weakness often hesitates in front of the stool while contemplating the task, There then occurs a curious little maneuver that is known colloquially as the fast-foot maneuver. Normal individuals can easily take the weight of their body on one leg, straightening out the knee as they stand on the footstool. Patients with weakness feel unsafe. They like to get both feet under them before straightening the knees and arising to their full height. To accomplish this, they place one foot on the footstool. While the knee of this leg is still bent, they quickly transfer the other foot from the floor to the footstool and then straighten the knees. This gives the impression of a hurried transfer of the trailing foot from floor to footstool, hence the name fait foot. As the weakness increases, the pelvis may dip toward the floor as the leading leg takes up the straiti and the patient's weight is transferred from the foot on the floor to the foot on the stool, the so-called hip dip. Finally, if the weakness is severe, patients may either use hand support on the thighs or gather themselves in and throw their bodies onto the footstool. Analysis of the various components, the hesitation, fast foot, hip dip, and throw, together with the presence or absence of hand support, may provide a sensitive measure of changes in an illness. Psychogenic
FIGURE 28.5 Gowers' maneuver. (A) Butt-first maneuver as the hips are hoisted in the air. (B) Hand support on the thighs.
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Weakness
An experienced examiner should be able to differentiate real weakness from psychogenic weakness. The primary characteristic of psychogenic weakness is that it is unpredictable and fluctuating. Muscle strength may suddenly give out when being evaluated. The patient has a difficult time knowing exactly how much strength is expected and therefore cannot adequately counter the examiner's resistance. This gives rise to a wavering, collapsing force. Tricks may be used to bring out the discrepancy in muscle performance when the patient is being tested and not aware of being observed. For example, if the thigh cannot be lifted off the chair in a seated position because of weakness, then the legs should not be able to swing up onto the mattress when the patient is asked to sit on the examining table. When an examiner suspects that weakness of shoulder abduction is feigned, the patient's arm can be put in abduction, with the examiner's hand on the elbow, and the examiner can instruct the patient to push toward the ceiling.
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At first, the downward pressure is kept very light and the patient is unable to move the examining hand toward the ceiling. However, the arm does not fall down either, and as the downward pressure is gradually increased, continued exhortation to push the examiner's hand upward results in increasing resistance to the downward pressure. The examiner ends up putting maximum weight on the outstretched arm, which remains in abduction. The examiner concludes that the strength is normal. Patients do not realize this because they believe that because they did not move the examiner's hand upward, they must be weak.
INVESTIGATING THE WEAK PATIENT In the investigation of diseases of the motor unit, the most helpful tests are measurement of the serum concenrration of creatine kinase (CK), elec trod i a gnosis, and muscle biopsy, which are available to virtually all physicians. Genetic testing is being used increasingly for definitive diagnosis. In addition, if facilities are available, exercise testing can provide useful information.
Serum Creatine Kinase The usefulness of measuring the serum CK concentration in the diagnosis of neuromuscular diseases is to differentiate between neurogenic disease, in which there may be normal or mild to moderate elevations of CK, and myopathics, in which the CK concentration is often markedly increased. Serial CK measurements may be used to follow the progress of the disease. Both of these uses have problems. Foremost is the determination of the normal level. A survey of 250 hospitals in Ontario, Canada, showed a surprising ignorance of the basic mechanisms involved in the test and the way in which normal values were derived. Some hospital laboratories were unaware that race, gender, age, and activity level must be taken into account in determining normal values. When blood samples are obtained from truly normal controls and not from inactive hospital patients who happen not to have overt muscle disease, the normal serum CK concentration is higher than anticipated. Furthermore, all studies on CK concentration show that values are affected by gender and race. A log transformation does much to convert this to a normal distribution curve, but even then the results are not perfect. In a survey of 1500 hospital employees, using carefully standardized methods, it was possible to detect three populations, each with characteristic CK values. The upper limits of normal (97.5 percentile) are as follows: Black men only: 520 U/liter Black women, non-black men: 345 U/liter Non-black women: 145 U/liter
The non-black population included Hispanics, Asians, and whites. Because the upper limit is expressed as a percentile of the mean, it must be understood that by definition 2 . 5 % of the normal population will be above that. Although this does not seem to be a large number, in a town of 100,000, it means that 2500 would be considered abnormal. The point is that the upper limit of normal CK concentration is not rigid and should be interpreted intelligently. The serum CK concentration can be useful in determining rhe course of an illness, although again judgment should be used because changes in CK values do not always mirror the clinical condirion. In treating inflammatory myopathies with immunosuppressive drugs Or corticosteroids, a steadily declining CK concentration is a reassurance, whereas concentrations that are creeping back up again when the patient is in remission are not. Serum CK concentrations also can be used to determine whether an illness is monophasic. A bout of myoglobinuria may be associated with very high concentrations of CK. The concentration then declines steadily by approximately 5 0 % every 2 days. This indicates that a single episode of muscle damage has occurred. Patients with CK concentrations that do not decline in this fashion or that vary from high to low on random days have an ongoing illness that should be treated as such. Interestingly, CK concentrations may be elevated as high as 10 times normal in patients with spinal muscular atrophy and occasionally in those with ALS (see Chapter 80). Finally, exercise may cause a marked elevation in CK, which usually peaks 12-18 hours after the activity but may occur days later. CK concentrations are more likely to increase in people who are sedentary and then undertake unaccustomed exercise than in a trained individual.
Electromyography The EMG is an observer-sensirive study, and an experienced electromyographer is essential to interpret EMG correctly. The principles of EMG are discussed in Chapter 36B. The EMG may provide much useful information. An initial step in the assessment of the weak patient is determination of whether the disease is caused by a neuropathic, myopathic, or neuromuscular junction transmission disorder. Nerve conduction studies and needle electrode examination arc particularly useful for identifying neuropathic disorders and localizing the abnormality to anterior horn cells, roots, plexus, or peripheral nerve territories (see Chapters 80-82). Repetitive nerve stimulation and single-fiber EMG can aid in elucidating disorders of the neuromuscular junction. Needle electrode examination may help establish the presence of abnormal muscle activity, including acute and chronic denervation, myotonia, neuromyotonia, fascicular ions, cramps, and myokymia.
PROXIMAL, DISTAL, AND GENERALIZED WEAKNESS
Muscle Biopsy The use of muscle biopsy is important for establishing the diagnosis in most disorders of the motor unit. Histochemistry evaluation is available at most hospitals and is particularly useful, and electron microscopy may provide a specific diagnosis. An important newer aspect of the muscle biopsy is the analysis of the muscle proteins. Individual muscle proteins, including dystrophin, sarcoglycans, and other structural proteins, may be missing in specific illnesses, and diagnosis is definitive with these analyses. The details of muscle biopsy are reviewed in Chapter 85, but a word about the selection of the muscle to be biopsied is appropriate here. In all biopsies, there is a risk of sampling error. Not all muscles are equally involved in any given disease, and it is important to select a muscle that is likely to give the most useful information. The gastrocnemius muscle, which is often chosen for muscle biopsy, is not ideal because it has the disadvantage of demonstrating type 1 fiber predominance in the normal individual and often shows denervation changes caused by minor lumbosacral radiculopathy. Also, it has more than its fair share of random pathological changes, such as fiber necrosis and small inflammatory infiltrates, even when no clinical suspicion of a muscle disease exists. For this reason, it is preferable to select either the quadriceps femoris or the biceps brachii if cither of these muscles is weak. Never perform a biopsy on a muscle that is the site of a recent EMG or intramuscular injection, because these produce focal muscle damage. If such a muscle has to be biopsied, allow at least 2-3 months after the procedure before performing the biopsy. In the patient with a relatively acute (duration of weeks) disease, it is wise to select a muscle that is obviously clinically weak. In patients with long-standing disease, it may be better to select a muscle that is clinically fairly normal to avoid an end-stage muscle. Sometimes an apparently normal muscle is selected for biopsy. For example, in a patient who is suspected of having motor neuron disease and who has wasting and weakness of the arms with EMG changes of denervation in the arms but no apparent denervation of the legs, biopsy of the biceps muscle would show the expected denervation and would add no useful information. If a biopsy of a quadriceps muscle showed denervation, this would provide support for widespread denervation, supporting the diagnosis of motor neuron disease. However, if the biopsy from the quadriceps muscle was normal, this would make the diagnosis of ALS less likely, because even strong muscles in patients with ALS usually show some denervation. Biopsies are generally not indicated in patients with ALS, unless the diagnosis is in question.
Genetic Testing The details of genetic testing and counseling are covered in Chapter 44. Genetic analysis has become a routine part of
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the clinical investigation of neuromuscular disease and in many situations has supplanted muscle biopsy and other diagnostic tests. This is a distinct advantage to the patient if a blood test may be substituted for a muscle biopsy. The use of genetic testing for diagnosis in an isolated individual implies that the gene is well characterized and that intragenic probes are available that allow the determination of whether the gene in question is abnormal. Examples of such abnormalities are deletions in the dystrophin gene seen in many cases of Duchenne's muscular dystrophy and the expansion of the triplet repeat in the myotonic dystrophy gene. Linkage studies can be used when the location of the gene is known, but tests for mutations of the gene itself arc not available. The success of such studies depends on having probes that are close to the gene. By using these closely situated probes, one can often demonstrate that the individual is or is not carrying the part of the chromosome (in which ;ui involved gene must have occurred in another affected family member. For linkage studies to be successful, a sufficient number of family members must be available for testing, both with and without the illness, to allow an identification of the segment of the chromosome at fault. This type of study is hampered by the tendency of parts of the chromosome to become detached during mciosis and to be exchanged with parts of another chromosome, a phenomenon known as recombination. The closer the probe is to the actual gene, the less likely recombination is to separate them. Genetic counseling based on linkage studies is less likely to be successful when only one or two patients with the illness and few family members are available. It is difficult to keep up with the mushrooming list of genes known to be associated with neuromuscular diseases, and yet it is imperative if we are to provide suitable advice for our patients. Useful references arc found in the journal Neuromuscular Disorders, which carries a list of all known neuromuscular generic abnormalities each month, and the Web sites Online Mcndelian Inheritance in Man (www. ncbi.nlm.nih.gov/omim/) and GeneTests-GeneClinics(www. genetests.org),
Exercise Testing Exercise testing may be an important part of the investigation of muscle disease, particularly in metabolic disorders. The two primary types of exercise tests that are used are forearm exercise and bicycle exercise. Forearm (grip) exercise has been designed ro provide a test of glycolytic pathways, particularly those involved in power exercise. Incremental bicycle ergometry gives additional information regarding the relative use of carbohydrates, fats, and oxygen. Forearm exercise is performed according to several schedules. The traditional method is to ask the patient to
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grip a dynamometer repetitively, with a blood pressure cuff on the upper arm raised above systolic pressure. If the work performed by rhe patient is sufficiently strenuous, the cuff is unnecessary, because the muscle is working at a level that surpasses the ability of blood-borne substances to sustain it. An adequate level of forceful exercise is maintained for 1 minute, and then venous blood is drawn at intervals after the exercise to monitor changes in metabolites. In the norma] individual, the energy for such short-duration work is derived from intramuscular glycogen. Lactate is formed when exercise is relatively anaerobic, as it is when the exercise is strenuous. Additionally, serum concentrations of hypoxanthinc and ammonia are elevated. Patients with defects in the glycolytic pathways produce normal to excessive amounts of ammonia and hypoxanthine, but no lactate. Patients with adenylate deaminase deficiency show the reverse situation; ncithet ammonia nor hypoxanthine appears, but lactate production is normal. In patients who cannot cooperate with the testing and whose effort is poor, neither lactate nor ammonia concentrations are very high. In mitochondrial disorders and other instances of metabolic stress, the production of both lactate and hypoxanthine is excessive. More recently, a modification of the ischemic forearm test has been reported as a sensitive and specific screen fot mitochondrial disorders. During exercise in normal individuals, mitochondrial oxidative phosphotylation increases 100-fold from that measured during rest. In mitochondrial disorders, the disturbed oxidative phosphorylation results in an impaired systemic oxygen extraction. In one study, 12 patients with mitochondrial myopathy were compared with 10 patients with muscular dystrophy and 12 healthy subjects. Cubital venous oxygen saturation was measured after 3 minutes at 4 0 % of maximal voluntary contraction of the exercised arm. Oxygen desaturation in venous blood from exercising muscle was markedly lower in patients with mitochondrial myopathy than in patients with othct muscle diseases and healthy subjects. Incremental bicycle ergometry allows one to measure the oxygen consumption and carbon dioxide production associated with varying workloads. The patient pedals a bicycle at a steady rate. The workload is increased every minute or two. Excessive oxygen consumption for a given work level suggests an abnormality in the energy pathway in muscle. In addition, the respiratory exchange ratio (RER), the ratio of carbon dioxide produced to oxygen consumed, is characteristic for various fuel sources. Carbohydrate metabolism results in an RER of 1.0. Fat, on the other hand, has an RER of 0.7. The resting RFR in normal individuals is approximately 0.8. For complex reasons, at the end of an incremental exercise test, the RFR is often as high as 1.2 in the normal individual. Patients with disorders of lipid metabolism often have an unusually high RFR because they preferentially metabolize carbohydrates, whereas patients with disorders of carbohydrate metabolism may never increase RER to more than 1,0 because they preferentially metabolize lipids.
APPROACH TO THE PATIENT WITH WEAKNESS Once it is established that a patient has weakness, either by history or examination, the clinical features may be so characteristic that the diagnosis is obvious. At other times, the clinician may be uncertain. Figure 28.6 displays an outline of diagnostic considerations based on the characteristics of the weakness, such as whether it is fluctuating or constant. The following sections amplify this approach,
Disorders with Prominent Ocular Weakness In oculopharyngeal muscular dystrophy, a slowly progressive weakness of the eye muscles causing ptosis and external ophthalmoplegia is associated with difficulty in swallowing. This disorder is an autosomal dominant trait and does not seem to shorten life. A number of patients also have facial weakness and hip and shoulder weakness. Swallowing difficulty may become severe enough to necessitate gastrostomy tube placement. The Kearns-Sayre syndrome is a distinctive collection of physical findings, including ptosis, extraocular muscle palsies, pigmentary degeneration of the retina, cerebellar ataxia, pyramidal tract signs, short stature, mental retardation, and cardiac conduction defects. These findings accompany an abnormality of the mitochondria in muscle and other tissues. It may be slowly progressive or nonprogressive. In addition, several other disorders may display prominent extraocular muscle involvement. Among these is centronuclear myopathy, one of the congenital myopathics. However, this condition is not restricted to the eye muscles and has prominent involvement of the limbs as well. Lastly, myasthenia gravis often, and occasionally Lambert-Eaton myasthenic syndrome, presents with isolated ptosis or extraocular muscle weakness. A subset of patients with myasthenia gravis will never generalize to other muscles and remain in the restricted ocular group.
Disorders with Distinctive Facial or Bulbar Weakness FSH muscular dystrophy may nor be noted until early adult life. Weakness of the face may lead to difficulty with whistling or blowing up balloons and may be severe enough to give rhe face a smooth, unlined appearance with an abnormal pout to the lips (Figure 28.7A). Weakness of the muscles around the shoulders is always seen, although the deltoid muscle is surprisingly well preserved and even pseudohypertrophic in its lower portion. When the patient attempts to hold the arms extended in front, winging of the scapula occurs that is quite characteristic. The whole scapula may slide upward on the back of the thorax. The inferomedial border always juts backward, producing the appearance of a triangle at right angles to the back, with the
PROXIMAL, DISTAL, AND GENERALIZED WEAKNESS
base of the triangle still attached to the thorax. In addition, a discrepancy in power is often seen between the wrist flexors, which are strong, and the wrist extensors, which are weak. Similarly, the plantar flexors may be strong, whereas the dorsiflexors of the ankles are weak. It is common for the weakness to be asymmetrical, with one side much less involved than the other (Figure 28.8). The disorder is inherited as an autosomal dominant trait, although mild forms of the illness may be missed in the parents. Myotonic dystrophy type I is a common illness with distinctive features, including distal predominance of weakness. It is inherited as an autosomal dominant trait, but often no family history is reported because the patients may be unaware that other family members have the illness. This is due to the phenomenon of anticipation, whereby successive generations are more severely affected, because of the expansion of the trinucleotide repeat. The diagnosis may be suspected in any patient with muscular dystrophy and predominantly distal weakness. The neck flexors and temporal and masseter muscles are often wasted. More charactetistic than the distribution of the weakness is the long, thin face with hollowed temples, ptosis, and frontal balding (Figure 28.7B). Percussion myotonia and grip myotonia are seen in most patients after age 13 years. An EMG can be diagnostic. Muscle biopsy may also show
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characteristic changes, and genetic testing shows the characteristic trinucleotide repeat in the myotonin gene on chromosome 19. A subset of patients with ALS present with isolated bulbar weakness of LMN type (i.e., progressive bulbar palsy) or UMN type (i.e., progressive pseudobulbar palsy). Frequently the condition shows a combination of UMN and LMN involvement. In these patients, dysarthria, dysphagia, and difficulty with secretions are the prominent symptoms. On examination, the tongue is often atrophic and fasciculating (Figure 28.9), and the jaw and facial reflexes are exaggerated- The voice is often harsh and strained as well as slurred, reflecting the coexistent UMN and LMN dysfunction. In patients with X-linked spinobulbar muscular atrophy {Kennedy's disease), bulbofacial muscles are also affected prominently. Patients often have a characteristic finding of chin fascial kit ions.
Disorders with Distinctive Shoulder-Girdle or Arm Weakness In Emery-Dreifuss muscular dystrophy, an abnormal gene on the X chromosome produces wasting and weakness of muscles around the shoulders, upper arms, and lower part
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
FIGURE 28.7 Facial weakness is a prominent feature of both facioscapulohumeral dystrophy (FSH) and myotonic dystrophy. However, the characteristic features are so distinctive that they are readily recognizable and not easily confused. (A) The patient with FSH dystrophy is unable to purse his or her lips when attempting to whistle. (B) The typical appearance .of a patient with myotonic dystrophy includes frontal balding, temporalis muscle wasting, ptosis, and faeial weakness. Related to F5H dystrophy is scapuloperoneal dystrophy, which has similar fearures but lacks the facial weakness. The two are differentiated because the scapuloperoneal distribution of weakness may be seen in some other congenital nonprogressive myopathies, which may lead to some confusion in the diagnosis.
of the legs, with contractures of the elbow, posterior neck, and Achilles tendon. Cardiac conduction abnormalities are common, and death may occur as a result of acute heart block.
Distal muscular weakness and atrophy are most commonly seen in neurogenic disorders. Among these is Charcot-Marie-Tooth disease, which is almost always characterized by distal weakness and wasting that starts
FIGURE 28.8 Asymmetrical scapular winging in facioscapulohumeral muscular dystrophy.
Kaminski, H. J., Preston, D. C, et al, eds, Neuromuscular Disorders in Clinical Practice, Buttcrworth-Heincmann, Boston.)
PROXIMAL, DISTAL, AND GENERALIZED WEAKNESS
in the distal lower limbs before involving the hands. ALS often begins as weakness and wasting in one distal limb. More important because it is treatable is multifocal motor neuropathy with conduction block, a rare demyelinating polyneuropathy that may be confused clinically with I.iVIN ALS. The initial features are often weakness, hyporcflexia, and fasciculations, especially of the hands. Clues to the diagnosis are a slow indolent coutse, weakness out of proportion to the amount of atrophy, and asymmetrical involvement of muscles of the same myotome but with a different peripheral nerve supply (e.g., weakness of ulnarinnervated C8 muscles out of proportion to weakness of median-innervated C8 muscles). Benign focal amyotrophy (Sobue's syndrome) presents with the insidious onset of weakness and atrophy of the hand and forearm muscles, predominantly in men between the ages of IS and 22. Two muscular dystrophies that are predominantly distal may affect the upper extremity: myotonic dystrophy, which has been discussed earlier in this chapter, and the hereditary distal myopathics. The hereditary distal myopathies are a heterogenous group of disorders. Welander's myopathy, transmitted as an autosomal dominant trait, is one of the more common forms. Ir has a predilection for the intrinsic hand and wrisr extensor muscles. In the older individual, involvement of the finger flexors with relative preservation of the finger extensors is commonly seen in inclusion body myositis. However, in these latter cases, weakness is also prominent in the lower extremities, especially die quadriceps.
Disorders with Prominent Hip-Girdle or Leg Weakness Although patients with these disorders often have more diffuse weakness, including arm and shoulder-girdle weakness, it is the hip and leg weakness that brings them to medical attention. Acute infantile spinal muscular atrophy (Werdnig-Hoffmann disease) is a severe and usually fatal illness with marked weakness of the limbs and respiratory muscles. Children with the intermediate form of spinal muscular atrophy (chronic Werdnig-Hoffmann disease or spinal muscular atrophy type 2) also are severely affected, rarely maintaining the ability to walk for more than a few years, so they are confined to a wheelchair in adult life. The progression of the illness is not steady; plateaus last for some years, interspersed with more rapid deterioration. Scoliosis is common. In the intermediate form of spinal muscular atrophy, a fine tremor of outstretched hands is characteristic. In juvenile spinal muscular atrophy the muscle weakness is more severe proximally, and the term pseudomyopatbic spinal muscular atrophy has been applied. The illness begins sometime during the first decade of life, and patients walk well into the second decade or even into early adult life. Scoliosis is less common than in the infantile form.
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The inherited muscular dystrophies cause progressive, nonfluctuating weakness. Duchenne's muscular dystrophyis an X-linked recessive disorder associated with an absence of dystrophin. Clinically, the combination of proximal weakness that is greater than distal weakness with hypertrophic calf muscles and contractures gives the clue to the diagnosis. The serum CK concentration is markedly elevated, and the muscle biopsy is diagnostic (see Chapter 85}. The clinical features of Becker's muscular dystrophy are identical except for later onset and slower progression. Severe childhood autosomal recessive muscular dystrophies, also known as sarcoglycanopathies, arc caused by deficiency in muscle of one of rhe dystrophin-associated glycoproteins (sarcoglycans) and have been linked to chromosomes 4, 5, 13, and 17. Severe childhood autosomal recessive muscular dystrophy is phenotypically similar to Duchenne's muscular dystrophy, including the calf hypertrophy, but affects both boys and girls. Cardiac involvement is rare, and mental retardation is not seen. The limb-girdle dystrophies are a well-accepted diagnostic classification, despite their clinical heterogeneity. Weakness begins in the hips, shoulders, or both and spreads gradually to involve the rest of the limbs and the trunk. The diagnosis is often established by exclusion of everything else. The most helpful test is the muscle biopsy, which shows dystrophic changes, separating limbgirdle dystrophy from other (inflammatory) myopathies and from denervating diseases. Immunohistochcmical analysis of dystrophic muscle will further clarify the diagnosis, followed by genetic analysis of the sarcoglycan genes. In patients with inclusion body myositis, the quadriceps and forearm ulnar finger flexor muscles are often preferentially involved. In some patients, this may be asymmetrical at the onset. The other inflammatory myopathies, polymyositis and dermatomyosiris, affect proximal, predominantly hip-girdle muscles in a symmetrical fashion, Though rare, the Lambert-Eaton myasthenic syndrome can also present with proximal lower extremity weakness, similar to a myopathy. Hyporeflexia and autonomic and sensory symptoms may suggest the diagnosis. EMG is often diagnostic. Distal muscle weakness and atrophy are most often caused by neurogenic disorders. In Charcot-Marie-Tooth disease of both the demyelinating form (type 1) and the axonal form (type 2) the problem in the legs antedates that in the hands. In ALS, the weakness is often asymmetrical and may be combined with UMN signs. As mentioned earlier, the last group is the hereditary distal myopathics. Distal leg weakness is usually the initial featute. Among these disorders are the Markesbcry-Griggs/ Udd, Nonaka, and Laing myopathies, which affect anterior compartment muscles, and Miyoshi myopathy, which affects predominantly the posterior calf muscles.
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Disorders with Fluctuating Weakness The first step is to determine whether the weakness is constant or fluctuating. Even constant weakness may vary somewhat depending on how the patient feels. We are all capable of better physical performance on the days when wc feel energetic and cheerful and do less well on days when we are depressed or sick. Such factors also affect the patient with neuromuscular weakness. Specific inquiries should be made to determine how much variability exists. Is the fluctuation related to exercise or time of day? Symptoms and signs that are provoked by exercise imply a disorder in the physiological or biochemical mechanisms governing muscle contraction, l'ain, contractures, and weakness after exercise are often characteristic of abnormalities in the biochemistry of muscle contraction. Pathological fatigue is the hallmark of neuromuscular junction
abnormalities. Factors other than exercise may result in worsening or improvement of the disease. Some patients notice that fasting, carbohydrate loading, or other dietary manipulations make a difference in their symptoms. Such details may provide a clue to underlying metabolic problems. Patients with a defect in lipid-based energy metabolism are weaker in the fasting state and may carry a candy bar or sugar with them. The patient with hypokalemic periodic paralysis may notice that rest after a high-carbohydrate meal precipitates an attack. Weakness that fluctuates markedly on a day-to-day basis or within .1 space of several hours is more often caused by a defect in neuromuscular transmission or a metabolic abnormality (e.g., periodic paralysis} than by one of the muscular dystrophics. Most neurologists recognize that the cardinal features of myasthenia gravis arc ptosis, ophthalmoparesis, dysarthria, dysphagia, and proximal weakness (see Chapter 84). On clinical examination, the hallmark of myasthenia gravis is pathological fatigue. Normal muscles fatigue if exercised sufficiently, but in myasthenia gravis, fatigue occurs with little effort. Failure of neuromuscular transmission may prevent maintenance of the arms in an outstretched position for more than a few seconds or maintenance of sustained upgaze. One of the problems with the diagnosis of myasthenia is that the patient may be relatively normal when examined in the office; the history and ancillary studies (acetylcholine receptor antibodies and EMG with repetitive stimulation or single-fiber EMG) must be relied on to establish the diagnosis. In the Lambert-Eaton myasthenic syndrome, fluctuating weakness may also occur but is less marked than in myasthenia gravis. Weakness of the shoulder and especially the hip girdle predominates, with the bulbar, ocular, and respiratory muscles relatively spared. There are exceptions to this latter rule, with few patients with LambertEaton myasthenic syndrome mimicking myasthenia gravis. Reflexes are typically reduced or absent at test. After a brief exercise, weakness and reflexes are often improved
{facilitation), which is the opposite of the situation in myasthenia gravis. The electrophysiological correlate of this phenomenon is the demonstration of a marked incremental response to rapid, repetitive nerve stimulation. The underlying pathophysiology of Lambert-Easton myasthenic syndrome is an autoimmune or paraneoplastic process mediated by anti-voltage-gated calcium channel antibodies; commercial testing for these antibodies is available. Patients with periodic paralysis note attacks of weakness, typically provoked by rest after exercise (see Chapter 85), In the primary periodic paralyses, the disorder is inherited as an autosomal dominant trait, secondary to a sodium or calcium channel defect (see Chapter 70), In the hyperkalemic (sodium channel) form, patients experience weakness that may last from minutes to days, beginning in infancy to early childhood, which is provoked by rest after exercise or potassium ingestion. Potassium levels are generally high during an attack. In the hypokalemic (calcium channel) form, weakness may last hours to days, is quite severe, beginning in the early teens, and is provoked by rest after exercise or high-carbohydrate ingestion. Potassium levels are generally low during an attack. In both types, patients may become totally paralyzed, although notably sparing bulbofacial muscles. Rarely, respiratory muscles are affected in hypokalemic periodic paralysis. Patients with paramyotonia congenita may also experience attacks of weakness, especially in the cold.
Disorders Exacerbated by Exercise Fatigue and muscle pain provoked by exercise, the most common complaints in the muscle clinic, are often unexplained, and diagnoses such as fibromyalgia and the aches, cramps, and pain syndrome are used to cloak our ignorance (see Chapter 29). Biochemical defects are being found in an increasing number of patients with exerciseinduced fatigue and myalgia. The metabolic abnormalities that impede exercise are disorders of carbohydrate metabolism, lipid metabolism, and mitochondrial function. The patient's history may give some clue to the type of defect. Fatty acids provide the main source of energy metabolism for resting muscle. The initiation of vigorous exercise requires the use of intracellular stores of energy, because blood-borne metabolites are initially inadequate. It takes some time for the cardiac output to increase, for capillaries to dilate, and for the blood supply to muscle to be increased, and .111 even longer time for fat stores in the body to be mobilized so the level of fatty acid increases in the blood. Muscle must use its glycogen stores in this initial phase of heavy exercise. Thus defects of glycogen metabolism cause fatigue and muscle pain in the first few minutes of exercise. As exercise continues in the normal individual, the blood supply increases, resulting in an increased supply
PROXIMAL, DISTAL, AND GENERALIZED WEAKNESS of oxygen, glucose, and fatty acids. After 10-15 minutes, the muscle begins to use a mixture of fat and carbohydrate. The use of carbohydrate cannot be tolerated for long periods, because it would deplete the body's glycogen stores and might result in hypoglycemia. After 30-40 minutes of continued endurance exercise, the muscle is chiefly using fatty acids as an energy source. Patients with a defect of fatty acid metabolism can exercise in the initial phase easily but may become incapacitated with endurance exercise lasting 30-60 minutes. Similarly, in the fasting state, the body is more dependent on fatty acids, which it uses to conserve glucose. Thus the patient with a disorder of fatty acid metabolism may complain of increased symptoms when exercising in the fasting state. Ingestion of a candy bar may give some relief, because this boosts the blood sugar level. Patients with fatty acid metabolism defects often have well-developed muscles, because their favorite exercise is relatively intense, brief power exercise, such as weight lifting, Disorders of mitochondrial metabolism are varied in presentation. In some types, recurrent eneephaloparhic episodes occur, often noted in early childhood and resembling Reye's disease (see Chapter 69). In others, there is particular weakness of the extraocular and other skeletal muscles. In some types, usually affecting young adults, the symptoms are predominantly of exercise intolerance. Defects occur in the electron transport system or cytochrome chain that uncouples oxygen consumption from the useful production of adenosine triphosphate. This causes metabolic pathways to run at their limit, even to keep up with the demands of a light exercise load. Resting tachycardia, high lactic acid levels in the blood, excessive sweating, and other indications of hypermetabolism are noted. This may lead to an erroneous diagnosis of hyperthyroidism. It is always worth measuring the scrum lactic acid concentration if a mitochondrial myopathy is suspected. In addition to lactate, ammonia and hypoxanthine concentrations also may be elevated. Patients with suspected metabolic defects require forearm exercise and bicycle exercise tests. Myoglobinuria may occur during an exercise test, so the patient should be cautioned about the possibility.
Disorders with Constant Weakness With constant weakness, the course is one of stability or steady deterioration. Without treatment, the periods of sustained, objective improvement or major differences in strength on a day-to-day basis are lacking. The division of this group into subacute and chronic also needs clarification. Subacute means that weakness appeared over weeks to months in a previously healthy person. In contrast, chronic weakness implies a much less definite onset and prolonged course. Although the patient may say that the weakness came on suddenly, a careful history elicits
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symptoms that go back many years. This division is not absolute. Patients with polymyositis, usually a subacute disease, may have a slow course, mimicking a muscular dystrophy. Patients with a muscular dystrophy may have a slow decrease in strength but suddenly lose a specific function, such as standing from a chair or climbing stairs, and believe their disorder to be acute. Acquired
Disorders
Causing
Weakness
Acquired disorders producing weakness are usually either motor neuron diseases, inflammatory, toxic, or endocrine disorders of muscle, neuromuscular transmission disorders, or peripheral motor neuropathies. The first task is to determine whether the weakness is neuropathic, myopathic, or secondary to a neuromuscular transmission defect. In some cases, this is straightforward clinically; in others, it may be very difficult. For instance, some cases of predominantly LMN ALS may mimic inclusion body myositis; Lambert-Easton myasthenic syndrome may mimic polymyositis. If fasciculations are present, the disorder must be neuropathic. If reflexes arc absent and clearly out of proportion to muscle bulk, one should suspect a demyelinating neuropathy, although presynaptic neuromuscular junction disorders may also have hyporeflexia. The presence of sensory signs or symptoms, even if mild, may indicate a peripheral neuropathy or involvement of the CNS. Often, serum CK concentration, EMG, and sometimes muscle biopsy are needed to separate these conditions. ALS is the most common presentation of an acquired motor neuron disease. Although more common in the 55-65-year-old age-group, it can occur at any adult age. It often follows a relatively rapid course, often preceded by cramps and fasciculations. Examination shows wasting and often widely distributed fasciculations. If the bulbar muscles are involved, difficulty with swallowing and speaking are also present. The diagnosis is relatively simple if unequivocal evidence of UMN dysfunction accompanies peripheral wasting and fasciculations. These signs include slowness of movement, hyper-reflexia, Babinski's signs, and spasticity. A weak wasted muscle, associated with an abnormally brisk reflex, is almost pathognomonic of ALS. The electrophysiological diagnosis is supported by the finding of widespread denervation on needle electrode examination in the absence of any sensory abnormalities or demyelinating features on nerve conductions. In all patients without bulbar involvement, it is important to rule out spinal pathology because the combination of cervical and lumbar stenosis may occasionally mimic the clinical and electrophysiological findings of ALS. In patients with only LMN dysfunction, it is essential to exclude the rare diagnosis of multifocal motor neuropathy with conduction block, a condition that is usually treatable with intravenous gammaglobulin. Parients with multifocal motor neuropathy with conduction block
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
usually have no bulbar features or UMN signs and have characteristic findings of demyelination (i.e., conduction block) on motor nerve conductions. Although most adults with motor neuron disease have ALS or one of its variants, sporadic forms of adult-onset spinal muscular atrophy and especially X-linked spinobulbar muscular atrophy (Kennedy's disease) can occur as well. In these cases, the progression of weakness is much slower and UMN involvement is absent. Of importance, these latter cases, especially Kennedy's disease, often have elevated C'K levels in the 500-1500 range. If the patient is shown to have an acquired myopathy, one must consider inflammatory myopathies, including polymyositis, dermatomyositis, or inclusion body myopathy, in addition to a large number of toxic, drug-induced, and endocrine disorders. Inflammatory myopathies, as exemplified by polymyositis, often run a steadily progressive course, although some fluctuation may be noted, particularly in children. If an associated skin rash is present, there is little doubt about the diagnosis of dermatomyositis. In its absence, polymyositis may be difficult to differentiate from any of the other causes of proximal weakness. Sometimes the illness occurs as part of an overlap syndrome, in which fragments of other autoimmune diseases, such as scleroderma, lupus, or rheumatoid arthritis, are involved. Polymyositis is sometimes difficult to differentiate from a limb-girdle muscular dystrophy, even after a muscle biopsy; some inflammatory changes may be seen in the latter. Other signs of systemic involvement, such as malaise, transient aching pains, mood changes, and loss of appetite, are more common in polymyositis than in limb-girdle dystrophy. Inclusion body myopathy also may mimic polymyositis clinically. More often it may mimic LMN ALS. Clues to the diagnosis are male gender, age older than 40 years, slower progression, and characteristic involvement of certain muscles, especially the quadriceps and long finger flexors. Some patients may have proximal muscle weakness, similar to polymyositis, whereas others may have predominantly distal weakness mimicking ALS and other neuropathic conditions. Scrum CK is generally elevated but may occasionally be normal. Like other chronic inflammatory myopathics, the interpretation of the EMG study may be difficult and requires an experienced examiner, because inclusion body myopathy often shows a combination of myopathic and neuropathic features. Inclusion body myopathy, unlike polymyositis, is often unresponsive to immunosuppressive therapy and has rimmed vacuoles and intracytoplasmic and intranuclear filamentous inclusions in muscle fibers on biopsy. Toxic, drug-induced, and endocrine disorders must always be considered in acquired myopathies. Among toxins, alcohol is still the most common and may produce both an acute and a chronic syndrome. A large number of prescription medicines are associated with myopathies. Most prominent are corticosteroids, cholesterol-lowering agents (the statins), and colchicine.
Although neuromuscular transmission disorders arc most often considered with disorders with fluctuating symptoms, the Lambert-Faton myasthenic syndrome may be an exception and often presents similar to a myopathy with progressive proximal lower extremity weakness. Clues to the diagnosis include a history of cancer, especially small cell lung cancer (although in many patients the myasthenic syndrome may predate the discovery of the cancer), hyporeflcxia, facilitation of strength and reflexes after brief exercise, and coexistent autonomic symptoms, especially urinary and sexual dysfunction in men. Most peripheral neuropathies are easily separated from disorders of the motor unit by the presence of clear-cut sensory symptoms and signs. The notable exception is multifocal motor neuropathy with conduction block discussed earlier. Other neuropathies may also present with predominantly motor symptoms. Among these are toxic neuropathies (dapsone, vincristine, lead, acute alcoholrelated neuropathy) and some variants of the Guillain-Barre syndrome (especially the acute motor axonal neuropathy syndrome). Lifelong
Disorders
Most patients in the neuromuscular clinic have lifelong or at least very chronic, presumably inherited disorders. These include inherited disorders of muscle (e.g., dystrophies, congenital myopathies), anterior horn cell (e.g., spinal muscular atrophies), peripheral nerves (e.g., CharcotMarie-Tooth polyneuropathy), or very rarely neuromuscular transmission (e.g., congenital myasthenic syndromes). In some, the responsible genetic abnormality has been identified. An important point in the differential diagnosis is to determine whether the weakness is truly progressive. The examiner should ask questions until the progressive or nonprogressive nature of the disease is certain. The severity of the disease is often taken as proof of progression. It is difficult to imagine that a 16-ycar-old girl, confined to her wheelchair with spinal muscular atrophy and scoliosis and having difficulty breathing, has a relatively nonprogressive disorder, but careful questioning may show that there has been no loss of function for the last several years. Further, it is not sufficient to ask the patient in vague and general terms whether the illness is progressive. Questioning should be specific, such as "Arc there tasks that you cannot perform now that you could perform last week, month, or year?" One must also be alert for denial, which is common in young patients with increasing weakness. The 18-year-old boy with limb-girdle dystrophymay claim to be the same now as in years gone by, but questioning may reveal that he was able to climb stairs well when he was in high school, whereas he now needs assistance in college. Lifelong, Nonprogressive Disorders. Some patients complain of lifelong weakness that has been relatively
I'ROXIMAL, DISTAL, AND GENERALIZED WEAKNESS unchanged over many years. Almost by definition such disorders have to start in early childhood. Nonprogression of weakness does not preclude severe weakness. Later-life progression of such weakness may occur as the normal aging process further weakens muscles that have little functional reserve. One major group of such illnesses is the congenital nonprogressive myopathies, including central core disease, nemaline myopathy, and congenital fiber-type disproportion. The typical clinical picture in these diseases is that of a slender dysmorphic individual with diffuse weakness {Figure 28.10A). There may be associated skeletal abnormalities, such as high-arched palate, pes cavus, and scoliosis. Deep tendon reflexes are depressed or absent. Though unusual, severe respiratory involvement has been noted in all of these diseases. The less severe (non-X-1 inked) form of myotubular (centronuclear) myopathy may be suspected because of the occurrence of ptosis, extraocular muscle weakness, and facial diplegia. Muscle biopsy usually can be relied on to provide the diagnosis in the congenital myopathies.
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Several varieties of congenital muscular dystrophy are recognized. The weakness in congenital muscular dystrophy is usually severe, contractures are prominent, and there may be associated findings. For example, in Fukuyama's muscular dystrophy, there are associated mental retardation and seizures. Other signs of damage to the CNS may be present, such as increased tendon reflexes and extensor plantar responses. Most patients with Fukuyama's dystrophy are severely disabled, both physically and intellectually. The serum CK concentration may be elevated markedly. The muscle biopsy is different from that in the congenital nonprogressive myopathies and shows fiber necrosis with fibrosis and phagocytosis. There are also patients whose biopsies show dystrophic changes but whose illnesses are much milder. One such illness has been termed stick man dystrophy because of the almost skeletal appearance of the limbs, with severely atrophic muscles (Figure 28.10B). Although there is diffuse weakness, the atrophic muscles generate more force than one would expect on the basis of their bulk. Patients also
B FIGURE 28.10 The patient with a congenital myopathy is slender, without focal atrophy. Shoulder-girdle weakness is apparent from the horizontal scr of rhe clavicles. (B) The patient with congenital muscular dystrophy of the "stick man" type is distinguished by his skeletal appearance and the presence of the prominent contractures.
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
have severe heel cord contractures and often contractures of the posterior cervical muscles.
have
Lifelong Disorders Characterized by Progressive Weakness. Most diseases in this category are inherited progressive disorders of anterior horn cells, peripheral motor nerve, or muscle. Among these are the spinal muscular atrophies, Charcot-Marie-Tooth polyneuropathies, and muscular dystrophies. Mild day-to-day fluctuations in strength may occur, but the overall progression is steady (i.e., the disorder is slowly progressive from the start and it remains that way); it will not suddenly change course and become rapidly progressive. As mentioned earlier, patients may experience long periods of stability when their disease is seemingly nonprogressive. Attempts to categorize disorders have traditionally been based on whether the disorder was caused by anterior horn cell, peripheral motiir nerve, or muscle disease, along with .1 specific pattern of muscle weakness. Certain characteristic patterns of weakness often suggest specific diagnoses. For example, FSH and oculopharyngeal muscular dystrophies are so named because of their selective involvement of muscles. In the modern day, all of these disorders are being further redefined and categorized based on their specific genetic abnormality and in some the specific structural protein the involved gene encodes.
Other Conditions No scheme of analysis is perfect in clinical medicine, and many exceptions exist to the guidelines provided earlier.
Most notable are disorders that are restricted to various parts of the body. The etiology and the reasons for such localized illness are not clear, but examples include branchial myopathy and quadriceps myopathy, as well as the focal form of motor neuron disease, which often remains in one segment of the body for years to decades (benign monomelic amyotrophy). These diseases are often "benign" in that they do not shorten life. The weakness may cause disability, although it is usually mild.
FURTHER READING Astrand, P. O. Sc Rodahl, K. 1986, Textbook of Work Physiology, McGraw-Hill, New York Brooke, M. H. 1986, A Clinician's View of Neuromuscular Disease, Williams &c Wilkins, Baltimore Guarantors of Brain. 1986, Aids to the Examination of the Peripheral Nervous System, 2nd ed, Balliere-Tindall, London Harris, E. K., Wong, E. T., & Shaw, S. T. 1991, "Statistical criteria for separate reference intervals; race and gender groups in creatine kinase," Clin Chem, vol. 37, pp. 1580-1.582 Henderson, A. T, McQueen, M. J., Patten, R. L„ et al. 1991, "Testing for creatine kinase-2 in Ontario: Reference ranges and assay types," Clin Chem, vol. 38, pp. 1365-1370 Jensen, T. D., Kazemi-Esfarjani, P., Skomorowska, E., & Vissing, J. 2002, "A forearm exercise screening test for mitochondrial myopathy," Neurology, vol. 58, pp. 1533-1538 Katirji, B., Kaminski, H. J., Preston, D, C„ et al., eds. 2002, Neuromuscular Disorders in Clinical Practice, ButterworthHcinemann, Boston McArdle, W. D., Katch, F. I., & Katch, V. L. 2001, Exercise Physiology: Energy, Nutrition, and Human Performance, Lippincott Williams & Wilkins, Philadelphia
Chapter 29 Muscle Pain and Cramps Waqar Waheed and Alan Pestronk Muscle Pain: Basic Concepts Nociceptors Pathological Conditions Producing Muscle Pain Clinical Features of Muscle Pain General Features of Muscle Pain
387 387 5SH 389 .IM'J
Pain is an uncomfortable sensation with sensory and emotional components. Short episodes of muscle pain or discomfort are a universal experience. Common causes of short-term muscle discomfort are unaccustomed exercise, trauma, cramps, and systemic infections. Chronic muscle discomfort is also relatively common. In the U.S. population between the ages of 25 and 74 years, 1 0 - 1 4 % complain of chronic pain rehired to the joints and musculoskeletal system. Pain localized to muscle may be caused by noxious stimuli in muscle but also may be referred from other structures, including connective tissue, joints, and bone. The referral of pain may involve secondary contraction of muscle during the pain or indirect neural activation evoked by the noxious stimulus. Some patients with small-fibet polyneuropathies have spontaneous pain that is localized to muscle. Pain in muscle and other tissues can be categorized according to temporal and qualitative features. Pain elicited by noxious stimulation of normal tissue has an early ("first") phase that is perceived as sharp and well localized and that lasts as long as the stimulus. This is followed by a somewhat delayed ("second") phase of pain that is dull, aching or burning, and more diffuse. Second-phase pain has both sensory and affective components and may predominate with visceral and chronic pain. Pain from stimulation of diseased tissue is often associated with hyperalgesia, in which a noxious stimulus produces an exaggerated pain sensation, or with allodynia, in which pain is induced by a normally innocuous stimulus. Neuropathic pain is associated with incteased activity in abnormal afferent axons and occurs spontaneously or after peripheral stimuli.
MUSCLE PAIN: BASIC CONCEPTS Nociceptors Many of the afferent nerve fibers that transmit painful stimuli from muscle (nociceptors) have small unmyelinated
Evaluation of Muscle Discomfort Muscle Discomfort: Specific Causes Myopathies with Muscle Pain Muscle Overuse Syndromes Myalgia Syndromes without Chronic Myopathy
389 389 389 390 392
(free) axon terminals (Graven-Nielsen and Mense 2001; Julius and Basbaum 2001). These terminal axons (nerve endings) are mainly located near blood vessels and in connective tissue but do not contact muscle fibers. Free nerve endings have a small diameter (0.5 jim) with varicosities (expansions). They contain glutamate and neuropeptides. Noxious stimuli produce graded receptor potentials in nerve endings, with the amplitude dependent on strength of the stimulus. If the amplitude is large enough to reach threshold, an action potential is generated. Action potentials arising in nociceptor terminals play two roles in inducing pain. Direct centripetal conduction along afferent axons brings nociceptive signals to the central nervous system (CNS). Indirect effects occur when action potentials are conducted centrifugally, invading other nerve terminals, which then release glutamate and neuropeptides into the extracellular medium. These algesic substances can stimulate or sensitize terminals on other nociceptive axons. Nociceptor
Stimulation
and
Sensitization
Muscle pain is induced by chemical or mechanical stimuli. The specific chemical factors that are involved in the peripheral generation of pain arc better defined in tissues other than muscle. Intramuscular injections of hypertonic saline arc used experimentally to induce pain that is similar to acute clinical muscle pain, without producing associated morphological abnormalities in muscle. Increased levels of glutamate in muscle correlate temporally with the appearance of pain due to hypertonic saline and after exercise. Other possible chemical algesic stimuli in muscle include ions (acid pH and potassium |high]), and neurotransmitters (adenosine triphosphate |ATP|, bradykinin, 5-hydroxytryptamine [5-HT], and adrenaline). Sensitization of nociceptive axon terminals is defined as reduction, into the innocuous range, of the threshold for their stimulation. Vanilloid receptors and tetrodotoxinrcsistant sodium channels can play roles in the sensitization of nerve terminals. The reduction in threshold of axon 387
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APPROACH TO COMMON NEUROLOGICAL PROBLEMS
terminals is induced by factors released during muscle damage or repetitive stimulation. Stimuli implicated in the sensitization of terminals include algesic substances (5-HT, prostaglandin E z [PGE21, and bradykinin), nerve growth factor, and repeated stimulation {heat, protons, or capsaicin via vanilloid receptors). Effects of stimuli may be mediated intracellularly by calcium and kinases. Sensitization of nociceptor terminals can increase the frequency of action potentials in normally active nociceptors or induce new action potentials in a population of normally silent small axons that is especially prominent in viscera. Substance P induces a low-frequency discharge in afferent axons that could contribute to spontaneous pain. Lcukotriene D4 may have a desensitizing effect on muscle nociceptors. The depression of muscle nociceptor activity by aspirin may reflect inhibition of the effects of PGE 2 . Afferent Axons Involved in
Nociception
AS group III and C group IV class axons play important roles in the conduction of pain-inducing stimuli from muscle to the CNS. The ability to detect acute noxious stimuli is largely eliminated by blockade of both AS and C class axons. AS class nociceptive axons are thinly myelinated, conduct impulses at moderately slow velocities (3-13 m per second), and have membrane sodium channels that are tetrodotoxin sensitive. AS axons are high-threshold medianoceptors that are stimulated by strong local pressure and mediate rapid, acute, sharp ("first") muscle pain. Spontaneous pain and dysesthesias are probably mediated by A3 class axons. C class nociceptive axons are unmyelinated, conduct impulses at very slow velocities (0.6-1.2 m per second), and have membrane sodium channels that are tetrodotoxin resistant. C class axons in muscle are often poly modal, responding to a range of stimuli, but stimulus-specific axon terminals are also present. C fibers mediate somewhat delayed, diffuse, dull, or burning ("second") pain evoked by noxious stimuli. Constituents of muscle nociceptor C axons include substance P, calcitonin gene-related peptide, and somatostatin. These constituents may place the nociceptive axons in a subgroup of C fibers that mediate hyperalgesia in response to inflammation. AS class axons are large and myelinated and conduct impulses at rapid velocities. They normally mediate innocuous stimuli and stimulation may reduce the perception of pain, liitlaiiiin.ivion or repetitive stimulation can sensitize AS axons, which then mediate mechanical allodynia in some tissues. This "phenotypic switch" in AS axons may be mediated by uprcgulation of neuropeptide Y and sprouting of terminals in the spinal cord from lamina III and IV into lamina II, with subsequent stimulation of ascending central pain pathways. Central terminations of nociceptive axons from muscle are located in lamina I in the dorsal horn of the spinal cord. Ascending central neurons, with cell bodies in lamina I or II, are stimulated by glutamate from the terminals of
primary afferent axons and convey sensory pain modalities via the contralateral spinothalamic tract to thalamic nuclei (Ren and Dubncr 2002). Transmission of affective features of pain may involve other pathways to the parabrachial nucleus, amygdala, thalamic intralaminar nucleus, and anterior cingulate gyrus. Inrerncurons and descending CNS pathways modulate afferent input, especially with chronic pain. Central sensitization to pain is associated with neurons containing substance-P receptors. Glutamate acting at N-mcthyl-D-aspartate (NMDA) receptors is essential for the initiation of central sensitization and for the hyperexcitability of spinal cord neurons and persistent pain. Facilitation via descending CNS pathways may lead to allodynia and the maintenance of hyperalgesia. Inhibitory descending pathways are associated with increased opioid sensitivity and may provide a system of endogenous analgesia. There is enhanced net descending inhibition at sites of primary hyperalgesia associated with inflammation.
Pathological Conditions Producing Muscle Pain Episodes of pain originating in muscle are commonly associated with exercise, inflammation, and trauma. Exercise can produce muscle pain by several pathways, including exhaustion of fuel supply (with lack of training, vascular insufficiency, or metabolic detect-,;, cramps, or injury to muscle fibers or tendons. When muscle contracts while it is being stretched (eccentric contraction), damage and pain are especially likely. During exercise with eccentric contraction, the shearing forces on connective tissue may directly activate muscle nociceptors. Similar painful shearing forces occur during cramps, when the contracting segment stretches the remainder of the muscle. Delayed-onset muscle soreness (DOMS) may be due to several factors, including muscle fiber and connective tissue damage, inflammation, and edema. Pain with DOMS is associated with increased levels of glutamate in muscle. In damaged muscles, tenderness, a decrease in pressure pain threshold, and pain with movement are due to sensitization of muscle nociceptors. The sensitized nociceptors have a lowered threshold of excitation and a greater response to noxious stimuli. With muscle inflammation, pain at rest may be due to nociceptive axons that develop a raised level of background discharge. Mediators of this phenomenon could include algesic substances including substance P, bradykinin, and serotonin. Pain during muscle ischemia may also be related to accumulation of algesic substances, but probably not to lactate accumulation. It has been suggested that myofascial (trigger-point) pain syndromes arc associated with hypercontraction of muscle fibers. However, this has not been well documented and the possible afferent pathway is unclear because muscle fibers are not innervated by nociceptive axons. A more objective
.VUlSCI.i: PAIN AND CRAMPS
definition of clinical and pathophysiological features of myofascial and fibromyalgia syndromes would be helpful.
CLINICAL FEATURES OF MUSCLE PAIN General Fearures of Muscle Pain Muscle discomfort is described using several different terms, including pain, soreness, aching, fatigue, cramps, or spasms. Pain that originates from muscle is perceived to arise from deep tissues. This property of muscle pain may reflect convergent afferent axons from various tissues that mask identification of a specific source by higher centers. Chronic muscle pain may be poorly localized, referred to another (usually deep) location, and associated with autonomic and affective symptoms. Pain with muscle cramps has an acute onset and short duration. Cramp pain is associated with palpable muscle contraction and is immediately relieved by stretching the muscle. Pain originating from fascia and periosteum is relatively precisely localized. Cutaneous pain differs from muscle or fascial pain by its distinct localization and sharp, pricking, stabbing, or burning nature. In fibromyalgia syndromes, patients commonly complain that fatigue accompanies their muscle discomfort. Depression is approximately twice as common in patients with chronic musculoskeletal pain (18%) than in a population without chronic pain (8%).
389
Nerve conduction evaluation may detect an underlying neuropathy, but objective documentation of small-fiber adenopathies can require quantitative sensory testing or skin biopsy with staining of distal nerve fibers (generally a research technique). Magnetic resonance imaging or radionuclide scans may reveal focal or diffuse anomalies in muscle, joints, or fascia and can be used to guide biopsy procedures. Phosphorous magnetic resonance spectroscopy may become useful in the evaluation and monitoring of some metabolic myopathies, but its specific utility is not yet determined. Muscle biopsy is most often useful in the presence of another abnormal test result, such as a high scrum lactate or CK level or an abnormal EMC. However, important clues to treatable disorders, such as fasciitis or systemic immune disorders (perivascular inflammation or granulomas), may be present in muscle in the absence of other positive testing. The yield of muscle biopsy in syndromes with muscle discomfort is increased if both muscle and connective tissue are examined. There is increased diagnostic yield from muscle biopsies if histochemistry includes staining for acid phosphatase, alkaline phosphatase, esterase, mitochondrial enzymes, glycolytic enzymes, and myoadenylate deaminase, in addition to routine morphological analysis and processing. Ultrastructural examination of muscle rarely provides additional information.
MUSCLE DISCOMFORT: SPECIFIC CAUSES Evaluation of Muscle Discomfort Disorders underlying muscle discomfort can be classified based on anatomy, temporal relation to exercise, muscle pathology, and the presence or absence of active muscle contraction during the discomfort {Kincaid 1997; Pestronk 2003). Evaluation of muscle discomfort typically begins with a history, including the type, localization, inducing factors and evolution of the pain, drug use, and mood disorders. The physical examination is conducted with special attention to the localization of weakness. However, accurate assessment of strength may be difficult in the presence of pain. The sensory examination is important because small-fiber sensory neuropathies commonly cause discomfort with apparent localization in muscle. A general examination is important to evaluate the possibility that pain may be arising from other tissues, such as joints. Blood studies may include a complete blood cell count, erythrocyte sedimentation rate, creatine kinase (CK), potassium, calcium, phosphate, and lactate levels, thyroid functions, and evaluation for systemic immune disorders. Urine myoglobin concentration should be evaluated in patients with a high CK level and severe myalgias, especially when they are related to exercise. Electromyography (EMG) is a sensitive test for myopathy. A normal EMG result suggests that muscle pain is arising from other anatomical loci.
Muscle pain can he broadly divided into groups depending on its origin and whether it occurs at the time of muscle contraction. Myopathies may be associated with muscle pain without associated muscle contraction (myalgias) (Tables 29.1 and 29.2). Muscle pain during muscle activity (Tables 29.2 and 29.3) may occur with muscle injury, myopathy, cramps, or long-term tonic contraction. Some pain syndromes that are perceived as arising from muscle originate in other tissues or have no clear morphological explanation for the pain (Table 29.4).
Myopathies with Muscle Pain Myopathies that produce muscle pain (see Table 29,1) are usually associated with weakness, a high serum CK level, and an abnormal EMC; (Griggs, Mendel I, and Miller I 995; Pestronk 2003). Only a minority of inflammatory myopathies are associated with pain and muscle tenderness. Pain is a typical feature of childhood dcrmatomyositis, immune myopathies with systemic disorders, eosinophilia myalgia syndromes, and infections. Myopathies caused by infections, including bacterial, viral, toxoplasmosis, and trichinosis, are usually painful. Metabolic myopathics, including phosphorylase and carnitine palmitoyltransferase II deficiencies, typically produce muscle discomfort or fatigue
390
APPROACH TO COMMON NEUROLOGICAL PROBLEMS
Table 29.1:
Pain syndromes, myopathic"1
Inflammatory Inflammatory myopathics Systemic connective tissue disease Transfer ribonucleic acid synthetase antibodies Childhood dcrmatomyositis Muscle infections Viral myositis Pyomyositis Toxoplasmosis Trichinosis Rhabdomyolysis ± metabolic disorder Myophosphorylase—McArdle's Phosphof r ucro kinase Carnitine palmitoyltransferase II Mitochondrial myopathies Malignant hyperthermia syndromes Other myopathics with pain Myoadenylate deaminase Myopathy with focal depletion of mitochondria Myopathy with tubular aggregates ± cylindrical spirals Myopathy with tubulin-rcactive crystalline inclusions Neuromyopathy wirh internalized capillaries Myoronias: PROMM; dominant myotonia congenita (occasional) Selenium deficiency Toxic myopathy: Eosinophilia myalgia; rhabdomyolysis Hypothyroid myopathy Mitochondrial disorders Camurati-F.ngelmann syndrome Drugs and toxins 'Usual features: weakness, high serum crearine kinase level, and abnormal electromyogram. that arises t o w a r d the end or after the c o m p l e t i o n of exercise and is less p r o m i n e n t at rest. As a general rule, disorders of c a r b o h y d r a t e use p r o d u c e pain a n d fatigue after short intense exercise, whereas lipid disorders cause muscle discomfort with sustained exercise. R h a b d o m y o l y sis is usually associated with muscle pain and tenderness that can persist for days after the initial event. It m a y o c c u r with a defined metabolic or toxic m y o p a t h y or s p o r a d i cally, in the setting of u n a c c u s t o m e d exercise, especially with hot weather. Because r h a b d o m y o l y s i s m a y p r o d u c e renal failure—a life-threatening c o m p l i c a t i o n — d i a g n o s i s , treatment, and a v o i d a n c e of further precipitating factors should be aggressively p u r s u e d . M e d i c a t i o n s , including " ' * s - a m i n o c a p r o i c acid a n d cholesterol-lowering a g e n t s , m a y produce a painful necrotic m y o p a t h y t h a t can be associated with r h a b d o m y o l y s i s . M u s c u l a r d y s t r o p h y a n d mitochondrial disorders a r e usually painless, b u t a small p r o p o r t i o n of patients, including some with mild Becker's muscular d y s t r o p h y with minimal or no w e a k n e s s , m a y experience myalgias a n d c r a m p s or r h a b d o m y o l y s i s . Several myopathies defined by specific m o r p h o l o g i c a l or physiological c h a n g e s in muscle c o m m o n l y have myalgias or exercise-related discomfort as part of their associated clinical s y n d r o m e . Features of these m y o p a t h i e s include tubular aggregates with or w i t h o u t cylindrical spirals, focal
Table 29.2:
Muscle discomfort associated with drugs and toxins
Inflammatory myopathy Definite Hydralazine Penicillamine Procainamide L-Tryptophan (impurity) Possible Cimetidine Ipecac Lansoprazole Leuprolide L-Dopa Penicillin Phenytoin Propylthiouracil Sulfonamide RliaKlomyolysis + chronic myopathy Alcohol "^-Aminocaproic acid Ampheramines Cocaine Cyclosporine Hypokalemia Isoniazid Lipid-lowcring agents* Bezafibrate Clofibratc Gemfibrozil Lovasrarin Simvastatin Pravastatin Fluvastatin Atorva statin Ccr vista tin Red yeast rice Lithium Propofol Zidovudine Painful myopathy ± rhabdomyolysis Colchicine Emetine Germanium Hypervitaminosis E
Taxenes Zidovudine Myalgia ± myoparhy All rrans-retinoic acid Azathioprinc Bryosratin 1 Captopril Ciguatoxin Corticosteroid withdrawal Cytotoxics Danazol Enalapril Gemcitabine Cold Interferon-a; 2 a and 2b Isotretinoin Kerorolac Labetalol Methotrexate* Metolazone Mycophcnolate mofctil Paclitaxel Retinoids Rifampin Spanish toxic oil Suxamethonium (succinylcholine) Vinca alkaloids Zimeldine Cramps Albuterol Anticholinesterase Bergamor (bergapten) Caffeine Clofibrate Cyclosporine Diuretics Laberalol Lithium Nifedipine Terburaline Tetanus Theophylline Vitamin A
'"Especially with concurrent: Cyclosporine A, Danazol, Erythromycin, Gemfibrozil, Niacin. + With concurrent pantoprazole. depletion of m i t o c h o n d r i a , internalized capillaries, a n d p r o x i m a l m y o t o n i c m y o p a t h y (myotonic d y s t r o p h y type 2 , DM2).
Muscle Overuse Syndromes C r a m p s (see T a b l e 29.3) are a localized form of muscle c o n t r a c t i o n a n d overuse. Pain s y n d r o m e s associated with c r a m p s include discomfort d u r i n g a muscle c o n t r a c t i o n and soreness after the c o n t r a c t i o n d u e to muscle injury. C r a m p s
MUSCLE PAIN AND CRAMPS Table 29.3:
Cramps*
Cramp syndromes Ordinary Common in normal subjects, especially gastrocnemius Pregnancy Systemic disorders Dehydration: Hidrosis; diuretics; hemodialysis Metabolic: Low Na + , Mg + , Ca 2+ , glucose levels Endocrine: Thyroid (hyper or hypo); adrenal insufficiency Drug induced Cramp faseiculation Contractures: Glycolytic disorders; Brody's syndrome; rippling muscle Neurogenic: Cramps and spasms Central disorders: Stiff person syndrome; spasticity Neuromyotonia Denervation, partial: Neuropathy; radiculopathy Familial syndromes Familial cramp syndromes Myopathic: Becker's muscular dystrophy; limb girdle muscular dystrophy (LGMD) 1C Myotonia: Congenita; occasionally dystrophy Contractures Brody's syndrome Glycogen disorders: Phosphorylase deficiency, etc. Rippling muscle syndrome Neuropathic Cramps: Autosomal dominant Dwarfism and muscle spasms Neuromyotonia Treatments for cramps Normalize metabolic abnormalities Quinine sulfate, 260 mg qhs or bid Carhamazepine, 200 mg bid or tid Phenytoin, 300 mg qd Tocainide, 200-400 mg bid Verapamil, 120 mg qd Amitriptyline, 25-100 mg qhs Vitamin E, 400 1U qd Riboflavin, 100 mg qd Diphenhydramine, 50 mg qd Calcium, 0.5-1.0 g elemental Ca 2+ qd *Usual features: sudden involuntary painful muscle contractions; usually involve single muscles, especially gastrocnemius; local cramps in other muscles often associated with neuromuscular disease. Precipitants: muscle contraction; occasionally during
are common in normal people in the gastrocnemius muscle and in patients with fasciculations. They usually atisc duting sleep or exercise and are more likely to occur when muscle is contracted while in a shortened posirion. Relief of cramps is often obtained rapidly by stretching the affected muscle. Active stretching, by contracting the antagonist, may be especially effective treatment because it evokes reciprocal inhibition. Cramps that occut ftequcntly in muscles othet than the gastrocnemius usually herald an underlying neuromuscular disorder. The EMG is useful for defining the specific type of cramp. Cramps of muscular origin include electrically acrive contractions, electtically silent contractures and myotonic
Tabic 29.4:
391
Pain syndromes without chronic myopathy*
Pain of uncertain origin Polymyalgia rheumatica Fibromyalgia Chronic fatigue syndrome Infections Viral and postviral syndromes Brucellosis Endocrine Thyroid: increased or decreased Parathyroid: increased or decreased Familial Mediterranean fever Pain with defined origin Connective tissue disorders Systemic Fasciitis Joint disease Bone: osteomalacia; fracture; neoplasm Vascular: ischemia; thrombophlebitis Polyneuropathy Small-fiber polyneuropathies Cm Ham-Bane Radiculoneuropathy Central nervous system: restless legs syndrome; dystonias (focal) Pain of muscle origin without chronic myopathy Muscle ischemia: atherosclerosis; calciphylaxis Muscle overuse syndromes Drugs and toxins Delayed-onset muscle soreness (DOMS) Cramps Muscle injury (strain) ""Usual features: muscle pain; may interfere with effort, but no true weakness; present at rest, may increase with movement; muscle morphology and serum creatine kinase level normal. types. Electrically active muscle cramps due to myopathy are manifest by itrcgular triphasic action potentials occurring at a rate of 40-60 Hz. They may be a feature of Becker's muscular dystrophy and thyroid disorders. Muscle contractures are active muscle contractions in the absence of electrical activity. These electrically silent muscle contractions occur in myophosphorylase deficiency and other glycolytic disorders, Brody's syndrome, rippling muscle disease, and hypothyroidism (myoedema). Contractures in myophosphorylase deficiency are typically provoked by exercise and may be prolonged and painful. Myotonia appears on EMG as repetitive bursts of action potentials in individual muscle fibers that last 1-30 seconds and have a variable frequency. The action potentials may be triggered by mechanical or electrical stimulation. Myotonic cramps are frequently not painful. Patients with recessive myotonia congenita often note fatigue. Neurogenic cramps may arise from peripheral nerves or the CNS, They often ptoduce discomfort. The common muscle cramp usually arises from motor netve terminals. EMG shows irregular triphasic action potentials at 40-150 Hz that increase and then decrease during the course of the ctamp. Several drugs may precipitate cramps
392 APPROACH TO COMMON NEUROLOGIC At. PROBLEMS (see Table 29.2). Muscle spasms are defined as intense painful muscle contractions that are more persistent than a cramp. There is often palpable tightness and resistance to movement in muscle. Occasionally there is distortion of posture. EMG shows tonic firing of motor unit action potentials. Neurogenic disorders that are associated with cramps, painful muscle spasms, or muscle discomfort include amyotrophic lateral sclerosis, neuromyotonia, spinal stenosis, stiff person syndrome, spasticity, restless legs syndrome, and focal dystonias. Treatment of cramps involves remedy of the underlying disorder or symptomatic trials of a variety of medications. Quinine was effective in treating nocturnal muscle cramps in a double-blind, placebo-controlled trial. Diffuse muscle contraction syndromes are often related to CNS disorders associated with drugs or toxins (see Table 29.2). They include malignant hyperthermia, neuroleptic malignant syndrome, and toxic disorders related to phencyclidine, amphetamine, tetanus, and strychnine. Diffuse contraction syndromes produce great discomfort in the awake patient. In the postoperative period, myalgia and fasciculations often occur after the use of succinylcholinc (suxamethonium).
Myalgia Syndromes without Chronic Myopathy Polymyalgia syndromes (see Table 29.4) are characterized by pain localized to muscle and other structures without muscle weakness. The pain may produce the appearance of weakness by preventing full effort. This type of "weakness" is characterized on examination by sudden reductions in the level of effort, rather than the smooth movement through the range of motion that is detected with true muscle weakness. Polymyalgic pain is often present at rest and is variably affected by movement. Serum CK levels and EMG are normal. There are no major pathological changes jn muscle unless the discomfort produces disuse and atrophy of type II muscle fibers. Muscle biopsies may show changes associated with systemic immune disorders, including inflammation around blood vessels or in connective tissue. Many polymyalgia syndromes have clear underlying disorders, including systemic immune disease, drug toxicity, and small-fiber polyneuropathies. Some syndromes associated with muscle discomfort, such as polymyalgia rheumatica, fibromyalgia, and chronic fatigue syndrome, are defined by a series of clinical criteria and have no well-defined pathophysiology. Polymyalgia rheumatica usually occurs after age 50 years and manifests with pain and stiffness in joints and muscles, weight loss, and low-grade fever. The pain is symmetrical, involves the shoulder, neck, and hip girdle, and is greatest after inactivity and sleeping. Polymyalgia rheumatica can be associated with temporal arteritis. Patients often have an elevated erythrocyte sedimentation rate (>40 mm/hour). Pain improves within a few days after treatment with corticosteroids (prednisone, 20 mg/day). The diagnosis of
fibromyalgia depends on a history of widespread musculoskeletal pain, most commonly around the neck and shoulders, for 3 months or more, and examination findings of tender points on the extremiries and trunk. Patients also may note fatigue and disturbed sleep, headache, irritable bowel syndrome, and aggravation of symptoms by exercise, anxiety, or stress. The diagnosis of chronic fatigue syndrome requires symptoms of muscle fatigue for at least 6 months. Myalgias, paresthesias, headache, dizziness, diaphoresis, fainting, and memory loss may also be noted. Findings on examination may include a low-grade fever, pharyngitis, and enlarged cervical or axillary lymph nodes. Many patients with chronic fatigue syndrome improve spontaneously over time. Treatment of both fibromyalgia and chronic fatigue syndrome frequently includes the use of tricyclic antidepressants. Among controversial syndromes that include myalgias are myoadcnylatc deaminase deficiency, adjuvant breast disorders, Gulf War syndrome, and multiple chemical sensitivity, Pain or discomfort localized to muscle may arise in other structures. For example, hip disease can be misdiagnosed as a painful proximal myopathy with apparent leg weakness. In this situation, external or internal rotation of the thigh commonly evokes proximal pain. Radiological studies confirm the diagnosis. Disorders of bone and joints, connective tissue, endocrine systems, vascular supply, peripheral nerve and roots, and the CNS may also present with discomfort localized to muscle. Pain originating from muscle, often acute, may occur in the absence of a chronic myopathy. Muscle ischemia causes a squeezing pain in the affected muscles during exercise. Ischemia produces pain that develops particularly rapidly (wirhin minutes) if muscle is forced to contract at the same time and subsides quickly with rest. Cramps and overuse syndromes are associated with pain during or immediately after muscle use. DOMS occurs 12-48 hours after exercise and lasts for hours to days. It is most commonly prccipiratcd by eccentric contraction or unaccustomed exercise.
REFERENCES Graven-Nielsen, T. He Mense, S. 2001, "The peripheral apparatus of muscle pain: Evidence from animal and human studies," Clin J Pain, vol. 17, pp. 2-10 Griggs, R. C., Mendel), J. R., &c Miller, R. G, 1995, Evaluation and Treatment of Myopathies, Davis, Philadelphia Julius, D. & Basbaum, A. 1. 2001, "Molecular mechanisms ot nociception," Mature, vol. 413, pp. 203-210 Kincaid, J. C. 1997, "Muscle pain, fatigue and fasciculations," Neurol Clin, vol. 15, pp. 697-709 Pestronk, A. 2003, *** St. Louis, Mo, Neuromuscular Disease Center, Washington University School of Medicine. Available at: www.neuro.wustl.edu/neuromuscular/mpain.html. Ren, K. & Dubner, R. 2002, "Descending modulation in persistent pain: An update," Pain, vol. 100, pp. 1-6
Chapter 30 The Floppy Infant Thomas O. Crawford Cardinal Signs Tone
Power Range of Movement Reflexes IjiJunuiLf
Bulk Sensation Associated Features Clinical Tests Useful in the Examination Traction Response Vertical Suspension Horizontal Suspension Fetal Posture
393 393 395
396 397 i99 399 400 400 400 400 401 401 401
The floppy infant is one of the more common neurological syndromes encountered in the premature neonate ( a nidi a in ,1 patient with acquired immunodeficiency syndrome.
involvement. MRI has greater sensitivity than CT in detecting CNS cytomegalovirus and its extent. MRI may demonstrate increased signal in the periventricular white matter on T2-weighted images and subependymal enhancement after contrast administtation.
inflammatory response and the presence of the organism's mucoid capsule, which isolates it from the patient's inflammatory cells. CNS cryptococcomas, lesions invading the brain parenchyma, are rare in patients with AIDS.
Cryptococcosis
Lymphoma
CNS cryptococcosis is caused by the saprophytic yeastlike fungus Cryptococcus neaformans. CNS cryptococcosis is the third most common CNS infection (after HIV encephalopathy and toxoplasma encephalitis) in patients with AIDS and is the most common fungal infection to involve the CNS in patients with AIDS. Cryptococcal meningitis is the sine qua non manifestation of CNS cryptococcosis. In addition, the perivascular (VirchowRobin) spaces usually are dilatated by cryptococcal spread. Once the perivascular spaces become infected, they tend to become confluent. At that point cystlike lesions, hypodense on CT (Figure .V7A.49) and low on TI-weighted images and bright on T2-weighted images, may be seen in the basal ganglia, mesencephalon, and dentate nuclei. Cryptococcal involvement of the choroid plexus and pituitary gland may occur. In patients with AIDS, cryptococcal meningitis and the other lesions described rarely enhance. This is because of the inability of the patient with AIDS to mount an
Primary CNS lymphoma is the most common CNS neoplasm seen in HIV-infected patients. AIDS-related CNS lymphomas are more often peripheral in location and tend to demonstrate necrosis more often than nonAIDS-related lymphomas. Up to 2 5 % of CNS lymphomas occur infratentorially. Non-AIDS lymphomas appear as hyper dense masses on noncontrast CT examination, whereas AIDS-related CNS lymphoma lesions may be hypodense, probablj related to a greater degree oi necrosis. On MRI, the dense cellularity of lymphoma renders these lesions isointense to hypoin tense on all sequences. Enhancement in non-AIDS lymphoma may be homogeneous, whereas in AIDS-related lymphoma enhancement may be heterogeneous or ringlike, which again may be related to the greater degree of necrosis (see Figure 37A.47). Brain positron emission tomography and single photon emission CT studies arc helpful in differentiating AIDSrelated lymphoma from non-neoplastic brain masses.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Congenital Lesions Two major types of congenital disorders of the CNS can be described (see Chapter 66). Disorders of organogenesis are those in which an alteration of CNS development occurs. Disorders of histogenesis are those with normal development but with abnormal cell differentiation. The disorders of organogenesis include abnormalities of divcrticulation, closure migration, and CSF flow (Chapter 66). The disorders of histogenesis include the phakomatoses (see Chapter 71). Disorders
of Diverticulation
Disorders of diverticulation are caused by failure of the primitive prosencephalon to develop into cerebral hemispheres, and various degrees of failure of separation of the brain and ventricles may occur. Holoprosencephaly. Holoprosencephaly represents absence of cleavage of the forcbrain (prosencephalon). Three types are seen, depending on the severity of the lesion (from most severe to least severe): alobar, semilobar, and lobar. Alobar is the extreme form of holoprosencephaly, resulting in a single monoventricular cavity with thin cortical tissue (Figure 37A.50), Septo-Optic Dysplasia. Scpto-optic dysplasia involves the anterior midline structures of the brain. It consists of an absent septum pellucidum and hypoplasia of optic nerves, chiasm, and infundibulum. On CT and MRI, there is absence of the septum pellucidum, atrophic optic nerves, and large ventricles. Disorders of Closure In agenesis of the corpus callosum, a large bundle of fibers (bundles of Probst) persists, passing anteroposteriorly on the medial aspect of the ventricles. On CT or MRI wide separation of the lateral ventricles occurs, occipital horns may show relative dilatation, and interposition of the third ventricle between the bodies of the lateral ventricles may occur (Figure 37A.51). On sagittal MRI, there is absence of the corpus callosum. In addition, the sulcal markings and gyri in the parasagittal area have a more vertical course. Disorders of Cerebrospinal Fluid Flow Chiari Malformations. In the Chiari type I malformation, the cerebellar tonsils are positioned below the foramen magnum, but the cerebellum is normal otherwise and the fourth ventricle is in a normal position. Syringohydromyelia is a common concurrent lesion, with an incidence of 2 0 - 2 5 % in Chiari 1 malformation (Figure 37A.52).
B FIGURE 37A.50 Alobar holoprosencephaly. (A) Axial computed tomographic scan demonstrates a large central monoventricular cavity with a peripheral rim of cortical tissue. (B) The thalami are fused, and the third ventricle cannot be identified.
STRUCTURAL NEUROIMAGING 5 65
FIGURE 37A.51 Agenesis of corpus callosum. (A) Tl-weighted axial image shows separated and parallel lateral ventricles. (B) Sagittal Tl-wcightcd image shows absence of a midline corpus callosum.
The Chiari II malformation is a dysgenesis of the hindhrain that results in a caudally displaced fourth ventricle and medulla. The essential feature is the pathologic downward displacement of the fourth ventricle extending into the cervical canal so that nonvisualization of the fourth ventricle is common. Anomalies associated
FIGURE 37A.S2 Chiari I malformation with syringohydromyelia. (A) Sagittal Tl-weighted image shows the tonsils extending below the foramen magnum {arrow). The very superior aspect of an intramedullary cyst is seen (long black arrow). (B) The sagittal T1-weighted image of the cervical spine in the same patient demonstrates a syringohydmniyeliu of the cervical spine (arrows). There are multiple scptations within the syrinx (arrowheads), and the cord is widened.
with Chiari II include lukcnschadel skull (pitting of the skull), clivus and petrous scalloping, enlarged foramen magnum, myelomeningocele, dural anomalies (widened tentorial incisura), hindhrain and midhrain
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
anomalies (bcaking of the tectum; Figure 37A.53), and forehrain anomalies. Dandy-Walker Syndrome. In Dandy-Walker syndrome, there is cystic enlargement of the fourth ventricle and hypoplasia of the vermis (Figure 37A.54). The tentorium, torcula, straight sinus, and vein of Galen arc displaced superiorly.
Aqucductal Stenosis. The causes of aqueductal stenosis include infection, Chiari II malformation, and neoplasm, although many cases are idiopathic. Chiari II malformation is the most common cause of hydrocephalus and aqueductal stenosis in early childhood. The lateral and third ventricles are moderately to severely enlarged (Figure 37A.55A). If Chiari II malformation is not present, the fourth ventricle usually is normal in size (Figure 37B.55B).
FIGURE 37A.53 Chiari II malformation. (A) Beaking of the tectum (arrows) is demonstrated in the axial computed tomographic scan of a patient with a Chiari II malformation. (BJ Tl-weighted sagittal image in another patient shows marked hydrocephalus, an enlarged massa intermedia (arrow), and bcaking of the tectum (white arroivhead). The fourth ventricle (open arrow) is not caudally displaced in this patient.
STRUCTURAL NEUROIMAGING
567
FIGURE 37A.54 Dandy-Walker syndrome. The fourth ventricle is replaced by an enlarged midline cyst in the axial computed tomographic scan. Note the hypoplasia of the vermis. Disorders of Sulcation and Migration Heterotopias. Heterotopias have classically been separated into three forms: • The nodular form consists of subependymal nodules of gray matter that arc usually bilateral. • The bulk form consists of islands of gray matter that are usually isolated in the hemispheric white matter (Figure 37A.56). • In band heterotopia, alternating layers of gray and white matter are symmetrical throughout both hemispheres. Schizencephaly. Schizencephaly is a disorder in which there are clefts spanning the cerebral hemispheres. Pathologically, these clefts are characterized by an infolding of the gray matter along the cleft from the cortex into the ventricles. There are two groups: those in which the walls of the cleft are fused (closed lip schizencephaly; Figure 37A.57) and those in which the walls of the cleft are separated (open lip schizencephaly). Destructive
Lesion
Hydranencephaly. In hydranencephaly, there is virtual absence of the cerebral hemispheres except for the
FIGURE 37A.55 Aqucductal stenosis. (A) T2-weighted axial magnetic resonance imaging demonstrates markedly dilatated lateral and third ventricles. (B) The sagittal TI-weighted image (postcontrast) shows the marked dilatation of the lateral and third ventricles hut a small fourth ventricle {arrow). The posterior fossa is small, and the aqueduct is not well seen. basal ganglia. The infra tentorial structures are intact (Figure 37A.58). A severe and early intrauterine vascular accident is the presumed cause. Disorders
of Histogenesis
Tuberous Sclerosis. Hamartomas, the most common lesions seen on MRI in patients with tuberous sclerosis,
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINTCAL NEUROSCIENCES
FIGURE 37A.56 Heterotopia. Bulk form of heterotopia is seen as an island of gray matter that is isolated in the hemispheric white matter. This island of tissue {arrows) has the signal characteristics of gray matter on this T2-weighted image.
FIGURE 37A.57 Schizencephaly. Closed lip schizencephaly appears as a cleft lined by gray matter extending through the full thickness of the cerebral mantle. The island of tissue has the signal characteristics of gray matter on this T2-weighted image (arrows).
are isointense on T l - and hyperintense on T2-weightcd images (see Chapter 71). Subependymal nodules usually are multiple and bilateral; they often calcify and usually are isointense to hyperintense on Tl-weighted images and hyperintense on T2-weighted images. These subependymal hamartomas may degenerate into a giant cell astrocytoma (see Figure 37A.11), which is most often found near the foramen of Monro. Neurofibromatosis. Neurofibromatosis is the most common of the neurocutaneous syndromes. There are two genetically distinct types: neurofibromatosis type 1 and type 2. Neurofibromatosis Type 1. Neurofibromatosis type 1 is inherited as an autosomal dominant disease and is also called peripheral neurofibromatosis or von Recklinghausen's disease. The CNS and calvarial manifestations are diverse and include gliomas of the optic nerves and chiasm (see Figure 37A.27); gliomas in other areas of the brain; neurinomas and neurofibromas of the cranial, spinal, and peripheral nerves; dysplasia of the sphenoid bone and orbit; plexiform neurofibromas of the scalp and elsewhere; and hyperintense brain lesions demonstrated on MRI with T2-weighted images. Neurofibromatosis Type 2. Neurofibromatosis type 2, also called central neurofibromatosis, is inherited as an
FIGURE 37A..S8 Hydranencephaly. Absence of the cerebral hemispheres, with intact basal ganglia and infratentorial structures.
PLATE 37A.I Brain single photon emission computed tomographic images with thallium-201 demonstrate a focal region of increased uptake corresponding to the same location as the lesion seen on computed tomographic scan (see Figure 37A.47). This is a biopsy-proven lymphoma. (Reprinted with permission from Ruiz, A., Ganz, W. L., Post, M. J. D., et al. 1994, "Use of thallium-201 brain SPECT to differentiate cerebral lymphoma from toxoplasma encephalitis in AIDS patients," Am J Neuroradiol, vol. 15, pp. 1885-1894.)
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autosomal dominant disease. The diagnostic criteria for neurofibromatosis type 2 include bilateral eighth nerve schwannomas (see Figure 37A.28) or a unilateral eighth nerve schwannoma with two of the following: neurofibroma or schwannoma in a different location, meningioma, glioma, or a relative with neurofibromatosis type 2, This entity is genetically different from that of neurofibromatosis type 1 and hence optic nerve gliomas, skeletal dysplasias, and cutaneous neurofibromas are rare.
Vascular Disorders Vascular
Malformations
Vascular malformations have been divided into four major types: AVM, cavernous angioma, capillary telangiectasia, and venous angioma (see Chapter 57D). Arteriovenous Malformation. Cerebral angiography is the definitive method of accurately delineating the vascular supply and venous drainage of intracranial AVMs. Morphologically, AVMs appear as wedge-shaped clusters of vessels with the apex directed toward the ventricular surface. The typical AVM appears on spin-echo MRI as a cluster of focal round lesions or serpentine areas of signal void (Figure .37A.59). At this time, conventional angiography is superior to MRA in depicting the arterial supply and venous drainage of the AVM. Cavernous Angioma. Cavernous angiomas are discrete, multilobulated, berrylike lesions rhat contain hemorrhage in various stages of evolution. They may be found in any part of the brain; most are supra tentorial and are generally in the frontal and temporal lobes. In the posterior fossa, the pons and cerebellar hemispheres are the most common sites. Most are not detected by angiography, but occasionally a faint blush can be seen in the late capillary or venous phase. On CT, these lesions may be isodense to hyperdense in noncontrast scans, and calcification is common. MRI is the best modality for demonstrating cavernous angiomas, showing a popcorn-like lesion of mixed signal consistent with hemorrhage in different stages. Capillary Telangiectasia. Capillary telangiectasias are small, angiographically silent or occult vascular malformations, usually revealed on magnetic resonance gradientecho sequences by the presence of small punctate or nodular areas of dark signal ("blooming") due to the susceptibility effect caused by the presence of hemosiderin in the lesion. They may be single or multiple and may cause seizures. Capillary telangiectasias may be associated with neurocutaneous syndromes such as those of Rendu-OslerWeber and Wyburn-Mason. Venous Angioma. Venous angiomas are clinically silent malformations of venous drainage without an arterial
B FIGURE .17A.59 Arteriovenous malformation (AVM). (A) Long repetition time-echo time spin-echo magnetic resonance image shows a wedge-shaped cluster of vessels in tlie left temporal lobe seen as linear and round areas of signal void. Note enlarged draining vein {arrow). (B) Magnetic resonance angiogram formed by a three-dimensional rime-of-flight volume slab through the base of the skull and circle of Willis shows an AVM (small black arrows) in the left temporal lobe. Feeding vessels arise from the left middle cerebral artery {arrowheads). A large medially draining vein is seen (probably a peri mesencephalic vein; large arrow).
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES spinal AVMs. Myelography may show filling defects caused by the enlarged vessels, but since the advent of MRI, the flow voids, flow enhancement in enhanced veins, and flow-related enhancement on MRA make myelography unnecessary in the majority of cases. Cerebral
FIGURE 37A.60 Venous angioma. Postcontrast axial Tlweighted image shows a prominent vein coursing within the left crural cistern {arrow). It is receiving multiple small feeding veins from within the substance of the midbrain {arrowhead}. These findings are typical of a venous angioma. component. Imaging studies delineate typical curvilinear vascular channels receiving drainage from a spoke wheelappearing collection of small tapering veins arranged in a radial pattern (Figure 37A.60). The larger draining veins empty into a targe cortical vein, a dural sinus, or a subependymal ventricular vein. Spinal
Arteriovenous
Malformations
Most spinal vascular malformations are AVMs or AVFs. AVMs have a nidus of vessels and arc fed by enlarged feeding arteries and drain via large veins. AVFs drain directly into enlarged venous outflow tracts. Spinal vascular malformations have been subdivided into four groups. Type I are dural AVFs, which are found mostly in the dorsal aspect of the lower thoracic spine. Type II are intramedullary AVMs that drain into a venous plexus that surrounds the cord and usually are located in the cervicomedullary junction. Type III are larger vascular masses that involve the cord and often have extramedullary extension. Type IV are intradural extramedullary AVFs. Most are anterior to the spinal cord and occur near the conus mcdullaris. MRI may show foci of flow void in enlarged vessels. The cord may be atrophic and often has high signal intensity on T2-weighted images. MRA is a good modality for evaluating these lesions, although spinal angiography has been the definitive diagnostic procedure for evaluating
Infarction
In the first 24 hours after an arterial occlusion with infarction, 8 0 % of MRI scan results are positive, compared with 5 0 % of CT scans. These infarcts are seen as regions of subtly increased signal on T2-weighted images. At this stage the abnormalities arc mostly in the gray matter. In infarcts 2 days to 3 weeks old, the subtle signal intensity changes seen initially become more obvious with increasing signal intensity on long TR images. White matter and gray matter abnormalities then are seen. In 2 0 % of cases there is a hemorrhagic component with increased signal seen on Tl-weighted images if the stroke is greater than approximately 48 hours old. More acute hemorrhagic strokes reveal hypointense to isointense areas on MRI, with factors such as field strength and pulse sequence playing an important role in the appearance. MRI is the most sensitive, accurate, and practical means of imaging acute strokes. The MRI of an infarct 3-6 weeks old is characterized by a smaller and better-defined zone of signal changes. The signal intensity on T2-weighted images is greater because of cystic cavitation. Focal atrophy is also present due to a loss of tissue volume. A crucial factor in stroke management is the determination of a hemorrhagic component in the infarct (Figure 37A.61). Acute hemorrhage may not be as obvious on MRI as on CT, especially if gradient-echo scans have not been done. Hyperacute hemorrhagic lesions may not have adequate time for the accumulation of dcoxyhcmoglobin, so CT scans may be more revealing in the early stroke period. The pattern of cerebral infarction resulting from blood vessel occlusion depends on vascular anatomy, and the signal changes closely follow the anatomical distribution of the arteries (Figure 37A.62). In the case of proximal disease and infarcts caused by systemic hypotension, the anastomotic border zones {watershed zones) between major vascular territories are involved most severely. MRI is superior to CT in evaluating infarcts in posterior fossa structures because CT resolution is limited by skull-base artifacts. Infarcts in the brainstem are small in relation to the extent of clinical damage. The small size of these lesions, in addition to the fact that these patients may be neurologically devastated and therefore poor candidates for MRI, sometimes make these lesions difficult to evaluate. The vessel most often involved in embolic disease is the middle cerebral artery. Smaller, more peripheral infarcts are common with embolic disease. If emboli are multiple, more
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FIGURE 37A.62 Right hemisphere infarct. Noncontrast computed tomographic scan demonstrates a low-density lesion (arrows) involving the right frontal, temporal, and parietal lohes in a patient who sustained a hullet injury to the skull, with injury to the right internal carotid artery.
Hemorrhage and Magnetic
Resonance
Imaging
Acute hemorrhage consists of intact red blood cells and plasma. Intracellular oxyhemoglobin is converted to deoxyhemoglobin (Figure 37A.63), which is then oxidized to methemoglobin (from the periphery to the center). Subsequently, as a result of red blood cell lysis, intracellular methemoglobin becomes free methemoglobin, and hemosiderin concomitantly appears in the periphery. Eventually, methemoglobin is resorbed, and only a hemosiderin cleft remains. As the hemorrhage evolves, each of the stages has unique Tl and T2 relaxation times on MRI, This allows us to determine the age of the hematomas (Table 37A.1).
Hydrocephalus than one vascular territory may be involved. The origin of small, deep infarcts in the capsular and ganglionic regions is unclear. During the chronic stage, these small infarcts resolve to become small cystic lesions, the typical lacunae.
Hydrocephalus is considered to be present when there are enlarged ventricles in the absence of atrophy or dysgenic brain (see Chapter 65). Therefore, a clear difference exists between hydrocephalus and ventriculomegaly
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
FIGURE 37A.63 Acute hematoma. There is a central area that is isointcnse to brain {arrows) in (A) Tl-weighted image and hypointcnsc {arrows) in {B) T2-weighred image, consistent with intracellular deoxy hemoglobin, and a peripheral area that is hyperintense in both Tl and T2 images, consistent with extracellular met hemoglobin, because the latter indicates large ventricles regardless of the cause, CT and MRI can characterize the different patterns of ventricular enlargement to determine the cause, Obstructive
or
Noncommunicating
Hydrocephalus
The hallmark of obstructive noncommunicating hydrocephalus is ventriculomegaly proximal to the site of obstruction with the common associated finding of periventricular edema secondary to transependyma! flow of CSF. The site of obstruction is determined by the characteristic ventricular dilatation. Aqucductal obstruction produces dilatation of the third and lateral ventricles,
whereas the fourth ventricle remains normal (see Figure 37A.55). A colloid cyst of the third ventricle produces only dilatation of both lateral ventricles. Cerebellar tumors may compress the fourth ventricle and cause obstructive hydrocephalus. Communicating
Hydrocephalus
In communicating hydrocephalus, the normal flow of CSF over the cerebral convexities and its resorption arc altered. The most common causes are subarachnoid hemorrhage and meningitis. However, seeding of meninges by metastatic diseases and chronic meningoencephalitic diseases
STRUCTURAL NEUROIMAGING such as sarcoidosis may result also in hydrocephalus. On imaging, all the ventricles are dilatated and the sulci are effaced. Normal
Pressure
Hydrocephalus
The classic clinical triad of normal pressure hydrocephalus (NPH} is dementia, gait apraxia, and urinary incontinence (see Chapter 65). Positive isotope cisternography of NPH shows reflux of the isotope into the ventricles after injection of the isotope into the lumbar thecal sac but no passage of isotope over the cerebral convexities. However, degenerative disorders also may show abnormal CSF flow, so this study is not entirely conclusive. The distinction on MRI or CT of atrophy from NPH is difficult. NPH usually causes uniform thinning and elevation of the corpus callosum and distention of the third ventricle, dilatating the optic and infundibular recesses. The normal CSF flow void in the aqueduct may be accentuated in NPH. There may or may not be periventricular transudation of fluid into the parenchyma in NPH.
SKULL BASE LESIONS MRI has become an essential part of the evaluation of skull base lesions; it can show the margin of the tumor relative to vital structures such as the cavernous sinus and the relationship to the carotid artery. Often, it can differentiate
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tumor from an obstructed paranasal sinus. Fat is found between the various muscle groups beneath the skull base. As the tumor invades this fat, the normal high signal on T l weigbted images is obliterated by the intermediate signal of the tumor. This is especially important in detecting tumor extension through the various neural foramina. For definition of fine cortical bony erosion at the base of the skull, CT is needed.
Nasopharyngeal Carcinoma Squamous cell carcinoma, the most malignant tumor seen in the nasopharynx, tends to be locally invasive and erode through the skull base into the intracranial cavity {Figure 37A.64). Tumor may extend through the petroclival suture and foramen lacerum into the posterior fossa and into the inferior aspect of the cavernous sinus.
Petrous Apex Lesions The two major lesions occurring in the pettous apex are the primary cholesteatoma, or epidermoid tumor, and the granulomatous cholesterol cyst. The latter results from air cells that have been partially obstructed by chronic otitis media and filled with liquid cellular debris and hemorrhage. An epidermoid (pearly) tumor tends to be low signal on Tl-weighted images and bright on T2-wcighted images.
FIGURE 37A.64 Nasopharyngeal carcinoma. (A) Axial computed tomographic scan after contrast administration demonstrates a mass in the nasopharynx, which extends anteriorly to involve the nasal cavity and left maxillary sinus. The lesion is invading the left pterygopalatine fossa {arrows). There is bony destruction of the posterior walls of the left maxillary sinus and lateral wall of the nasal cavity. Tin.1 IIUSS extends posteriorly to the prevertebral space and laterally involves the left carotid space. (B) The mass extends superiorly to involve the ethmoids and left orbit (arrows).
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
The granulomatous cholesterol cyst is bright on both sequences because of the tccurrcnt hemorrhage.
Signal voids representing blood flow scattered throughout the lesion arc characteristic.
Glomus Jugulate Tumor
Chordoma
Glomus jugulare tumor (paraganglioma) arises in the lateral portion of the jugular foramen. There can be significant extension inferiorly beneath the temporal hone and intracranially. On Tl-wcighted images these lesions usually are of intermediate signal intensity, and on T l wcighted images they ate hyperintense (Figure 37A.65).
Chordoma is a tumor of notochordal origin that is seen mainly in the sacium and the clivus. Those originating at the clivus level usually grow and spread through the duta into the middle or postetiot cranial fossa and compress the brainstem. They may extend anteriorly into the nasopharynx and often develop calcification,
FIGURE 37A.65 Glomus jugulare tumor. Axial Tl-weighted images (A) before and (B) after intravenous administration of gadolinium show a lesion in the region of the jugular foramen, which enhances densely (arrows). (C) Axial T2-weighted image demonstrates an isointense to hypointcnse lesion, which has a few signal voids. (D) Computed tomographic scan using bone technique through the skull base shows erosion of the jugular foramen (arrows).
STRUCTURAL NEUROIMAGING On Tl-weighted MRI, a chordoma is seen as a moderately hypointense lesion that replaces the hyperintense clival fat (Figure 37A.66). On T2-weighted images chordomas usually are hyperintense, and calcifications that may be present are seen as hypointensities in the mass (Figure 37A.67). CT shows the bony erosion and calcification to best advantage.
Chondrosarcoma Chondrosarcoma may arise from the base of the skull, commonly in the region of the petroclival suture. It may have an endochondral hone, cartilaginous, or bony origin. On CT and MRI, an erosive, destructive lesion of the skull base or a mass compressing the brainstem may be found. Calcification due to bony lysis or calcium deposition in the tumor may be seen. The tumor spreads by local invasion and rends to recur after surgical removal. The tumor may also arise from the nasopharynx, vomer, and sphenoethmoidal regions and invade the skull base.
ORBITAL LESIONS Orbital Tumors Hemangiomas Hemangiomas are the most common primary tumor of the orbit. Capillary hemangiomas are seen in childhood and cavernous hemangiomas in adults. Capillary hemangiomas appear during the neonatal period and not later than the
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first 2,5 years of life. They show an infiltrating gtowth (Figutc 37A.68) but may regress spontaneously. Cavernous hemangiomas have an insidious onset and never disappear on their own. They are well circumscribed and have an encapsulated pattern. On imaging, the cavernous hemangioma demonstrates a well-circumscribed intraconal orbital lesion (Figutc 37A.69). On MRI these lesions are of low intensity on Tl-weighted images, are markedly hyperintense on T2-weighted images, and enhance with contrast. With MRI the precise delineation of the mass and its relation to the optic nerve and muscle cone can be determined, which is important in the surgical planning. Lymphangioma Lymphangioma is a vascular lesion that is less common than hemangioma. Most of these lesions present at a young age. They show slow progressive growth without regression, and because they ate likely to hemorrhage, sudden symptoms such as proptosis are possible. On MRI these lesions ate hetctogeneous with areas of hemorrhage of varying ages and with regions of cystic change. Dermoid
Lesions
Dermoid lesions are derived from congenital epithelial cell rests. They contain sebaceous glands and other skin appendages. In their growth, they may expand the inner and outer tables of the skull and produce sharply demarcated bone defects with well-defined borders and slightly sclerotic margins. The usual site is in the orbital roof, near the orbital zygomatic suture, and the growth FIGURE 37A.66 Clival chordoma. Sagittal Tl-weighted image demonstrates lesion involving the clivus with destruction of the clivus and extension to the prepontine cistern and apparent encasement of the carotid artery {arrows).
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCLS
FIGURE 37A.67 Chordoma. Coronal (A) Tl-weighted and (B) T2-weighted axial images show a well-defined mass present in the prepontine cistern {arrowheads). Its extra-axial nature is suspected because of the presence of erosion of the clivus and petrous apex (large arrows in B). The small punctate areas that do not enhance are flecks of calcification in the tumor. The displaced basilar artery is outlined with black arrows in A {white arrow in B). These findings are typical for a primary clival chordoma. A meningioma is the major differential possibility for an extra-axial mass in this location, but the presence of bone erosion (B) would be atypical.
FIGURE 37A.68 Capillary hemangioma. Orbital computed tomographic scan of a capillary hemangioma after administration of contrast material. A large mass is noted, primarily in the left orbit. (Reprinted with permission from Sklar, E. M. L., Qucncer, R. M., Byrne, S. F., et al. 1986, "Correlative study of the computed tomographic, ultrasonographic and pathologic characteristics of cavernous versus capillary hemangiomas of the o r b i t , " / Clin NeuroOpbthalmol, vol. 6, pp. 14-21.)
FIGURE 37A.69 Cavernous hemangioma. Orbital computed tomographic scan shows a well-circumscribed intraconal mass located in the temporal portion of the left muscle cone. (Reprinted with permission from Sklar, E. M. L., Qucncer, R. M., Byrne, S. F., et al. 1986, "Correlative study of the computed tomographic, ultrasonographic and pathologic characteristics of cavernous versus capillary hemangiomas of the orbit,' 1 / Clin NeuroOphthalmol, vol. 6, pp. 14-21.)
STRUCTURAL NEUROIMAGING
extends to involve the frontal bone. Less often they arise in the lateral wall of the orbit and rarely in the inferior wall. Focal areas of fat are identified easily on MRI. These lesions usually do not enhance. Orbital
Pseudotumor
An inflammatory lesion with acute onset usually occurring in middle age, orbital pseudotumor is difficult to differentiate clinically from a true orbital tumor. Some show spontaneous recovery, whereas others necessitate aggressive therapy, including systemic or local corticosteroid therapy or orbital decompression. Pseudotumor causes diffuse inflammation and resultant edema. Thickening of the sclera may be seen (uveal-scleral pseudotumor), whereas in other cases there is a mass, extraocular muscle thickening, or diffuse orbital infiltration. Fluid surrounding the optic nerve may be seen as a thickened optic nerve. Obliteration of retrobulbar fat planes, an isolated lacrimal gland, or a retrobulbar mass may be seen. If the insertion of an extraocular muscle into the globe is involved, pseudotumor is a more likely diagnosis than thyroid eye disease. On MRI, these lesions are isointense to muscle on T I weighted images, but on T2-weighted images they are hyperintense, making a distinction between pseudotumor and lymphoma possible because orbital lymphoma is most commonly hypointense on T2-weightcd images. Optic Nerve Glioma Optic gliomas are low-grade pilocytic astrocytomas, which may be isolated abnormalities or may be associated with
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neurofibromatosis, especially if bilateral. Three fourths present by age 10 years. Some gliomas have extensive thickening of the pcrioptic meninges (peritumoral arachnoidal hyperplasia), which may be characteristic of patients with neurofibromatosis. Optic nerve gliomas are isointense to normal white matter on Tl-weighted images, and enhancement with contrast is common. In a patient with an optic glioma, the entire visual pathway must be studied because a large number of these tumors involve the chiasm (see Figure 37A.27) and retrochiasmal pathways, extending to the level of the lateral geniculate bodies. A significant proportion of visual pathway gliomas are limited to the chiasm and retrochiasmal tracts, sparing the intraorbital optic nerve. The signal intensity varies with the site of involvement of the visual pathway. Specifically, intraorbital optic nerve masses are of low intensity on T2-weighted images, which may correlate with arachnoid hyperplasia. The chiasmal and retrochiasmal lesions tend to be hyperintense on T2-weighted images. Optic
Nerve
Meningioma
Perioptic meningiomas account for one third of primary tumors of the optic nerve or sheath. Bilateral perioptic meningiomas may be associated with neurofibromatosis. In general, perioptic meningiomas arc most common in adults, and optic nerve gliomas occur in children. These lesions often calcify and enhance markedly on CT (Figure 37A.70). MRI has a major advantage in evaluating optic nerve lesions; MRI allows visualization of the optic nerve directly and separates it from surrounding subarachnoid space and therefore distinguishes optic nerve FIGURE 37A.70 Optic nerve meningioma. Con t ra st- e n h a n ccd computed tomographic scan shows the typical thickening and peripheral enhancement of the right optic nerve characteristic of a perioptic meningioma. Extension from die intrascleral portion of the optic nerve posteriorly to the orbital apex is noted.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSC1ENCES
lesions from sheath lesions. MRI can evaluate also the intracanalicular portion of the optic nerve. MRI signal intensity patterns are variable depending on the site of the lesions (i.e., perioptic versus cxtraconal intraorbital location). The majority of perioptic meningiomas enhance with contrast, and fat suppression techniques with contrast are helpful in delineating regions of gadolinium enhancement.
Ocular Lesions Melanoma Malignant melanoma is the most common intraocular malignancy in adults and usually is unilateral. MRI aids in the differential diagnosis of these lesions because there are other entities (such as choroidal metastases, choroidal nevi, choroidal hemangiomas, sarcoidosis, granulomas, and choroidal detachment) that can simulate a melanoma. Also, MRI helps delineate extraocular exrension, which occurs in 1 3 % of cases. On MRI, melanomas are focal masses that extend into the vitreous and enhance afrer contrast, a characteristic common to most ocular neoplasms (Figure 37A.71). In one series, the majority of melanomas were hyperintense on Tl-weighted images and were hypointense on T l weighted images because of their content of melanin, which has the paramagnetic characteristic of shortening of Tl and T2 relaxation times. However, melanomas may vary in their degree of pigmentation, and lesions may be amclanotic and then indistinguishable from other ocular lesions. These lesions can be confusing because they can exhibit varying paramagnetic behavior when they are melanotic or hemorrhagic, and they are often associated with hemorrhagic retinal detachments. In general, MRI can distinguish a melanotic melanoma from an associated hemorrhagic (or nonhemorrhagic) subretinal fluid collection and from an amelanotic neoplasm on the basis of their intensity signals. Retinoblastoma Retinoblastoma is the most common intraocular malignancy of childhood. The average age at diagnosis is 18 months. The roles for imaging include limiting the diagnostic possibilities, because the differential diagnosis of leukokoria (reflection from a white mass in the eye, giving the appearance of a white pupil) is extensive; defining the extension of the lesion, because retinoblastoma can spread in a variety of ways, including to the retrobulbar orbit and to the CSF spaces, seeding the CNS; and determining whether the contralateral orbit is affected, because bilateral lesions are common (up to one third of patients). Also, the trilateral retinoblastoma (bilateral retinoblastoma associated with a pineal tumor) can be detected by MRI.
FIGURE 37A.71 Choroidal melanoma. (A) Axial Tl-weighted image demonstrates a lesion in the posterior aspect of the globe, whkh is partially hyperintense (arrow). This is consistent with a melanotic melanoma, (B) Sagittal fat-suppressed image shows the hyperintense lesion located in the inferior aspect of the globe {arrow). No retrobulbar extension is seen.
On MRI, retinoblastoma has variable signal intensity. Histopathologically, retinoblastoma is similar to othet PNFT tumors of the CNS and therefore has signal intensity patterns similar to those of these tumors and also may demonstrate hemoirhage and necrosis. The classic CT finding of retinoblastoma is retinal calcification. Because of the insensitivity of MRI for calcification, CT remains the initial diagnostic imaging study of choice when a retinoblastoma is suspected.
STRUCTURAL NFUROIMAG1NG
SPINAL LESIONS Spinal Tumors
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These lesions enhance intensely and homogeneously (Figure 37A.72), except when there is an intratumoral cyst.
Extramedullar-)? Intradural Tumors The two most common extramedullary intradural tumors are the neurinoma (or neurilemmoma) and meningioma. As with any other extramedullar}' intradural mass lesion, these tumors displace the spinal cord and widen the ipsilateral subarachnoid space. Nerve Sheath Tumors. Nerve sheath tumors are the most common intraspinal neoplasm. Neurinomas can occur at any spinal level, are equally common in both sexes, and often present in the fourth decade of life. Although these tumors are most commonly extramedullary intradural in location, they also can be purely extradural or dumbbell-shaped, with both an intradural and an extradural component, the latter extending through the intervertebral foramen. On MRI, these tumors tend to have slightly greater intensity than muscle in T l - and T2-weighted images.
Meningiomas. Meningiomas typically are found in adults. They usually occur in the thoracic spine or at the foramen magnum and are seen more often in women than men. They are primarily extramedullary and intradural in location, but they can be also both intradural and extradural or purely extradural. On MRI with short TR images, these lesions are hypointense to isointensc to spinal cord, and T2-weighted images show meningiomas to be slightly hypcrintcnsc to the spinal cord. These lesions enhance homogeneously and intensely after gadolinium administration. Intramedullary
Tumors
In the extradural and extramedullary intradural spaces, MRI has proved to be as effective as CT myelography while being noninvasive. However, for lesions in the cord, MRI is superior to CT myelography. Although noncontrast MRI
FIGURE 37A.72 Neurofibroma. Postgadolinium Tl-wcighted (A) axial and (B) sagittal images demonstrate an enhancing intradural extramedullary mass {arrows) on the left, displacing rhe cord (arrowheads) to the right. Continued
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NLTJROSCTENCES FIGURE 37A.72, cont'd. (C) On intraoperative spinal sonography in a sagittal plane, the mass is noted displacing the cord anteriorly (arrows).
scans generally detect lesions, gadolinium can help in further delineating them. Astrocytomas. The peak incidence of spinal astrocytomas is in the third and fourth decades of life, but they are not uncommon in children. They are most often located in the thoracic cord, but in children holocord involvement can be found. On MRI with Tl-weighted images astrocytomas are hypointense to normal cord, whereas on T2-weighted images they are hyperintense. The margins of the lesions are poorly defined. After intravenous contrast administration, these lesions almost always enhance, with a homogeneous or in homogeneous pattern. MRI is also
helpful in distinguishing tumor cysts from benign cysts associated with tumor; tumor cysts are surrounded by enhancement, whereas the walls of benign cysts lack enhancement. Ependymomas Ependymomas usually present in patients in the fourth and fifth decades of life, in men more often than women. It is the most common primary cord tumor of the lower spinal cord, conus medullaris, and filum terminalc. Noncontrast MRI demonstrates cord widening (Figures 37A.73 and Figure 37A.74). The lesion is hypointense or hyperintense on T2-weighted images. Areas of hemorrhage may be seen, and intratumoral cysts are common. Hemosiderin deposition is common at the superior and
FIGURE 37A.73 Ependymoma. (A) Tl-weighted and (B) T2-weighted sagittal images demonstrate spinal cord widening at the conus. The lesion is hypointense on short repetition time (TR) images and hyperintense on long TR images. Hemosiderin deposition is noted at the inferior borders of the tumor (arrows).
STRUCTURAL NEUROIMAGING inferior borders (see Figures 37A.73 and 37A.74}. After intravenous contrast, ependymomas tend to enhance intensely and homogeneously. Hemangioblastoma. Hemangioblastoma is an uncommon intramedullary lesion that represents 1-5% of spinal cord tumors. Presentation usually is during the fourth or fifth decade of life, and the cervical and thoracic cord usually are affected. On MRI, a cord cyst with an enhancing
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nodule and, occasionally, evidence of a prominent enhancing feeding arterial vessel may be seen. Twenty percent of hemangioblastomas are associated with von Hippel-Lindau disease. The tumor may present with hemorrhage. Extradural
Tumors
Metastases are the most common of the extradural tumors. They can destroy the vertebral bodies and extend into the FIGURE 37A.74 Ependymoma. (A) Sagittal T2-weighted image shows a hyperintense lesion, which is scalloping the posterior bony margins of the lumbar and sacral vertebral bodies (arrows). (B) Computed tomographic axial image through the sacrum shows the bony erosive changes of the sacrum secondary to the pathologically proven ependymoma,
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
B FIGURE 37A.75 Spinal metastases. (A) Sagittal T1-weighted image demonstrates a metastatic lesion involving the T9 body, with epidural extension of soft tissue tumor into the ventral aspect ot the (.anal. I Hi ()n l 2-weiiihti'il inias'.e (widl a larger field of 1 iev, | multiple levels are involved with high signal lesions. Also, compression of T5, T9, and L2 exists. Epidural extension of tumor is noted at T9 with compression of the cord (arrow).
spinal canal, displacing the subarachnoid space and spinal cord. The tumor and adjacent bony changes and the extent of the epidural and paraspinal involvement are well demonstrated on MRI (Figure 37A.75).
Degenerative Disease of the Spine Degenerative Disc Disease As an intervertebral disc degenerates, it loses water, and fibrous tissue replaces nuclear material as the disc collapses (see Chapter 77). Annular fibers weaken,
resulting in disc bulging, and annular tears predispose to disc herniation. A bulging disc extends diffusely beyond the adjacent vertebral body margins, although the concentric annular fibers are intact. An extruded disc extends through all the layers of the annulus and appears as a focal soft tissue mass (Figure 37A.76). These disc herniations may be subligamentous (anterior to the posterior longitudinal ligament} or may rupture through and be posterior to the posterior longitudinal ligament. A free disc fragment is herniated disc material that has separated from the parent disc and may migrate to a position removed from the original disc space. Approximately 9 0 % of lumbar herniated discs occur
STRUCTURAL NEUROIMAGING
at L4-L5 or L5-S1, 7% at the L3-L4 level, and 3% at L1-L2 or L2-L3. On MRI, most bulging discs extend beyond the verte bral body margin in a diffuse manner and have decreased signal intensity on T2-weighted images because of disc degeneration and loss of water, whereas a herniated disc is seen as a focal soft tissue mass displacing the epidural fat or thecal sac (see Figure 37A.76) and can show enhancement along the periphery of the disc because of the presence of reactive vascular connective tissue.
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degenerative arthritis involving the synovial joints such as the facet joints. These terms often are used synonymously because the conditions often coexist. Both lead to narrowing of the spinal canal or neural foramina and as a result can cause cord compression or root entrapment.
Spinal Stenosis and Spondylosis
Lumbar Spinal Stenosis. The term lumbar spinal stenosis includes stenosis of the spinal canal, lateral recess, and foramina. Canal stenosis is most common at L2 to L5 levels and causes radiculopathy. Stenosis may be caused by a combination of diffuse disc bulging, facet hypertrophy, and ligamentous thickening.
The most common degenerative process of the spine is spondylosis deformans (osteophytosis). Osteophytes occut because of underlying disc disease. Osteoarthritis is
Cervical Spinal Stenosis. Cervical canal stenosis is most often caused by spondylosis deformans and ligamentous thickening. Foraminal stenosis is caused by hypertrophy of
FIGURE 37A.76 L4 to L5 herniated disc. (A) Herniated disc (arrow) on a gradient-eclio sagittal image is outlined by the high signal intensity of the thecal sac. (B) in this gradient-echo axial image, note the eccentric herniated disc (arrows) deforming the ventral-lateral aspect of the thecal sac.
B
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NEUROLOGICAI. INVESTIGATIONS AND RELATED CLINICAL NEUROSC1ENCES
the uncinate process and superior articular facet. Patients are at particular risk for myelopathy or radiculopathy if the anteroposterior diameter of the cervical canal is less than 11 mm. T2*-weighted gradient-echo images are most effective for evaluating cervical spondylosis because spurs can be distinguished from discs, and the anteroposterior diameter of the canal can be measured. CT scans have been considered the procedure of choice for diagnosing neural foramina! stenosis. However, with .3D gradient-echo techniques, thin sections may be obtained to evaluate the neural foramina, and the accuracy of these sections approaches that of high-resolution CT myelography.
Spinal Trauma Spinal trauma is one of the leading causes of disability. Since the 1970s, important imaging developments have improved diagnosis and paralleled the development of better clinical and more aggressive surgical management of spinal injuries. In choosing a particular radiographical protocol, one must take several factors into account, including the neurological status of the patient, level of injury, age of the lesion, and potential henefit that might be derived from each of the different imaging modalities. Acute Cervical Spine Trauma Fractures Bilateral Interfacetal Dislocation. Bilateral interfacetal dislocation is dislocation of both interfacetal joints at the same level. Interlocking of the articular facets begins with the movement of the inferior articular facets of one vertebra forward over the articular facets of the underlying vertebra.
This causes the laminae and spinous processes to distract and the vertebral bodies to sublux. Radiographically, this is characterized by anterior displacement of the dislocated segment. The inferior facets of the dislocated vertebra lie anterior to the superior facets of the adjacent segment. Often this injury is called double-locked vertebrae. This lesion is acutely unstable because of skeletal and soft tissue disruption at the level of injury, Unilateral Interfacetal Dislocation. Unilateral interfacetal dislocation results from simultaneous flexion and roration. The posterior ligament complex and the capsule of the dislocated facetal joint are disrupted. The interfacetal joint on the side of the direction of rotation acts as the pivotal point, whereas the contralateral side including its inferior facet rides upward and forward over the tip of the superior facet of the inferior vertebra. The dislocated facet is locked and fixed. The contiguous facets are no longer in apposition and arc uncovered, or exposed, "naked" facets. There may be fractures of either of the articular facets; tiny fragments have no clinical significance, but large fractures render the interfacetal dislocations unstable. In the anteroposterior radiograph, unilateral interfacetal dislocation is evidenced by rotation of the spinous processes from the level of the dislocation upward off the midline in the direction of the side of the dislocated interfacetal joint. In the lateral view, forward displacement of the dislocated vertebra is seen. Although the vertebrae below are in the true lateral projection, the vertebrae above are seen obliquely because of the rotational component of the mechanism of injury. This results in a bowtie appearance of the articular pillars of the dislocated vertebra (Figure 37A.77). In the anteroposterior projection the spinous processes are displaced from the midline toward the side of the dislocated interfacetal joint at the level of the dislocation and above.
E1GURE 37A.77 Unilateral interfacetal dislocation. (A) Sagittal reformatted images of computed tomographic scanning show dislocated inferior facet of C6 {arrowhead) anterior to the contiguous superior facet of C7 (arrows). (B) The axial computed tomographic scan shows the dislocated articular mass of C6 {arrowhead) anterior to its subjacent counterpart, the superior facet of C7 {arrow), which is "naked." Continued
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FIGURE 37A.77, cont'd. (C) Axial computed tomographic scan above the level of dislocation shows rotation of the vertebra and spinous process. (D) Axial computed tomographic scan below the level of dislocation shows no rotation. Clay Shoueler's Fracture. Clay shovcler's fracture is an avulsion of the spinous process of C6, C7, or T l . Hangman's Fracture. Usually, hangman's fracture represents bilateral fractures of the pars inrerarticularis of the axis. Less commonly, one or both fractures may involve the superior articulating facet or may be more anteriorly located at the junction of the posterior arch and posterior aspect of the body of C2 (Figure 37A.78).
Jefferson Bursting Fracture. The original description of the Jefferson bursting fracture was that of bilateral fractures of both the anterior and posterior arches of CI. However, the Jefferson fracture may result from a single break in each ring. In the frontal projection of plain films, there is bilateral displacement of the articular masses of C I . In the lateral projection, the anterior arch fracture is seen rarely, but the posterior arch fracture ofren is noted. On the
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
lateral projection, the Jefferson fracture cannot be distinguished from an isolated hyperextension of the posterior arch of the atlas. These fractures can be demonstrated on CT and less well on MRI (Figure 37A.79). Burst Fracture. The burst fracture of the lower cervical spine is a comminution fracture of the vertebral body with retropulsion of bone into the spinal canal, well demonstrated on lateral radiography. CT demonstrates that a posterior arch fracture usually is present. The alignment of the posterior elements is normal. A vertical fracture of the vertebral body is seen on the frontal projection, but the posterior fracture is seen only on CT. Odontoid bractures. Fractures of the dens can occur with either forced hyperflexion or forced hyperextension of the head or the neck. Hyperflexion injuries cause the dens
B
to be displaced anteriorly, and there is forward subluxation of C1 on C2. Hyperextension injuries cause the dens to be displaced posteriorly, with posterior subluxation of CI on C2. The dens moves with CI unless the transverse ligament is ruptured. Fractures of the dens without displacement of CI on C2 can be most difficult to recognize. Polytomography of the dens may be helpful in detecting these fractures. Odontoid fractures have been classified into three types. Type I is an avulsion fracture of the top of the dens. Type II is a transverse fracture of the dens above the body of the axis. Type III is a fracture of the superior portion of the axis body that involves one or both articulating facets (Figure 37A.80). This type of fracture is not really a fracture of the dens but a fracture of the superior portion of
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HCUR1 37A.HU Type III odontoid fracture. (A) Axial computed tomographic semi rbroii^h rlu- .ixi--- body shows tt-.u-inn- lines lli.n traverse both transverse foramina {arrows). (B) Coronal reconstructed image shows fracture through the axis body. (C) Sagittal reconstruction through the midline shows the anterior displacement of the dens. (D) Right parasagittal reconstructed image shows fractures extending through the transverse foramen and therefore not allowing posterior transarticular screw fixation (arrow).
the axis body. Because it involves an area of cancellous bone, it almost always heals. Type III fracture is considered to be mechanically unstable. The low dens fracture disrupts the axis ring. This ring is composed of the cortex of the junction of the pedicle, the vertebral body, the cortex at the junction of the axis and body superiorly, and the posterior cortex of the axis body. Spinal Cord. The information that MRI can provide regarding the acutely injured spinal cord is unrivaled, MRI has been found to be superior in detecting spinal cord parenchymal abnormalities compared with myelography and CT myelography. MRI is the only imaging study that can directly image the spinal cord parenchyma with sufficient resolution and demonstrate intrinsic signal abnormality even in the absence of cord enlargement. Myelography and CT myelography can provide only information regarding spinal cord size or spinal cord compression. MRI can reliably determine whether acute post-traumatic cord enlargement is related to edema or hemorrhage and identify hemorrhage or contusion change in a nonenlarged cord.
Three types of MR! signal patterns in patients imaged 1 day to fi weeks after injury were reported in one study. In 19 patients who demonstrated MRI evidence of cord injury, S had evidence of cord hemorrhage with decreased T2 signal within 72 hours of injury. A peripheral hyperintense rim with persistence of central T2 hypointensity images was seen up to 7 days after injury. In a second group of 12 patients, only cord edema was appreciated (Figure 37A.81). This cord edema showed evidence of some resolution from 7 days to 3 weeks after injury, A mixture of hemorrhage and edema with central hypointensity surrounded by a rim of hyperintensity on T2-weighted images was identified as a third pattern of cord injury in two patients. Resolution of cord lesions with blood products was slower than that of cord lesions that were non hemorrhagic. In I he carh period after injury, Tl-weighred images were useful only in demonstrating cord swelling and failed to reveal significant signal change in the cord parenchyma. Intramedullary cord hemorrhage and extensive cord edema are poor prognostic indicators for neurological recovery. T2* images are the most sensitive sequences for hemorrhage detection in the acute phase.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
FIGURE 37A.81 Cord edema. Focal lesion in the cord, which is hypointense in (A) T1-weighted image and hyperinrense in (BJ T2-weighted image, is consistent with an area of edema {arrows) in a patient with acute spine injury. On the T2-weighted image, the markedly hypointense areas at C5-C6 and C6-C7 disc spaces represent calcified osteophytes.
Deoxyhemoglobin results in signal loss on T2 0, images (Figure 37A.82). Cervical Spine Trauma: Progressive Post-Traumatic Myelopathy Spinal Cord Cysts. Post-traumatic myelopathy can occur in up to 3 2 % of patients with chronically injured spinal cords. Post-traumatic myelopathy may present as early as 2 months after injury or as late as 36 years afrer injury. Progressive post-trauma tic myelopathy may be related to several conditions. One of the more common treatable
parenchymal abnormalities is a spinal cord cyst (Figure 37A.83). Progressive myelopathy also can be seen in the presence of myelomalacia and cord tethering. Cord tethering probably plays a significant role in the development of myelomalacia and spinal cord cysts. There is also evidence that myelomalacia and spinal cord cysts are part of a continuum. Imaging plays a key role in differentiating between spinal cord cyst and myelomalacia because the two are difficult to distinguish clinically. MRI is the modaliry of choice in evaluating patients with a progressive post-traumatic myelopathy. Less common causes of posttraumatic myelopathy that are also detectable by MRI
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FIGURE 37A.82 Cord hematoma. T2* gradient-echo sagittal image shows hypointensity in the cord from C4 to C7 {arrows), consistent with acute hemorrhage (deoxyhemoglobin) in the cord. include cord compression from vertebral malalignment, herniated disc or osteophytes, arachnoid cysts, and cord atrophy. Spinal cord cysts almost always follow CSF signal intensity on MRI (see Figure 37A.83}. CSF pulsationinduced signal loss or flow-related enhancement may be seen in large pulsatile cysts and can alter the MRI appearance. Although cyst contents may contain an elevated protein content compared with CSF and theoretically shorten Tl and T2 relaxation, this is rarely a problem. A well-defined border usually can be traced around the cyst,
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FIGURE 37A.83 Post-traumatic intramedullary cyst. A large multisegmented intramedullary cyst is present from C1 to T l . This patient was worsening n euro logically after a fracture-subluxation in the distant past and had a prior wide posterior laminectomy. Note linear bands in the cyst, which represent fibroglial septa traversing the cyst. although when a cyst develops in a region of severely damaged spinal cord tissue the entire border may not be well defined. Post-traumatic spinal cord cysts may be a single cavity or contain septations; they may occur above, below, or at a site of initial injury. Cine images may be helpful in determining cyst pulsatility. Postoperative cine evaluation may help determine whethct shunting of the cyst was successful.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Myelomalacia. Closed spinal cord trauma is a common mechanism leading to a myelomalacia or soft cord. Histologically, myelomalacia is characterized by microcysts, reactive astrocytosis, and thickening of the piaarachnoid. Intraoperative observations at our institution have always revealed cord tethering. Untethering of the spinal cord may lead to clinical improvement. By MRI, a myelomalacic cord typically reveals abnormal hypointcnsc signal that is greater in intensity than the CSF on Tl-weighted images (Figure 37A.84). T2-weightcd images reveal corresponding hyperintensity within the spinal cord. The proton density sequence may be helpful when there is difficulty distinguishing between myelomalacia and a spinal cord cyst. Myelomalacia does not parallel CSF and reveals isointense to hyperintcnsc signal change relative to normal spinal cord on the proton density images. The margins of a myelomalacic cord also are usually irregular and ill defined. A myelomalacic cord may be normal in size, atrophic, or expanded. Thoracolumbar Trauma. Fractures of the thoracolumbar spine are second in frequency to fractures of the cervical spine. Thoracolumbar fractures make up one third of spinal fractures. Fractures of the Upper Thoracic Spine (Tl to T10). Fractures of the upper thoracic spine are different from other levels of spinal fractures because they are stable: The rib cage and the strong attaching costovertebral ligaments limit the degree of motion of this segment of the spine. The most common type of fracture that occurs in the upper thoracic spine is the compression or axial loading fracture, which leads to different degrees of anterior wedging of the vertebral body affected. When neurological deficit occurs, it usually is caused by cord compression secondary to the presence of retropulsed bone in the spinal canal. Alternatively, the cord may be compressed by herniated nucleus pulposus or epidural hematomas. In addition to the anterior wedging fractures, the upper thoracic spine may be affected by burst fractures, usually secondary to a severe axial loading force applied to the vertebra. Burst fractures of the upper thoracic spine may have associated fractures of the posterior neural arch {Figure 37A.85). Any comminuted retropulsed bone fragment can cause cord compression or cord maceration, a finding that is well demonstrated on MRI. A third type of post-traumatic upper thoracic spine fracture is the sagittal slice fracture, in which the vertebra above telescopes into the vertebra below with secondary displacement of the latter. Although most upper thoracic spine fractures are stable, instability necessitating surgical correction is seen in instances of complete dislocations, kyphosis greater than 40 degrees, progressive kyphosis, persistent pain, and progressive neurological deficits. Another indication for surgical intervention in patients with upper thoracic fractures is MRI demonstration of disruption of the spina!
FIGURE 37A.84 Post-trauma tic myelomalacia. Sagittal Tlweighted magnetic resonance image shows postsurgical anterior cervical decompression and fusion from C4 through C6. The cord at C5 appears expanded, with an ill-defined hypointensity. The differential diagnosis was between a post-traumatic syrinx and a microcystis myelomalacia with tethering of the cord anteriorly and posteriorly to the surrounding dura. supporting ligaments. In the setting of acute trauma, radiographics! findings suggestive of spinal instability include vertebral subluxation, widening of the interspinous or interlaminar distance, disruption of the posterior body line, and vertebral wedging greater than 4 0 % . Fractures of the Thoracolumbar function (Tl 1 to L2). The thoracolumbar junction is one of the areas most commonly affected during spinal trauma. Most thoracolumbar injuries occur between T12 and L2, the area of transition between a stiff and more mobile segment of the spine. Several authors have creared a mechanistic classification for the thoracolumbar fractures. This classification divides the vertebra into three main regions: the anterior column, middle column, and posterior column (the "threecolumn" concept}. The anterior column is composed of the anterior longitudinal ligament, the anterior annulus fibrous, and the anterior vertebral body. The middle column
STRUCTURAL N EURO IMAGING 591 posterior elements arc distracted. There are several types of hypcrflcxion injuries. Hyperflexion compression fractures (Figure 37A.86) commonly affect T12, LI, and L2. The compression force can occur anteriorly or laterally, which becomes manifest on radiography or MRI by loss of height of the vertebral body anteriorly or laterally. There is focal kyphosis and scoliosis, fracture, or all three, usually of the
FIGURE 37A.85 Male patient involved in a motor vehicle accident. Two contiguous axial cuts (bone windows! through '17 show the severe nature of the fracture. The burst fracture is associated with fracture of the posterior arch and costotransverse process. There is mild compromise of the canal. (Reprinted with permission from Ruiz, A., Post, J. D., 8c Sklar, E. M. L. 1996, "Traumatic thoracic and lumbar fractures," Appl Radiol, Oct, pp. 49-57.) consists of the posterior longitudinal ligament and the posterior annulus fibrous. The posterior column consists of all structures behind the posterior longitudinal ligament (neural arch). The main purpose of this classification is to predict the stability and neurological sequelae of the fractures of the thoracolumbar region. An intact middle column implies stability and vice versa. Fractures of the anterior column rarely are associated with a neurological deficit. Three basic forces act to injure the middle column: axial compression, axial distraction, and lateral translation. These vectors of force are applied in the x-, y-, or ?-axis of the spine, producing the following types of injuries. Hyperflexion Injuries, Hyperflexion injuries are the most common type of injury affecting the thoracolumbar spine. The anterior column is compressed, whereas the
FIGURE 37A.86 Chronic hypcrflcxion compression fracture of T12. Sagirtal Tl- and T2-weighted images. There is severe loss of height of the T12 body anteriorly with associated endplatc disruption. Note the focal kyphos deformity and the degree of retropulsed bone compressing the sac and indenting the cord. (Reprinted with permission from Ruiz, A., Post, J. D., &: Sklar, E, M. I„ 1996, "Traumatic thoracic and lumbar fractures," Appl Radiol, Oct, pp. 49-57.)
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NEUROLOGICAL INVEST!CATIONS AND RELATED CLINICAL NEUROSC1ENCES
anterosuperior endplate, and commonly a paraspinal hematoma. Flexion distraction injury more often occurs from LI to L3. This injury may occur in two different ways. In one instance, the middle and posterior column may be disrupted by the tensional forces applied, with secondary rupture of the annulus fibrosus and subluxation. A second way this type of spinal injury occurs is when the hyperflexion is around an axis anterior to the anterior longitudinal ligament. When this occurs, the entire vertebra is pulled apart or distracted by the tensile force. This type of spinal
injury leads then to what is known as a Chance fracture or seat belt injury (Figure 37A.87). Radiographics!ly, a split fracture through the spinous processes, pedicles, and laminae is demonstrated. The fracture line extends upward to involve the vertebral endplate anterior to the neural foramen. There is also severe disruption of the spinal ligaments and distraction of the intervertebral disc and facet joints. The fracture is unstable and usually associated with severe abdominal injuries. Axial Compression Fracture. The characteristic fracture in this group is the burst fracture (Figure 37A.88). An axial
FIGURE 37A.87 Chance fractures. Female adolescent involved in a motor vehicle accident while wearing a lap seat belt. The patient sustained a flexion distraction injury. Contiguous sagittal T2-weighted images demonstrate a split fracture through the posterior elements and posterior 1.2 body. There is injury to the posterior spinal ligament. (Reprinted with permission from Ruiz, A., Post, J. D., 6c Sklar, E. M. L. 1996, "Traumatic thoracic and lumbar fractures," Appl Radiol, Oct, pp. 49-57.)
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FIGURE 37A.88 Axial compression fracture of T12. Sagittal Tl-weighted images demonstrating superior endplate fracture, wedging deformity, and retropulsion of T12, severely compressing the cord. The decreased signal of T12 vertebra is caused by marrow edema. (Reprinted with permission from Ruiz, A., Post, J. D., 8; Sldar, E. M. L. 1996, "Traumatic thoracic and lumbar fractures," Appl Radiol, Oct, pp. 49-57.) loading force pushes the intervertebral disc through the endplate inferiorly (vertical disc herniation) with secondary comminution of the vertebral body. Approximately 9 0 % of burst fractures occur from T9 to L5. A second burst fracture is present in less than 1 0 % of cases. Radiographic findings characteristic of this fracture are severe anterior vertebral body wedging, bone retropulsion with differenr degrees of neural canal narrowing, neural element compression, increased interpediculate distance, and a vertical fracture
through the vertebral body, pedicle, or laminae. Depending on the degree of hone retropulsion and level of injury, different degrees of cord, conus, and cauda equina damage may be present. This injury is unstable. C T a n d MR! are the best modalities to evaluate this injury. The former demonstrates the degree of bony canal narrowing, whereas the latter provides the best information about the relationship between the retropulsed bone and neural elements, including level and degree of neural damage.
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Extradural
Lesions
Traumatic disc herniations can occur at the cervical, thoracic, and lumbosacral levels. The thoracic spine is not affected often because the rib cage and thoracic muscles protect this patt of the spine. A herniated disc may be unrecognized if CT or MRI is not used. In patients with fractures or dislocations who are to undergo stabilization, the discovery of one associated herniated disc may indicate the need for a prompt surgical intervention, specifically a decomptession discectomy and fusion.
Spinal epidural hematomas may produce spinal cord and or cauda equina compression. The clinical presentation is that of a sudden acute back or neck pain followed by sensory and motor deficits wirh progression to paraplegia or quadriplegia. Although epidural hemorrhage in the spinal canal has been regarded in the literature as uncommon, with the availability of MRI, this diagnosis is being made mote often. These hematomas may show some compression of the thecal sac and compression of the spinal cotd (Figutc 37A.89). They show variable signal intensity. MRI is an excellent
STRUCTURAL NKUROIMAGING modality for making the diagnosis ol spinal epidural hematomas. Chronic Sequelae of Trauma. Post-traumatic spinal cord cysts and myelomalacia can occur in the thoracic spine and in the cervical region. Subarachnoid cysts may follow trauma, and the definitive diagnosis is difficult. Prom our experience, MRI appears to be the most efficient study in diagnosing and characterizing acquired subarachnoid cysts and associated abnormalities.
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of the disc occurs in one half of cases, and spread of infection beneath the anterior [ongirndin.il ligament may involve noncontiguous vertebral bodies. This multiplicity of vertebral body involvement sometimes makes differentiation from metastatic disease difficult. Paraspinal infection and gibbus deformity are common in tuberculous spondylitis. The size of the paraspinal lesion has been noted to be generally larger in tuberculosis than in pyogenic infections. These paravertebral ahscesses may calcify and thus may be better identified on CT.
Infection of the Spine. Infections of the spine often involve the vertebral body or disc space. The organism most often implicated is Staphylococcus aureus, responsible for 6 0 % of such infections, even in patients with AIDS. Although CT is useful in detecting bone destruction associated with vertebral osteomyelitis, its depiction of the intraspinal soft tissue structures is limited. Because MRI detects bony changes earlier and shows associated soft tissue abnormalities, it is the imaging study of choice for evaluating inflammatory disease of the spine. Discitis and
Vertebral Osteomyelitis
Pyogenic Infections. Pyogenic infections have a peak incidence in the sixth to seventh decades. Infectious spondylitis involves both the vertebral body and adjacent disc space. The most common site of pyogenic infection is the cancellous bone adjacent to the endplate because of its rich vascularity. The infection then spreads into the disc space. Two thirds of patients have infection limited to the disc space and the adjacent vertebral bodies, and one fourth have involvement at more than one level. MRI detects infection earlier than other imaging modalities. The replacement of marrow by inflammatory tissue is seen as abnormally low signal intensity in the vertebral body on Tl-weighted images (Figure 37A.90). Disc space involvement usually is seen as narrowing of the disc space and a slight loss of signal of the nucleus pulposus on Tl-weighted images and high-intensity signal in the disc on T2-weigh ted images. In many patients these changes in the bone and disc are associated with adjacent inflammatory tissue anteriorly or posteriorly in the epidural space of the spinal canal. After contrast administration, enhancement is seen in the infected disc space and vertebral bodies. Tuberculous Infections. The most common site of infection of tuberculous spondylitis is at LI; it is much less common in the cervical and sacral regions. Classically, spinal tuberculosis is thought to begin in the anteroinferior portion of the vertebral body. The infection can spread beneath the anterior longitudinal ligament involving adjacent vertebral bodies. Bone destruction typically is more extensive than in pyogenic infections. Contiguous vertebral body involvement with destruction
FIGURE 37A.90 Disc space infection. L4-L.S disc space infection in a 65-year-old intravenous drug abuser with blood cultures positive for Staphylococcus aureus. Magnetic resonance imaging scans reveal changes consistent with disc space infection and osteomyelitis at L4-L5. (A) Tl-weighted image shows abnormal low signal in the 1.4 and 1.5 bodies. Continued
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Epidural Abscess. An epidural abscess, although an uncommon entity when not associated with osteomyelitis or discitis, is important to recognize because early diagnosis greatly improves patient outcome. MRI generally facilitates the diagnosis and may be positive earlier than a radionuclide scan. Early diagnosis is important because timely decompression can save neurological function. Flexion-rotation injury is unusual but very unstable and often associated with severe neurological damage and sequelae such as paraplegia. The anterior column is compressed during rotation, whereas the middle and posterior columns are disrupted by tensional forces. Subluxation and dislocation are common imaging findings as are widening of the intcrspinous distance and fractures
of the laminae and transverse processes, facets, and adjacent ribs Although MRI and CT myelography are equally sensitive ( 9 1 % and 9 2 % , respectively) in detecting epidural abscesses, MRI offers the advantage of distinguishing epidural abscesses from other entities, such as herniated discs, spinal tumor, or spinal hematoma (Sklar et al. 1993). Another advantage of MRI over CT myelography is its noninvasive nature, avoiding the potential of spreading the infection and producing meningitis via the spinal puncture needed for myelography. On plain MRI, an epidural abscess appears as a mass that is isointense to spinal cord on Tl-weighted images and often has high-intensity signal on T2-wcighrcd images. The epidural abscess may go
STRUCTURAL NLUROIMAGING unrecognized if its signal is similar to that of adjacent CSF. With contrast enhancement, however, an epidural abscess can be delineated clearly on MRI. Most epidural abscesses enhance in a homogeneous fashion, occur adjacent to an infected disc space level, and involve two to four spinal segments. The organism most commonly responsible for epidural abscesses is S, aureus, as in vertebral osteomyelitis.
REFERENCES Ruiz, A., Ganz, W. L., Post, M. J. D., et al. 1994, "Use of thallium201 brain SPECTT to differentiate cerebral lymphoma from
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toxoplasma encephalitis in AIDS patients," Am J Neuroradiol, vol. 15, pp. 1885-1894 Sklar, E. M. L., Post, M.J. D,, & Lebwohl, N. H. 1993, "Imaging of infection of the lumbosacral spine," Neuroimaging Clin N Am, vol. 3, pp. 577-590 Sklar, E. M. L., Queneer, R. M., Bowen, B. C, et al. 1992, "Magnetic resonance application in cerebral injury," Radiol Clin North Am, vol. 30, pp. 353-366 Sklar, E. M. I.., Queneer, R. M., Byrne, S. R, et al. 1986, "Correlative study of the computed tomographic, ultrasonographic and pathologic characteristics of cavernous versus capillary hemangiomas of the orbit," / Clin Neuroophthaimol, vol. 6, pp. 14-21
Chapter 37 Neuroimaging B. COMPUTED TOMOGRAPHIC AND MAGNETIC RESONANCE VASCULAR IMAGING Brian C. Bowen, Gaurav Saigal, and Armando Ruiz Magnetic Resonance Angiography 599 Traditional Methods 599 3D Contrast-Enhanced MRA 602 Applications 603 Extracranial Circulation: Carotid and Vertebral Arteries 603 Intracranial Circulation 607
Vascular Malformations and Tumors Extracranial Circulation: Spine Computed Tomographic Angiography Methods Applications Conclusion
For the past decade, a major focus of neuroimaging has been the development of noninvasive methods far delecting vascular disease. Three techniques, magnetic resonance angiography (MRA), computed tomographic angiography (CTA), and Doppler sonography (DS), are now used commonly in clinical practice and have progressed to the point that, individually or in combination, these techniques rival catheter angiography in accuracy of detection of certain vascular lesions, such as extracranial carotid stenosis or dural venous sinus thrombosis. Although MRA has been applied more extensively than CTA, the use of CTA is growing rapidly because of the availability of helical computed tomography (CT) scanners. CTA has achieved results comparable to those of MRA in detecting cervical carotid stenosis and intracranial aneurysms (White et ai. 2 0 0 1 ; Randoux et al, 2001).
tipped through a small angle (typically 10-40 degrees) so that it now has two components: a transverse magnetization, which produces the detectable magnetic resonance (MR) signal, and some residual longitudinal magnetization. The transverse magnetization is defined by two properties: its magnitude and its orientation (or phase angle). The magnitude produced by nuclei in flowing blood (moving or flowing nuclei) can be made to differ from that produced by nuclei in the adjacent stationary tissue (stationary nuclei). This difference is the basis for vascular contrast in TOF MRA. Alternatively, the orientation produced by flowing nuclei can be made to differ from that of stationary nuclei using a directional flow-encoding magnetic field gradient. This is the basis for vascular contrast in PC MRA.
MAGNETIC RESONANCE ANGIOGRAPHY Traditional Methods In general, two methods that do not include an injectable contrast agent have been used to generate contrast between flowing blood in a vessel and surrounding stationary tissues. The first and most commonly used method is rime-of-flight (TOF) MRA, and the second is phase contrast (PC) MRA. In both methods, hydrogen nuclei (protons) in a selected volume of interest are excited using a radiofrequency (RF) pulse, which is typically part of a gradientrecalled echo pulse sequence. Before excitation, the nuclei have a net longitudinal magnetization parallel to the main magnetic field. After excitation, the magnetization has been
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The difference in magnitude, and hence signal, for flowing nuclei and stationary nuclei in TOF MRA results from the following effects. The stationary nuclei remain in the volume of interest throughout the time of the MR scan and arc repeatedly exposed to an RF excitation pulse at short intervals (recovery time [TR] less than 50 milliseconds). After a few excitations, the longitudinal magnetization of the stationary nuclei is reduced significantly to a steady-state value, well below the initial value. Consequently, the magnitude of the transverse magnetization on successive excitations is small, resulting in an MR signal from stationary tissue that is markedly reduced, or saturated. Flowing nuclei, on the other hand, do not remain in the volume of interest. Because of continual wash-in and wash-out, the flowing nuclei experience only one or a few excitations (Plate 37B.I). The MR signal from flowing blood therefore is unsaturated (appearing bright on the MRA image) and greater than that of stationary tissue (appearing dark). The gradient-recalled echo pulse sequence $99
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parameters that primarily affect vascular signal are the TR and the flip angle. As noted previously, the MR signal also depends on the phase of the transverse magnetization. The TOF method minimizes this dependence by using pulse sequences that compensate for the phase variation caused by position or velocity and by sampling the MR signal as soon as possible after excitation (echo delay time |TE] less than 7 milliseconds}. In PC MRA, a magnetic field gradient is used to sensitize the phase of the transverse magnetization to the motion (velocity) of flowing nuclei. Two data sets are acquired with opposite sensitization and then subtracted to produce an image. For stationary nuclei, the net phase is zero, and their signal is eliminated in the final image. However, flowing nuclei move from one position in the field gradient to another between the time of the first sensitization and that of the second sensitization. Because phase varies with position in the field, the net phase after subtraction of the two data sets is nonzero, and there is residual signal from flowing blood (Figure 37B.1). To fully characterize the moving nuclei in three dimensions, flow-encoding (sensitizing) gradients must be applied along each of three orthogonal axes (e.g., superior-inferior, right-left, and anterior-posterior). The pulse sequences used in PC studies are designed to impart a phase shift that is proportional to the velocity of the moving nuclei. This phase shift must be between -180 and +180 degrees, and the larger the phase shift within this range, the greatet the vascular signal. Thus
FIGURE 37B.1 Phase contrast method. Flow in the superior sagittal sinus produces bright signal against a dark background of stationary tissue. Elow-encoding gradients were applied along all three axes, with an estimated maximum blood flow velocity of 10 cm per second. The sinus, which has predominantly anteriorposterior and superior-inferior (low, and the cerebral veins, which drain into it and have predominantly right-left flow, all appear bright.
before PC angiography data are acquited, the anticipated maximum blood flow velocity (VENC) must be enteted into the pulse sequence protocol. If the flowing blood has velocities that ate the same as or slightly less than the selected VENC, optimal vascular signal results. Blood flow velocities gfcatet than VENC can produce aliasing artifacts, whereas velocities much smaller than VENC tcsult in a weak signal. Saturation effects are less in PC MRA than in TOF MRA because even heavily saturated nuclei in flowing blood generate a phase angle that is latget than that of stationary nuclei. For both the TOF and PC methods, there are two apptoaches to data acquisition and image reconstruction: two-dimensional (2D) and three-dimensional (3D) Fourier transformation techniques. In 2D TOF MRA, a section (approximately 1,5 mm thick) of tissue is excited, the signal data are acquired, and the image is reconstructed. This process is tepcatcd multiple times as sequential sections (typically mote than 50 sections) are acquired, until the volume of interest has been covered (Figure 37B.2), Ideally, the plane of each section is approximately perpendicular to the vessels of interest so that there is inflow of fresh, unsaturated nuclei into each section. This results in high intravascular signal and good sensitivity to slow flow. This method is useful fot differentiating between slow flow and occlusion. If a long segment of the vessel of intetest lies in the section, however, thete can be satutation of the flowing blood and nonvisualization of the vessel. In 3D TOF MRA, a slab that is a few centimeters thick is excited and partitioned into thin sections (approximately 0.7-0.8 mm). On reconstruction of the 3D data set, a stack of images (partitions or soutce images) is generated (Figure 37B.3). Because these sections ate thinner than the 2D sections, the 3D TOF method has better spatial resolution and is more useful for imaging tortuous and small vessels (e.g., inttactanial arteries). A disadvantage of the 3D method is that flowing blood spends more time in the slab than that in a 2D TOF individual section. Consequently, a vessel passing through the slab may have good vascular contrast on enteting the slab but become barely visible near its exit from the slab. To lessen this saturation effect, multiple thin slabs are used to covet a large region of interest. Additional modifications of the basic 3D TOF method that have been implemented on various MR scanners to improve vessel detection or reduce artifacts include magnetization transfer suppression of stationary tissue, a ramped or tilted optimized nonsaturating excitation (TONE) RF pulse (Atkinson et al. 1994), and a sliding interleaved kY acquisition (SLINKY; Liu et al. 1999). Both the 2D and 3D TOF methods have the disadvantage that stationaty material with high signal intensity, such as subacute thrombus, can mimic blood flow. PC methods are useful in this situation because the high signal from stationaty tissue is eliminated when the two data sets are subtracted to produce the final flow-sensitive images.
PLATE 37B.I Time-of-flight method. (A) The section (or slab) to be imaged has thickness D. The flowing blood in a vessel that traverses the section may have a mean velocity as low as V 0 (no blood flow) or as high as V 3 . At a higher velocity, there is greater wash-in of unsaturated blood (orange) and wash-out of partially saturated blood (brown). Stationary tissue (cross-hatched region) remains in the section and becomes saturated after several radio frequency excitations. (B) As mean blood flow velocity increases, the signal intensity of the vessel increases. Maximum signal is attained at Vi, which corresponds to complete replenishment of the blood in the section in the time (TR) between radio frequency excitations.
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FIGURE 37B.2 Two-dimensional time-of-flight magnetic resonance angiography. Axial (transverse) sections are acquired one at a time from the region of the carotid bifurcation to the skull base. A presaturation band (PRF.SAT) is applied at a set distance above each section as it is acquired and thus "travels" with the section. Signal from the internal jugular veins is suppressed, whereas signal in the carotid and vertebtal arteries is bright.
FIGURE 37B.3 Three-dimensional time-of-flight magnetic resonance angiography. (A) A single slab with axial orientation covers the region of the circle of Willis and proximal cerebral artery branches. There are 51 axial partitions or source images. The dotted line located superior to the slab in the figure represents the lower border of the fixed presaturation band. The signal from downstream flow in the superior sagittal sinus is suppressed. (B) A single source image from the lower portion of the slab. (C) An axial magnetic resonance angiogram produced from all .51 source images using the maximum intensity projection technique. The circle encompasses the proximal left middle cerebral artery, where there are two sites of focal stenosis (sec Figure 37R.9).
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The PC method also incorporates 2D and 3D Fourier transformation techniques to generate images with vascular contrast. In the 2D PC technique, flow-encoding gradients are applied along two or three axes (see Figure 37B.1). A projection image displaying the vessel against a featureless hackground is produced. As described previously, PC studies are less sensitive to saturation effects than TOF studies. Therefore slow blood flow is more easily detected as long as an appropriately low VF.NC has been selected for the data acquisition. The most common applications of the 2D PC method include rapid acquisition of a localizer image of the carotid bifurcation in the neck and detection of flow in the superior sagittal (or other dural venous) sinus, or in the circle of Willis, in patients with suspected vascular occlusion. IntonthHion on flow dynamics can be obtained by acquiring cardiac-gated 2D images, called cine PC MRA. Compared with the 2D techniques, 3D PC MRA provides higher spatial resolution and information on flow directionality along each of three flow-encoding axes (superior-inferior, right-left, and anterior-posterior). The summed information from all three flow directions is displayed as a speed image, in which the signal intensity is proportional to the magnitude of the flow velocity. In general, the 3D PC method has been used less often in clinical studies than the 3D TOF method, primarily because of the longer time needed for data acquisition and uncertainties associated with the choice of VENC. The data set that is acquired in a 3D TOF, 3D PC, or sequential 2D TOF study may be envisioned as a 3D array of pixels corresponding to the stack of partitions or sections. To display the course of a vessel, the hyperintense signal from the vessel-containing pixels is mapped onto a desired viewing plane using a maximum intensity projection (MIP) algorithm, producing a projection image. To obtain an overview of the vascular architecture, MIP images are generated in several viewing planes and then evaluated together. Targeted MIP images are produced from a region of interest within the full 3D volume (Figure 37B.4). On the MIP images, called angiograms because they show the courses of vessels, hyperintense signal from blood flow in both arteries and veins can cause confusion. To simplify interpretation in TOF studies, presaturation bands often are applied during data acquisition. Usually located on one side of the imaging volume, the presaturation band is a zone in which both flowing and stationary nuclei are saturated by an RF pulse that is added to the gradient-recalled echo pulse sequence. The downstream signal of a vessel that passes through the presaturation /one is suppressed because of the saturation of the flowing nuclei. In TOF studies, the location of the presaturation band may be fixed (see Figure 37B.3), or the presaturation band may travel, keeping the same distance from each imaging section or slab (see Figure 37B.2) as it is acquired. In general, the placement of presaturation bands can be chosen so as to identify flow directionality (e.g., subclavian steal),
With the widespread clinical use of TOF MRA to assess neurovascular disease, it has become evident that two effects can limit the method's accuracy (Saloner et al. 1996}. The first effect is intravoxel phase dispersion: the presence of flowing nuclei with different phases in a single voxel. This effect is the result of a complex or disordered fluid flow pattern (acceleration, pulsatility, or turbulence). The net MR signal from the nuclei in the voxel is diminished by cancellation of the diffetcnt phases. This phenomenon is often tesponsiblc for the signal loss in an artery at a site of stenosis or marked curvature or at a bifurcation. This effect is reduced as the TE is shortened. The second effect that can limit the accuracy of the TOF method is saturation of flowing nuclei, which is most sttiking on 3D studies of small vessels. Saturation is lessened by the use of a longer TR, lower flip angle, thinner slab, or the presence of an exogenous paramagnetic contrast agent (gadolinium chelate). Gadolinium lowers the proton Tl relaxation time, preferentially increasing intravascular signal intensity for approximately 30 minutes after infusion.
3D Contrast-Enhanced MRA The simplest type of 3D contrast-enhanced MRA (CEMRA) uses values for TR, TE, and flip angle (e.g., 30-50 milliseconds, 5-7 milliseconds, 20 degrees) and other scan parameters that are typical of the traditional 3D TOF method and is sometimes called contrast-enhanced 3D TOF MRA. The scan time pet 3D volume is on the order of 5-10 minutes, and data are acquired in the first 10-15 minutes after the bolus infusion of a gadolinium contrasr agent (0.1-0.2 mmol per kilogram). Under these steady-state conditions, small intracranial arteries are somewhat better seen, and there is a marked improvement in the visibility of large and small veins. The use of gadolinium overcomes the problem of saturation of the slow-flowing blood in
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intracranial and spinal venous structures that lie within the 3D slab. Presatu ration bands usually are ineffective at suppressing the downstream signal from vessels when gadolinium is present. In the more technically demanding type of 3D CE-MRA (called fast, dynamic, or time-resolved CE-MRA), TR and TE are much shorter (TR less than 10 milliseconds and TF, less than 3 milliseconds), and the total scan time pet 3D volume (usually about 30-50 partitions) is reduced to 5-50 seconds, depending on hardware (gradient strength and rise time) and software (k-space sampling strategy) capabilities (Levy and Maki 1998; Melhem ct al. 1998; Golay ct al. 2001; Fain et al. 2001; Turski et al. 2001). Data are acquired as the bolus of the gadolinium contrast agent (0.2-0.3 mmol per kilogram and 2 - 3 mL per second infusion rate) passes through the vessels of interest, taking advantage of the marked increase in intravascular signal (first-pass method). Vessel signal is determined primarily by gadolinium concentration, analogous to conventional angiography, in which vessel detection depends on the concentration of injected contrast. Intravascular signal loss caused by phase dispersion is negligible because the TE is so short. Because the 5T> CE-MRA method entails more tapid data acquisition, and hence higher temporal resolution, than the traditional TOF method, spatial resolution may be less; however, zero-filling of the data matrix and k-space sampling strategies, such as elliptical centric encoding with sampling of higher spatial frequencies, are used to improve vessel detail. The 3D CE-MRA method has been applied primarily to evaluating the carotid and vertebral arteries in the neck. These ate imaged during the first pass of the gadolinium bolus, before the jugular and other neck veins are enhanced. Data acquisition in which the central lines of k space are sampled during peak arterial enhancement is key to the success of CE-MRA. The most common approaches to synchronizing the 3D data acquisition with the arrival of the gadolinium bolus in the arteries are measurement of the bolus arrival time for each patient using a small (2 mL) test dose of contrast followed by a separate 3D acquisition incorporating the appropriate time delay, automated detection of bolus attival upstream of the arterial segment of interest followed by triggering of the 3D data acquisition (Foo et al. 1997), and real-time monitoring of the bolus location by the scanner operator, who manually triggers the 3D acquisition (Fain et al. 2001). A separate approach avoids the synchronization steps by rapidly and repeatedly acquiring 3D volumes (less than 10 seconds per volume) in the neck beginning at the time of contrast bolus injection. The very rapid scan time ensures that at least one 3D volume showing only attcries will be acquired (Turski et al. 2001). For all of these techniques, both arterial and venous phase images are acquired. Subtraction of venous source images from arterial images, called digital subtraction MRA, increases vessel-to-background contrast.
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APPLICATIONS Extracranial Circulation: Carotid and Vertebral Arteries One of the major clinical applications of MRA is the estimation of stenosis in the region of the carotid bifurcation. The attention given to this application is based primarily on the following conclusions: The percentage of stenosis, determined by catheter angiography using well-defined criteria, has proved effective at stratifying patients at risk for stroke in several multicentcr trials. The North American Symptomatic Carotid Endarterectomy Trial reported that recently symptomatic patients with 7 0 - 9 9 % carotid stenosis who were treated surgically, compared with those treated medically, had an absolute risk reduction of 17% for ipsilateral stroke occurring within 2 years of treatment (Barnett et al. 1998). The European Carotid Surgery Trial showed a similar benefit (European Carotid Sutgcry Trialists Collaborative Group 1998). The Asymptomatic Carotid Atherosclerosis Study found that in asymptomatic patients with more than 6 0 % internal carotid stenosis, carotid endarterectomy reduced stroke risk by 5 3 % over 5 years (Executive Committee for the Asymptomatic Carotid Atherosclerosis Study 1995). The risks of death and disabling stroke due to catheter angiography (1.2% in the Asymptomatic Carotid Atherosclerosis Study) can exceed those of surgery itself (1.1%). The accuracy of the noninvasive neurovascular imaging techniques (MRA, CTA, and DS) has steadily increased in the last decade and, for concordant MRA and DS results, approaches that of catheter angiography, the gold standard. Time-of-FUghl
MRA
Based on the results of early clinical series, several conclusions may be drawn regarding carotid bifurcation stenosis estimated from TOF MRA images (Bowen et al. 1994; Norris and Rothwcll 2001). First, the degree of stenosis tends to be overestimated by the traditional 2D TOF MRA method (Figure 37B.5). A corollary of this observation is that a 2D TOF study with normal or near normal findings effectively excludes the possibility of severe (70-99%) stenosis. The most accurate results are obtained when short TE and small voxel size are used. Second, a consensus estimate of stenosis derived from a combination of the 2D and 3D TOF methods results in greater specificity than 2D TOF alone. This improvement results primarily from the inclusion of the 3D TOF method, in which stenosis is less likely to be overestimated, particularly if original (Figure 37B.6) or reformatted source images are
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stenosis, as determined by catheter angiography (see Figure 37B.5). Third, in detecting stenosis appropriate for carotid endarterectomy, TOF MRA is less sensitive than DS (75% MRA, 8 7 % DS) but more specific (88% MRA, 4 6 % DS); however, when stenosis estimates by TOF MRA and DS are concordant (Polak et al. 199.3) and then taken together, the combined MRA and DS examination is more sensitive (96%) and specific (85%) than either study alone. Furthermore, when patients are classified as to whether carotid endarterectomy is indicated by the noninvasive examination and then judged against the results of catheter angiography, the misclassification rate for the concordant MRA and DS results is much lower than that of cithct test alone (MRA and DS 7.9%, MRA 1 8 % , DS 28%) (Johnston and Goldstein 2001). Therefore surgical decisions are more likely to be correct when based on concordant TOF MRA and DS results. Three-Dimensional
vascular contrast than the two-dimensional and three-dimensional TOF techniques and demonstrates an approximately 50% stenosis {arrow}.
evaluated rather than the MIP images (Anderson et al. 1994). In the combined TOF approach, the 2D TOF method is used primarily to distinguish slow flow from occlusion, and in general the combined TOF approach is considered superior to DS in differentiating high-grade stenosis from occlusion. A "flow gap," which is a segmental dropout of signal from the carotid (or other vessels) caused by intravoxel phase dispersion or saturation, is often taken as a sign of stenosis measuring 7 0 % or more. This association should be viewed with caution, however, because in one published series of patients, flow gap was observed with the 2D TOF technique at sites of 5 0 - 6 0 %
CE-MRA
Compared with 2D and 3D TOF MRA, 3D CE-MRA delineates carotid arterial stenosis better (Willig et al. 1998) (see Figure 37B.5). Surface morphology (e.g., ulcerated plaque) and nearly occluded vessels (e.g., "string sign") are more easily identified, and carotid arterial occlusions are more confidently identified. In recent studies, severe carotid bifurcation stenosis was detected by 3D CE-MRA with high sensitivity (93-100%) and specificity (88-96%) (Remonda et al. 2002; Johnson et al. 2000; Huston et al. 2 0 0 1 ; Lenbart et al. 2002; Wutke et al. 2002), using conventional catheter angiography as the gold standard. Two groups of investigators have reported results for 3D CE-MRA and TOF MRA (Houston et al. 1998; Johnson et al. 2000; Huston et al. 2001). Both groups found that CE-MRA had higher sensitivity than TOF MRA in detecting severe stenosis: 9 3 % versus 8 8 % (Houston et al. 2001) and 94% versus 8 2 % (Johnson et al. 2000), respectively. Specificity of CE-MRA was slightly lower t h a n t h a t o f T O F M R A : 8 8 % versus 8 9 % and 9 5 % versus 100%, respectively. Although we are unaware of any published reports of the sensitivity, specificity, or misclassification rate (for carotid endarterectomy) based on concordant results of 3D CE-MRA and DS, such an investigation seems a likely next step in the process of evaluating noninvasive carotid imaging techniques as alternatives to conventional catheter angiography. Atherosclerotic narrowing of the carotid system less commonly involves the intracranial carotid siphon and the origin of the common carotid artery. Tandem stenosis occurs in approximately 5% of patients with significant bifurcation disease, and the second site usually is the siphon. Although there have been no published reports documenting the accuracy with which MRA detects tandem bifurcation-siphon stenoses, it is sensible to cover the siphon in addition to the bifurcation and cervical internal
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FIGURE 37B.6 Carotid stenosis. Comparison of magnetic resonance angiogram and source image to catheter angiogram. (A) Catheter angiogram of the right carotid system shows narrowing [arrow) at the origin of the internal carotid artery. The findings suggest intraluminal thrombus. (B) A threedimensional time-of-flight angiogram demonstrates similar narrowing (arrow). (C) The axial three-dimensional time-offlight source image at the site of stenosis shows clearly that the lumen is narrowed (arrow) by approximately 50%, In this case, there is agreement between the narrowing shown on source image and that detected by the maximum intensity projection image (B).
carotid artery (ICA) during preoperative screening. For 3D TOP MRA with pulse sequences designed to limit saturation effects (described earlier}, the carotid arteries may be satisfactorily imaged from the level of the midportion of rhe common carotid to the circle of Willis. The origin of the common carotid typically is omitted for several reasons, including inadequate RF coil coverage and respiratory motion artifacts. With CE-MRA the entire length of each carotid can be imaged; however, the spatial resolution may be inadequate to allow confident evaluation of even moderate stenosis of the siphons. At our institution, evaluation of the carotid system by MRA involves a 3D TOF study, using SLINKY, from the common carotid bifurcation to the circle of Willis, and a sequential 2D TOF study from the carotid bifurcation to the skull base (see Figure 37B.2). If there is a flow gap, poorly shown surface morphology, or findings indeterminate for near occlusion
versus occlusion involving the bifurcation and cervical internal carotid, then a time-resolved 3D CE-MRA is done. Atherosclerotic narrowing of the vertebral artery commonly involves the origin or distal intracranial portion. For TOF MRA evaluation of posterior circulation cerebrovascular disease, the vertebral origins usually are not evaluated, for the same reasons that the common carotid origins are nor evaluated. Typically, a 3D TOF study covering the vertebral-basilar system from the C2 level to the tip of the basilar artery is done (Wentz et al. 1994). However, sequential 2D TOF MRA of the neck is useful in determining whether proximal occlusion is present and in demonstrating flow direction in the vertebral arteries in patients with suspected subclavian steal. A 2D TOF study obtained with no presaturation band shows flow enhancement in both vertebral arteries, whereas a study obtained with a superiorly located, walking presaturation band
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FIGURE 37B.7 Vertebral artery arrifactual signal loss. Comparison of traditional magnetic resonance angiography (MRA) and contra st-en ha need MRA (CE-MRA) with conventional catheter angiography. (A and B) Normal catheter angiograms of the right (A) and left (B) vertebral arteries. The left vertebral artery is dominant in this patient with a history of resection of a foramen magnum meningioma. Continued shows flow only in the vertebral artery with normal antegrade flow. The 3D CE-MRA techniques can display both the origins and distal intracranial portions of the vertebrals in a single acquisition and are particularly useful in evaluating vertebral artery segments with partial or complete signal loss caused by slow flow and in-plane saturation effects (Figure 37B.7). The accuracy of 3D CEMRA measurements of stenosis at the vertebral artery origin has yet to be reported, although the accuracy is unlikely to equal that of carotid bifurcation measurements because of the smaller size of the vertebral origins (Koliias et al. 1999). Nevertheless, an analysis of the elliptical centric encoding technique predicts that it can achieve an isotropic spatial resolution of 1 mm (before zero filling) in a field of view (FOV) typically used for bilateral carotid and vertebral imaging (Fain et al. 1999). Stenosis or occlusion of the subclavian artery is now routinely evaluated with 3D CE-MRA. Carotid or vertebral artery dissection may be delected adequately using routine T l - and T2-weighted images; however, subacute, hyper intense thrombus is better seen if fat suppression is implemented on Tl-weigbted acquisitions
to eliminate the high signal intensity from perivascular adipose tissue. When the evaluation includes a 2D or 3D TOF combined study or 3D CE-MRA (Koliias et al. 1999), the detection of stenosis (Figure 37B.8), pseudoaneurysm, or occlusion is improved. Also, the presence of a thrombosed false lumen is more convincingly demonstrated when spin-echo images are supplemented with PC or TOF images showing absence of flow in the false lumen.
Intracranial Circulation Arteries The accuracy of TOE MRA in detecting stenosis or occlusion of the larger intracranial vessels, compared with that of conventional catheter angiography, has been determined by several investigators (Furst ct al. 1996; Stock et a I. 1995). Initially, accuracy was limited by technical shortcomings, such as long TE, lower spatial resolution, and single slab acquisition, that permitted greater loss of vascular signal caused by inrravoxel phase dispersion,
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FIGURE 37B.7, cont'd. (C) Two-dimensional time of flight (TOF) MRA shows extensive signal loss involving the horizontal portions of the right {arrowhead) and left (arrow) vertebral arteries at the level of the foramen magnum. Ill-defined background hyper in ten shy medial to the arrowhead results from cerebrospinal fluid flow in the subarachnoid space. (D) Three-dimensional TOF MRA with higher spatial resolution provides better depiction of small arteries and continuity of the right vertebral artery {arrowhead), yet marked signal loss (arrow) in the left vertebral artery persists. Continued
susceptibility effects, and salutation effects. Signal loss was typically evident in the petrous, cavernous, and supraclinoid segments of the ICA and in the proximal Ml segment of the middle cerebral artery (MCA), Second- and thirdorder btanches of the cerebral arteries were poorly shown. Later, investigators reported that normal vessels and completely occluded vessels could be graded correctly, when compared with catheter angiogtaphy results; however, stenotic segments wete correctly graded (as cither less than ot more than 5 0 % narrowing) in only about 6 0 % of stenoses. Subsequently, technical improvements in the .3D TOF method (variable flip angle, magnetization transfer suppression, multiple thin-slab acquisitions, and higher spatial resolution [512 matrix or greatet]) improved the accuracy of stenosis grading, with investigators reporting
that 8 0 % of stenoses gteater than 7 0 % and 8 8 % of stenoses less than 7 0 % are quantified correctly at MRA. The current approach to evaluating the inttactanial arteries is a multislab 3D TOF acquisition that covets the head from the foramen magnum to the roof of the thitd ventricle. Each slab has a transaxial orientation and may or may not have a superiorly located presaturation band. The axial source images and the rcprojected MIP images (Figure 37B.9) arc reviewed in conjunction with other MR images (e.g., Tl-weightcd, T2-weighted, fluid-attenuated inversion recovery, diffusion-weighted, and susceptibility-weighted [perfusion| images) in an integtated approach to characterizing brain infarction (Wittsack et al. 2002). In the setting of acute infarction with the potential for thrombolytic treatment, protocols often include a rapidly acquired
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FIGURE 37B.7, cont'd. (E) CEMRA shows the entire vertebrobasilar arterial system. Spatial resolution is less than in (D). (F) Zoomed view of the distal vertebral arteries from (E) reveals complete restoration of signal in the right vertebral artery (arrowhead) and nearly complete restoration of signal in the left vertebral artery [arrow), Persistent focal signal loss resulted from a small metal surgical clip adjacent to the left vertebral artery; the clip is obscured by contrast in (B). All MR angiograms were produced with the targeted maximum (pixel) intensity projection technique.
2D PC MR study of the circle of Willis instead of the more time-consuming 3D TOP study. Other clinical settings in which MRA reportedly complements routine MR imaging include sickle cell disease, moyamoya disease, and hemifacial spasm and ttigeminal neutalgia. Flow dynamics (magnitude and direction) in the circle of Willis are more easily determined with the PC method, especially when vessel diameters are 1 mm or more. As described earlier, the simplest type of 3D CE-MRA technique uses scan parameters typical of 3D T O P MRA acquisitions with scan times on the otder of 5-10 minutes per 3D volume. Under these steady-state conditions, visibility of the small intracranial arteries is greater after intravenous gadolinium administration; however, a much greater increase in visibility occurs for the intracranial veins. Consequently, the MIP images become cluttered with veins, resulting in greater difficulty in identifying and
delineating specific arteries. With dynamic 3D CE-MRA, as used for extracranial catotid imaging, temporal resolution is improved, and visibility of arteries is greater than that of veins. However, vascular image detail is variably diminished depending on CE-MRA technique, and temporal resolution usually is incomplete because only about 5 seconds separates the onset of intracranial arterial enhancement from venous enhancement. Some investigators have suggested using careful region-of-intetest MIP postprocessing to further exclude veins from intracranial artery displays. Despite the limits placed on spatial resolution by the dynamic 3D CE-MRA technique, Parker and colleagues (1998} have shown that, in theory, imaging with a TR of 710 milliseconds (e.g., scan time approximately 1 minute per 3D volume} and a Tl relaxation time of 2.S-50 milliseconds for flowing blood containing gadolinium (first-pass arterial concentration of approximately 5-10 mM) can produce
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FIGURE 37B.8 Resolution of carotid dissection followed with magnetic resonance angiography. (A) Magnetic resonance angiogram produced by the three-dimensional time-of-flight technique shows a segmental stenosis [arrows) involving the distal cervical portion of the left internal carotid artery. (B) A repeat study, obtained after anticoagulant therapy, demonstrates a return to normal caliber of the internal carotid artery segment (arrows).
images of the intracranial arteries (approximately 0..S mm diameter) with vascular contrast comparable to that produced by the steady-state 3D CE-MRA technique. Investigational studies indicate that dynamic 3D CE-MRA will play a significant role in evaluating intracranial arterial steno-occlusive disease, but the accuracy, reproducibility, and reliability of CE-MRA measurements compared with those of catheter angiography and TOF MRA in controlled clinical trials have not yet been reported. 3D TOF MRA is now readily accepted as a noninvasive screening tool for familial aneurysmal disease. It has also been used as an alternative to catheter angiography (intraarterial digital subtraction angiography [IA-DSA]) for the surgical management of ruptured aneurysms. A review of the relevant literature for 1988-1998 found that TOF MRA (and CTA) depicted aneurysms with an accuracy of about 9 0 % (White, Wardlaw, and Easton 2000). Sensitivity was much greater for detection of aneurysms larger than 3 mm (94%) than for detection of aneurysms 3 mm or smaller (38%). Diagnostic accuracy was similar for anterior and posterior circulation aneurysms {Figure 37B.10). In general, noninvasive imaging evaluation
includes a review of T l - and T2-weighted (fast) spin-echo images and T2'*-weightcd gradient-echo images, in addition to the source images and MIP images from the MRA acquisition. The role of 3D TOF MRA in assessing intracranial aneurysms before endovascular treatment is adjunctive to the definitive IA-DSA study (Adams, Lait, and Jackson 2000). Based on a composite assessment that included aneurysm detection rate, aneurysm morphology, neck interpretation, and branch vessel relationship to the aneurysm, Adams and colleagues found MRA to be inferior to IA-DSA overall and to have missed aneurysms smaller than 3 mm. Nevertheless, MRA provided complementary information to IA-DSA in anatomically complex areas or in the presence of intramural thrombus. The authors applied the assessment to four different types of image data display: axial source images, multiplanar reconstruction (MPR) of the source image data, MIP images, and 3D isosurfacerendered images. Among these types of images, the MPR and 3D isosurface images were comparable to the IA-DSA images in all categories of the composite assessment, whereas the MIP images scored poorly in all categories
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FIGURE 37B.9 Proximal middle cerebral artery (MCAJ stenosis (same patient as in Figure 37B.3). (A) Coronal reprojection magnetic resonance angiogram was produced from die axial source images shown in Figure 37B.3. The coronal view shows better than the axial view (Figure 37B.3C) that there is stenosis (arrows) involving both M2 branches of the MCA. (B) Catheter angiography confirms the presence of both stenoses (arrows). except aneurysm detection. These findings indicate that better noninvasive characterization of aneurysms with TOF MRA can be achieved by adding MPR or 3D isosurfacerendered images to the source and MIP images that are now routinely reviewed in clinical practice. Although there is no conclusive evidence that CE-MRA is superior to TOF MRA in depicting intracranial aneurysms in general, Jager and colleagues (2000) have shown that 3D CE-MRA is the method of choice for detecting the lumen and connecting vessels of giant cerebral aneurysms {aneurysms larger than 25 mm), Although both the simple steady-state and the dynamic CE-MRA techniques reliably showed the lumen and exiting vessels, the dynamic MRA technique provided superior contrast between flow and background and eliminated the short Tl contamination artifact caused by subacute intraluminal or extraluminal blood clot. Another application of MRA in which CEMRA shows promise is in the follow-up of intracranial aneurysms treated with detachable coils. In a prospective study of 68 patients, boulin and Pierot (2001) found that
the steady-state 3D CE-MRA technique correlated with DSA regarding the presence or absence of residual aneurysm in 9 0 % of cases. In the remaining cases, the primary difference was that MRA failed to detect a remnant lumen measuring less than 3 mm. Because small aneurysm remnants or recurrences were thought not to be clinically significant, the authors concluded that CE-MRA is an option for post-tteatment follow-up and may partly replace IA-DSA. Veins and Venous Sinuses The approach to evaluating the intracranial veins and dural venous sinuses differs from that of arteries because of the lower velocity of venous flow and the morphology of the venous sinuses. For suspected dural sinus occlusion resulting from thrombosis or tumor invasion, the primary technique is 2D TOF MRA in conjunction with spin-echo imaging. To establish the diagnosis of venous thrombosis, lack of visualization of a vein or sinus on the source images
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FIGURE 37B.10 Basilar tip aneurysm. Magnetic resonance angiogram (frontal view), produced from a three-dimensional rime-offlight axial slab acquisition, shows an aneurysm (closed arrow) arising from the basilar artery terminus and measuring 9 mm in longitudinal diameter. Although targeted to the posterior circulation primarily, the maximum intensity projection image includes portions of the precavernous internal carotid arteries {open arrows). and angiogram must 1>L- accompanied by identification of the clot on the spin-echo images at the location of the suspected occlusion (Figure 37B.11). With the 2D TOF technique, optimal flow enhancement is achieved when a section is perpendicular to the flow direction. This condition is best approximated using coronal sections to image the sagittal, straight, and transverse sinuses (as well as the internal cerebral veins, basal veins of Rosenthal, and, to a lesser degree, the vein of Galen). The acquisition of coronal sections can be augmented by the acquisition of oblique sagittal sections to allow better flow enhancement in the postetior portions of the transverse sinuses and the cortical veins draining into the superior sagittal sinus. With the 2D TOF MR venography technique, arterial signal is reduced or eliminated by an axial presaturation band placed across the upper neck below the skull base. A common diagnostic pitfall of the technique is the presence of flow gaps in the transverse sinus. Ayanzen and colleagues (2000) observed these gaps in 31 % of patients with normal MR imaging findings. Flow gaps were not observed in the superior sagittal, straight, or dominant transverse sinuses, so gaps occurring in these locations should raise suspicion of venous obstruction. The authors found that the nondominant transverse sinuses (90% of gaps) or codominant transverse sinuses (10%) that demonstrated the flow gaps were hypoplastic yet patent by conventional catheter angiography, Alternative techniques for demonstrating intracranial veins and dutal venous sinuses lack the robustness of the 2D TOF technique. The 3D TOF technique suffers from saturation effects and hence frequent signal loss in the veins and dural sinuses. The 2D PC technique is limited by
gradient imperfections, eddy currents, aliasing artifacts, and lower spatial resolution. Although the PC technique can be useful in differentiating very slow flow in the dural sinuses from thrombosis, it was recently found to be inferior to the 2D TOF technique and a contrast-enhanced 3D FLASH (fast low-angle shot) MRA technique in displaying the normal septal veins, internal cerebral veins, and the basal veins (Kitchhof er al. 2002), Both the 3D FLASH technique and a 3D magnetization-prepared, rapid-acquisition gradient echo MR imaging technique (Liang et al. 2001) are contrast-enhanced (CE) methods and reportedly are superior to the 2D TOF technique in depicting normal venous structures, especially in overcoming the flow gap artifact. However, these CE techniques have two fundamental limitations: Both techniques involve tapid acquisition (1-2 minutes per 3D volume), so that the intensity of the intravascular signal depends on the timing of the contrast infusion relative to data acquisition, and chronic thrombus enhances with gadolinium and can mimic a patent lumen. Consequently, these two CE techniques should be viewed as adjuncts to the 2D TOF technique.
Vascular Malformations and Tumors Traditional MRA methods (2D and 3D TOF and PC MRA) have played a secondary role to IA-DSA in evaluating inttactanial arteriovenous malformations (AVMs) because of a lack of consistent and complete demonstration of all components of an AVM: feeding attcrics, nidus, and draining veins. For this reason, and
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FIGURE 37B.11 Acute superior sagittal sinus (SSS) thrombosis. (A) Magnetic resonance angiogram (lateral view) produced from 80 sequential two-dimensional time-of-flight coronal sections covering the posterior half of the head. Flow-related signal is observed in the transverse (open arrows) and sigmoid sinuses but not in the SSS {closed arrows) or the straight sinus. Short segments of vessels projecting over the posterior course of the SSS represent patent superficial cerebral veins lateral to the sinus. (B) Postgadolinium, midsagittal Tl-weighted image shows hypointense signal in the SSS [arrows) and enhancing margins. Combined with the results in (A), these findings are consistent with the presence of intraluminal thrombus. because of the general impression that TOF MRA adds little to the spin-echo MR imaging findings useful for preliminary staging of an AVM (nidus size and location and central versus peripheral pattern of venous drainage in the Spetzler and Martin criteria) before definitive IADSA, many investigators have considered TOF MRA of AVMs superfluous. PC techniques have been used by some investigators to estimate blood flow velocities and volume flow rates in the largest arteries supplying the AVM. A high-resolution 3D gradient-echo technique based on the paramagnetic property of deoxyhemoglobin has been used to detect cerebral veins with submillimeter resolution, resulting in greater sensitivity in identifying the presence of small AVMs compared with TOF MRA; however, the technique provides poorer detection of feeding arteries and is markedly limited in its delineation of nidus size and shape when there are susceptibility artifacts from nearby bone, air, or blood products (hemosiderin) (Essig et al. 1999). More recently, high-resolution real-time auto-triggered elliptic centtic-ordered 3D CE-MRA (Farb et al. 2001) and lower-resolution time-resolved 2D CF-MRA (Klisch et al. 2000) have been applied to the evaluation of AVMs and the results compared with those of TOP MRA and IA-DSA, In an initial investigation, Farb and colleagues found that their 3D CE-MRA technique was superior to 3D TOF MRA, particularly in depicting nidus and draining veins. The 3D
CE-MRA technique consistently showed AVM components and their spatial relationships on MIP images and was equivalent to IA-DSA in depicting AVM components in 7 0 - 9 0 % of cases (total patients = 10), based on blinded, independent assessments by two experienced neuroradiologists. Dural arteriovenous fistulas (AVFs) most commonly involve the cavernous, transverse, and sigmoid sinuses along the skull base. Arterial feeders not seen on spin-echo MR sometimes are detected on 3D TOF MRA but much less often than on catheter angiography. Transverse and sigmoid sinus occlusion and dilated cortical veins are detected better by MRA than spin-echo imaging, yet neither technique achieves the accuracy of carheter angiography. Traditional 3D TOF MRA is useful in detecting cavernous sinus fistulas because flow enhancement in the cavernous sinus and contiguous veins can provide evidence of the fistula (Figure 37B.12). This finding must be regarded with caution because venous flow signal has been observed in the cavernous sinus and inferior pettosal sinus in a variable percentage (from 4% to 3 6 % , depending on unspecified technical differences between MR scanners) of patients without clinical evidence of carotid cavernous fistula (Ouanounou et al. 1999). The diagnostic imaging features of venous malformations (angiomas, developmental venous anomalies) are well shown on postgadolinium Tl-weighted spin-echo images.
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B FIGURE 37B.12 Spontaneous resolution of a left carotid-cavernous dural arteriovenous fistula. Magnetic resonance angiograms (axial maximum intensity projection images) of the sellar region and the circle of Willis were acquired with rhe three-dimensional time-of-flight technique (no gadolinium enhancement). The studies, performed (A) at the time of clinical presentation, (B) i months later, (C) 3 years later, show progressive resolution of the venous drainage from the fistula. Flow-related signal in the left cavernous sinus [closed arrow), sphenoparietal sinus {open arrow), and cerebral veins results from shunting of high flow rate arterial blood through the fistula. Note the progressive decrease in signal in the sphenoparietal sinus. Flow-related signal in the left orbit is caused by the ophthalmic artery (arrowheads), not the superior ophthalmic vein, which was found by catheter angiography to be thromhosed at the time of presentation. Continued These features include rhe radially oriented collection of small vessels (medullary veins) that produce a caput medusa or spoke-wheel configuration. This is contiguous with a large trunk vein that drains into cither subependymal or superficial cerebral veins or a dural sinus. The 2D TOF technique and the PC method with low VENC often
display these slow-flow malformations without the use of gadolinium and allow determination of flow direction; however, the 3D TOF technique, which provides greater spatial resolution, requires gadolinium to avoid saturation effects. Cavernous malformations and capillary telangiectasias do not show flow enhancement on MRA studies, and
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FIGURE 37B.12, cont'd. the former usually are identified on spin-echo and gradientecho images by the heterogeneous signal intensity caused hy blood products from prior hemorrhage. The role of MRA in diagnosing intracranial tumors has yet to be defined, and evaluation more commonly involves bolus-chase susceptibility-weigh ted ("perfusion") MR imaging. In general, tumor-associated neovascularity consists of numerous small vessels, which are poorly delineated on traditional MRA compared with catheter angiography. The 2D TOF technique has been used to document dural sinus invasion or displacement by a neoplasm, and the 3D TOF technique is helpful in distinguishing a parasellar tumor from a patent aneurysm. Steady-state CE-MRA delineates small superficial and deep cerebral veins and has been used for preoperative planning in patients with a proven intracerebral mass.
Extracranial Circulation: Spine Spinal MRA is used as an adjunct to MR imaging to improve the visibility of the millimeter-sized intradural vessels and to help differentiate abnormal from normal ones. The combined MR examination provides better characterization of spinal vessels and thus more effective noninvasive screening for vascular lesions, such as dural AVFs, than MR imaging alone (Saraf-Lavi et al. 2002). The improved screening facilitates decisions regarding invasive catheter angiography for definitive diagnosis and endovascular treatment. The combined MR examination also allows the largest normal vessels to be localized noninvasively before surgical or endovascular procedures that carry a risk of cord injury (Yamada et al. 2000).
Enhancement of the intradural vessels with gadolinium contrast agents has been found necessary for optimal detection on MRA. The 3D CE-MRA technique with steady-state conditions (i.e., TOF pulse sequence parameters) has been shown to detect the largest intradural veins in healrhy volunteers: the posterior and anterior median veins and the great medullary veins draining from the surface of the cord to the epidural space. This technique, and to a lesser extent the 3D PC technique, also detects the abnormally enlarged and tortuous veins draining dural AVFs (figure 37B.13) and intramedullary AVMs. In detecting the presence of dural AVFs, the steady-state 3D CE-MRA technique combined with spin-echo MR imaging had a sensitivity ranging from 8 0 % to 100%, specificity of 8 2 % , and accuracy of 8 1 - 9 4 % in a randomized, blinded review by three neuroradiologists of 11 control subjects and 20 patients with proven dural AVFs (Saraf-Lavi et al. 2002). More importantly, in determining the vertebral level of the fistula, the correct level ± one level was predicted in 7 3 % cases by combined MRA and MRI, representing a significant improvement over MRI alone. Improved noninvasive localization of the fistula level potentially expedites the subsequent invasive catheter angiography study. Preliminary studies of spinal vascular malformations using timeresolved or fast 3D CE-MRA indicate that such first-pass studies may provide better depiction of the dural AVF in the neural foramen because of diminished extradural venous enhancement and improved visibility of the feeding arteries of AVMs (Binkert, Kollias, and Valavanis 1999). Although intraspinal vascular tumors such as hemangioblasroma, paraganglioma, hemangiopericytoma, and angioblastic meningioma are rare, preoperative imaging findings that suggest this differential diagnosis arc
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES hemangiopericytoma, in which the mass can mimic ependymoma or schwannoma on routine MR imaging, MRA findings suggesting vascular tumor can lead to the performance of catheter angiography and, if indicated, preoperative embolization.
COMPUTED TOMOGRAPHIC ANGIOGRAPHY Methods
FIGURE 37B.13 Spinal dura] arteriovenous fistula. Gadoliniumenhanced magnetic resonance angiogram (frontal view), targeted to the posterior half of the lower thoracic canal, demonstrates an enlarged and tortuous vessel (arroiv) that courses from the region of the right T12 neural foramen to the posterior surface of the spinal cord, where there are numerous abnormal vessels. The enlarged vessel is the right Tl 2 posterior medullary vein, and it is contiguous with the coronal venous plexus around the cord. The veins are enlarged and tortuous because of retrograde filling by the shunted arterial blood from a fistula in the Tl 2 foramen. The right vertebral foramina at T10, Tl 1, and T12 are labeled. , . . . . . i • , , important tor surgical planning and evaluation. In the few cases that have been reported, the steady-state 3D CH-MRA technique detected abnormal intradural vessels (primarily perimedullary veins) associated with these tumors better than did routine spm-echo imaging (Bowen and Pattany 2000). In cases of lumbar paraganglioma or
With the advent of helical CT scanning, uninterrupted volume acquisition of data from the head and neck region can easily be obtained in less than 1 minute. In general, data are acquired using a slice (collimated) thickness of 1-3 mm and a pitch of 1-2 as a bolus of iodinated contrast traverses the arteries of interest. For CTA of the carotid and vertebral arteries in the neck, the helical volume extends from the aortic arch to the skull base. Typical acquisition parameters are 7.5 images per rotation of the x-ray tube, 2.5 mm slice thickness, and a reconstruction interval (distance between the centers of two consecutively reconstructed images) of 1.25 mm. For the circle of Willis and proximal cerebral arteries, the helical volume extends from the skull base to the roofs of the lateral ventricles and has a smaller field of view than the neck study. Typical acquisition parameters for this higher spatial resolution scan are 3.75 images per rotation, 1.25 mm slice thickness, and an interval of 0.5 mm, To produce intravascular enhancement, a volume of contrast ranging from 100 to 150 mL is injected into a peripheral vein at a rate of 2 - 3 mL per second and followed by a saline chase or flush (20-50 mL). Adequate enhancement of the arteries in the neck or head is obtained approximately 15-20 seconds after injection of the contrast. Most helical scanners have a special feature that allows visual and analytical monitoring of contrast in a chosen vessel upstream from the 3D volume to be scanned. As with CE-MRA, the most common approaches to synchronizing the 3D CT helical data acquisition with the arrival of the contrast bolus are determination of the bolus arrival time using a preliminary test dose, automated detection of bolus arrival and subsequent triggering of data acquisition, and real-time monitoring of bolus arrival and opera tor-triggered data acquisition. Data from the axial source images typically are postproccssed using one or more of the following techniques: multiplanar reformatting, MIP, and 3D volume rendering.
Applications Extracranial
Circulation
Carotid Artery Stenosis. In evaluating occlusive disease of the carotid bifurcation, CTA complements conventional angiography and is an alternative to DS and MRA
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(Figure 37B.14). In the grading of carotid stenosis using North American Symptomatic Carotid Endarterectomy Trial criteria, Randoux and colleagues (2001) found that the rate of agreement between 3D CTA and IA-DSA was 9 5 % . Relative to IA-DSA (the gold standard), severe stenosis (70-99%) was detected with a sensitivity and specificity of 100% and 100% for CTA and 9 3 % and 100% for CE-MRA, respectively. In addition, CTA and CH-MRA were significantly correlated with IA-DSA in depicting the length of the stenotic segment. Other investigators have reported lower sensitivity (range of 80-89%) yet comparable specificity (range of 96-100%) for CTA in detecting severe stenosis (Magarelli et al. 1998; Binaghi et al. 2001). Those investigatots found that TOF MRA had higher sensitivity (92-93%) than CTA and similar specificity (98-100%). Binaghi and colleagues also compared CTA with DS and showed that the sensitivity was the same (89%), whereas specificity was higher fot CTA (100%) than for DS (81%). CTA has several advantages and disadvantages in comparison to the other techniques. Investigators have noted the following advantages: Better visualization of calcifications compared with IA-DSA Images less affected by carotid kinks and loops compared with TOP MRA, which may show false stenotic lesions or flow gaps at such sites (Link et al. 1995) Better localization of the level of carotid bifurcation by including reference points such as the cervical spine and mandible in the image volume Better delineation of plaque irregularities and ulceration compared with IA-DSA (Randoux et al. 2001) Disadvantages of CTA include the following: Use of an iodinated contrast agent with its associated risks Inability to show the carotid siphon adequately so as to exclude tandem stenosis, which may preclude surgery Currently, either CTA or MRA is used to evaluate suspected carotid occlusive disease, with the choice of method determined by clinical conditions (e.g., pacemaker), accessibility of CT and MR scanners, and additional imaging capabilities (CT or MR perfusion brain imaging). The advantages of MRA are the availability of both TOF and CE-MRA techniques and the more extensive history of clinical testing, including the validation of combined DS and TOF MRA examinations in which concotdant results correlated highly with IA-DSA results. Carotid Dissection. Dissections of the extracranial ICA account for up to 2 0 % of ischemic strokes in young
FIGURE 37B.14 Computed tomographic angiography of the cervical internal carotid artery in a patient with a history of transient ischemic attacks. Maximum intensity projection image shows no evidence of stenosis; however, a calcified plaque is demonstrated at the origin of the internal carotid artery {arrow}. Large plaques may obscure the arterial lumen. Improved assessment is possible with a virtual endoscopic view of the affected lumen.
adults (Leys et al. 1995). Although catheter angiography has been considered the gold standard for diagnosing ICA dissections, MRI, MRA, and CTA (Leclerc et al. 1996, 1998) have emerged as alternative, noninvasive approaches to the diagnosis and monitoring of acute ICA dissection. The CTA findings include demonstration of a narrowed eccentric arterial lumen in the presence of a thickened vessel
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wall and occasionally pseudoaneurysm. In subacute and chronic dissection, CTA has been shown to detect a reduction in the thickness of the arterial wall, rccanalization of the arterial lumen, and reduction in size or resolution of pseudoaneurysm. CTA (or MRA) is superior to DS in depicting the middle to distal portions of the cervical ICA, which are commonly involved in dissections (sec Figure 37B.8). CTA is likely to be superior to MR imaging alone in evaluating pseudoaneurysms because MR findings often ate complicated by the presence of flowrelated artifacts. CTA usually is inferior to MRI and MRA in depicting dissections at the level of the skull base because CT findings can be masked by beam hardening and other
artifacrs and by similarities in the densities of the tempotal and sphenoid bones and the dissected ICA on source and reformatted images. Intracranial
Circulation
Acute Ischemic Stroke. Reports by several investigators (Shrier et al. 1997; Knauth et al. 1997) have shown that CTA is a reliable alternative to MRA in evaluating arterial occlusive disease near the circle of Willis in patients with symptoms of acute stroke (Figure 37B.15). CTA shows clinically televant occlusions of major cerebral arteries and enhancement caused by collateral flow distal to the site of
FIGURE 37B.15 Maximum intensity projection (MIP) images. (A) Axial MIP image. (B and C) Oblique MIP images were obtained to improve display of each of the MCA trifurcations. MCA stenosis is ruled out. Note the excellent resolution and anatomical detail of the major circle of Willis vessels and secondarid third-order vessels in the posterior cerebral artery and anterior eerebral artery distributions.
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occlusion. In the diagnosis of MCA occlusion, CTA has shown good correlation with transcranial Doppler (TCD) sonography but is inferior to MRA. More recently, CTA was found to be superior to TCD in diagnosing atherothromboric MCA disease in Asian patients presenting with MCA stroke (Suwanwela, Phanthumchinda, and Suwanwela 2002), CTA detected MCA stenosis measuring more than 5 0 % in twice as many patients as TCD. The difference resulted primarily from the improved detection by CTA of distal Ml and M2 stenosis. Because half of the patients studied by Suwanwela and colleagues had distal Ml and M2 disease, the authors concluded that TCD sonography should not be used to screen for MCA stenosis. In the detection of inttacranial steno-occlusive disease, Hirai and colleagues (2002) have shown that combined CTA and MRA provide substantially higher sensitivity, specificity, and accuracy than MRA alone. Review of the CTA depiction of vessels in conjunction with the 3D TOF MRA display reduced the ftequency of overestimation of stenosis when compared with MRA alone. In the identification of 5 0 % or greater stenosis, the sensitivity, specificity, and accuracy for the combined CTA and MRA evaluation were 100%, 9 9 % , and 9 9 % , respectively, and the values for 3D TOF MRA alone were 9 2 % , 9 1 % , and 9 1 % , respectively. The grading of stenosis by the combined approach agreed with the IA-DSA grading in 9 8 % of cases. In a retrospective review of their cases, the authors found that CTA did not always correctly delineate arterial lumina with circumferential calcification and the cavernous portion of the ICA. Cerebral Aneurysms. Catheter angiography has been the gold standatd for imaging diagnosis and preoperative evaluation of ruptured and unruptured cerebral aneurysms; however IA-DSA is invasive and subject to complications tesulting from catheter manipulation. Thus in asymptomatic patients at greater risk for cerebral aneurysms, the use of noninvasive techniques such as MRA and CTA to screen for aneurysms is particularly attractive. These techniques have advantages and disadvantages. The most thoroughly investigated MRA technique is 3D TOF MRA, and its main disadvantages arc long scanning times, difficulty in detecting very small aneurysms, difficulty in establishing the relationship of the aneurysm to adjacent (and surgically important) osseous anatomy, and occasional difficulty in distinguishing between patent lumen and thrombus. The main disadvantages of CTA are radiation exposure, the use of iodinated contrast material, and difficulty in detecting very small aneutysms. In a prospective blinded comparison between CTA and 3D TOF MRA (142 patients), White and colleagues (2001) found no significant difference in diagnostic performance between the two techniques. The sensitivity for detecting aneurysms smaller than 5 mm was 5 7 % for CTA and 3 5 % for MRA, compared with 9 4 % and 86%, tespectively, for aneurysms 5 mm or larger (Figures 37B.16 and 37B.17). This is somewhat discouraging
FIGURK 37B.16 Proximal left middle cerebral artery aneurysm. Comparison of computed tomographic angiography (CTA) with conventional catheter angiography, (A) Maximum intensity projection image from CTA of the circle of Willis shows a berry aneurysm of the Ml segment. (B) Catheter angiography submentovertex view, following left internal carotid artery injection, shows excellent correlation,
because the critical size at which aneurysms significant risk of rupture has been reported to (Crompton 1996). The limited sensitivity of CTA in detecting small aneurysms has prevented widespread application of these techniques for
are at a be 4 mm and MRA the more screening
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FIGURE 37B.17 Left internal carotid artery aneurysm. Comparison of computed tomographic angiography (CTA) postprocessed images with catheter angiography. (A) Catheter angiography lateral view, following left internal carotid artery (ICA) injection, shows aneurysm originating from the supraclinoid portion of the ICA. (B) CTA axial source image reveals tabulated aneurysm (arrow), (C, D, and E) CTA 3D vol time-rendered images with transparency feature for user-selected tissue regions (called "4D angiography"). (C) Lateral view from the left side of the patient demonstrates the relationship of the aneurysm, measuring 14 mm from neck to dome, to the anterior clinoid process. Continued
or pretreatment evaluation of aneurysms (Adams, Laitt, and Jackson 2000). Villablanca and colleagues (2002) have presented promising CTA results for detecting and characterizing very small (less than 5 mm) intracranial aneurysms. Using optimized helical CTA acquisition and postprocessing protocols, which included 3D perspective volume rendered images, 3D thick slab and gray scale 2D single-section images, and thick slab multiplanar reformatted 2D images, the authors reported a sensitivity of CTA for very small aneurysm detection that ranged from 9 8 % to 100%, compared with 95% for IA-DSA. The specificity of CTA and of IA-DSA was 100%. CTA image analysis times ranged from 6 to 36 minutes (mean = 16 minutes). The smallest aneurysm detected was 1,9 x 1.6 x 1.3 m m ' , and 4 8 % of aneurysms were detected in the presence of subarachnoid hemorrhage. The sensitivity of CTA exceeded that of IA-DSA primarily because the optimal projection necessary to visualize some aneurysms could be displayed on the postprocessed CTA images but was not or could not be displayed by IA-DSA. Other disadvantages of IA-DSA that have been noted by investigators include superimposition of normal vessels obscuring a small aneurysm and the lack of an internal image scale for estimating the aneurysm sac and neck dimensions. Villablanca and colleagues showed that CTA can provide quantitative information, such as dome-to-neck ratios, and aneurysm characterization, such as the presence of mural thrombi or calcium, branching pattern at the neck, and the incorporation of arterial segments in the aneurysm. The 3D images in particular provided a surgically useful display of the aneurysm sac in relation to skull base structures (see Figure 37B.17). The authors concluded that with adequate
attention to detail, all clinically relevant aneurysms can he detected by CTA using routine scanners, protocols similar to those described in the article, and commercially available image-processing workstations. Furthermore, CTA can be a reliable source of information for treatment planning. Cerebral veins show much more anatomical variation than arteries. The presence of an unexpected vein, or the lack of collateral drainage from a region drained by a vein that may need to be sacrificed during surgery, can alter the approach to resection of an aneurysm. Kaminogo and colleagues (2002) used 3D CTA to demonstrate the venous anatomy accurately. They showed the usefulness of this information in selecting a therapeutic procedure (surgery versus endovascular coiling) and in planning the approach for surgical treatment.
CONCLUSION Noninvasive imaging of neurovascular disease has progressed greatly in the past decade and is gaining acceptance as the primary approach to screening for several different types of vascular lesions, including atherosclerotic narrowing of the cervical ICA, carotid or vertebral dissection, cerebral aneurysm in the asymptomatic patient at risk, dural venous sinus thrombosis, and spinal dural fistula. The number of indications for noninvasive screening is likely to increase as improvements in MRA (increased field strength to 3 Tesla or more, faster gradient rise times, and improved phased-array technology and k-space sampling techniques) and CTA (greater heat storage capacity and multidetector array helical scanning) result in greater accuracy and reliability of these methods. What remains to be elucidated
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are the algorithms t h a t will be followed to d i a g n o s e a vascular lesion or category of lesions in the most timely a n d cost-effective m a n n e r for a given clinical p r e s e n t a t i o n . As these algorithms are developed, it seems certain t h a t M R A and C T A will play large and c o m p l e m e n t a r y roles, w i t h catheter studies reserved for e n d o v a s c u l a r or i n t r a o p e r a t i v e intervention and evaluation.
REFERENCES Adams, W. M., Laitt, R. D., & Jackson, A. 2000, "The role of MR angiography in the pretreatment assessment of intracranial aneurysms: A comparative study," AJNR Am J Neuroradiol, vol. 2 1 , pp. 1618-1628 Anderson, C. M., Lee, R. E., Levin, D. L, et al. 1994, "Measurement of internal carotid artery stenosis from source MR angiograms," Radiology, vol. 193, pp, 219-226 Atkinson, D., Brant-Zawadzki, M., Gillan, G-, et al. 1994, "Improved MR angiography: Magnetization transfer suppression with variable flip angle excitation and increased resolution," Radiology, vol. 190, pp. 890-894 Ayanzen, R. H., Bird, C. R., Keller, P. J., et al. 2000, "Cerebral MR venography: Normal anatomy and potential diagnostic pitfalls," AJNR Am J Neuroradiol, vol. 2 1 , pp. 74-78 Barnett, H. J., Taylor, D, W., Eliasziw, M., et al. 1998, "Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators," N Engl] Med, vol. 339, pp. 1415-1425 Binaghi, S., Macder, P., Uskc, A., et al. 2001, "Three-dimensional computed tomography angiography and magnetic tesonance angiography of carotid bifurcation stenosis," Eur Neurol, vol. 46, pp. 25-34 Binkert, C. A., Kollias, S. S., Sc Valavanis, A. 1999, "Spinal cord vascular disease: Ccharacterization with fast three-dimensional contrast-enhanced MR angiogtaphy," AJNR Am J Neuroradiol, vol. 20, pp. 1785-1793 Roulin, A. & Pierot, I.. 2001, "Follow-up of inttactanial aneurysms treated with detachable coils: Comparison of gadoliniumenhanced 3D timc-of-flight MR angiography and digital subtraction angiography," Radiology, vol. 219, pp. 108 113 Bowen, B. C. & Pattany, P. M. 2000, "Contrast-enhanced MR angiography of spinal vessels," Magn Ream Imaging Clin N Am, vol. 8, pp. 597-613 Bowen, B. C, Quencer, R. M., Margosian, P., & Pattany, P. M, 1994, "MR angiography of occlusive disease of the arteries in the head and neck: current concepts," Am J Roentgenol, vol. 162, pp. 9-18 Crompton, M. 1996, "Mechanisms of growth and rupture in cerebral berry aneurysms," BMJ, vol. 1, pp. 1138-1 142 Essig, M., Reichenbach, j. R., Schad, L. R., et al. 1999, "Highresolution MR venogtaphy of cerebral arteriovenous malformations," Magn Rcson Imaging, vol. 17, pp. 1417-1425 European Carotid Surgery Trialists Collabotative Group. 1998, "Randomised trial of endarterectomy for recently symptomatic carotid stenosis: Final results of [he MRC European Catodd Surgery Trial (ECST)," Lancet, vol. 3 5 1 , pp. 1379-1387 Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. 1995, "Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the
Asymptomatic Carotid Atherosclerosis Study," JAMA, vol. 273, pp. 1421-1428 Fain, S. B., Ricdcrcr, S. J., Bernstein, M. A., & Huston, J. III. 1999, "Theoretical limits of spatial resolution in elliptical-centric contrast-enhanced 3D-MRA," Magn Reson Med, vol. 42, pp. 1106-1116 Fain, S. B., Riedeter, S. J., Huston, J. Ill, & King, B. F. 2 0 0 1 , "Embedded MR fluoroscopy: High temporal resolution realtime imaging during high spatial tesolution 3D MRA acquisition," Magn Reson Med, vol. 46, pp. 690-698 Farb, R. I., McGregor, C, Kim, J, K,, et al. 2001, "Intracranial arteriovenous malformations: Real-time auto-triggered elliptic centric-ordered 3D gadolinium-enhanced MR angiogtaphyinitial assessment," Radiology, vol. 220, pp. 244-251 Foo, T. K. F., Saranathan, M., Prince, M. R., & Chenevert, T. L. 1997, "Automated detection of bolus attival and initiation of data acquisition in fast, three-dimensional, gadoliniumenhanced MR angiography," Radiology, vol, 203, pp. 275-280 Furst, G., Hofcr, M,, Steinmetz, H., et al. 1996, "Intracranial stenoocclusive disease: MR angiography with magnetisation transfer and variable flip angle," AJNR Am / Neuroradiol, vol. 17, pp. 1749-1757 Golay, X., Brown, S. J., Itoh, R., & Mclhcm, E. R. 2001, "Timeresolved contra st-en ha need carotid MR angiography using sensitivity encoding (SENSE)," AJNR Am J Neuroradiol, vol. 22, pp. 1615-1619 Hirai, T., Korogi, Y., Ono, K., et al. 2002, "Prospective evaluation of suspected stenoocclusive disease of the intracranial artery: Combined MR angiography and CT angiography compared with digital subtraction angiography," Am J Neuroradiol, vol. 2 3 , pp. 93-101 Huston, J., Nichols, D. A., Luetmer, P. H., et al. 1998, "MR angiogtaphic and sonographic indications for endarterectomy," AJNR Am J Neuroradiol, vol. 19, pp. 309-315 Huston, J. Ill, Fain, S. B., Wald, J. T., et al. 2001, "Carotid artery: elliptic centric contrast-enhanced MR angiography compared with conventional angiogtaphy," Radiology, vol. 218, pp. 138-143 Jagcr, H. R., Ellamushi, H,, Moore, E. A., et al. 2000, "Conttastenhanced MR angiography of intracranial giant aneurysms," AJNR Am J Neuroradiol, vol. 2 1 , pp. 1900-1907 Johnson, M. B., Wilkinson, I. D., Wartam, J., et al. 2000, "Compatison of Doppler ultrasound, magnetic resonance angiographic techniques and catheter angiography in evaluation of carotid stenosis," Clin Radiol, vol. 55, pp. 912-920 Johnston, D. C. 8c Goldstein, L. B. 2001, "Clinical carotid endarterectomy decision making: Noninvasive vascular imaging versus angiography," Neurology, vol. 56, pp. 1009-1015 Kannnogo, M., Hayashi, H., Ishimaru, H., et al. 2002, "Depicting cerebral veins by th tee-dimension a I CT angiography before surgical clipping of aneurysms," AJNR Am J Neuroradiol, vol. 2 3 , pp. 85-91 Kirchhof, K., Welzel, T., Jansen, O., &i Sartor, K. 2002, "More reliable noninvasive visualization of the cerebral veins and dural sinuses: comparison of three MR angiographic techniques," Radiology, vol, 224, pp. 804-810 Klisch, J., Strecker, R., Hennig, J., & Schumacher, M. 2000, "Time-resolved projection MRA: Clinical application in intracranial vascular malformations," Neuroradiology, vol. 42, pp. 104-107 Knauth, M., VonKummet, R., Jansen, O., et al. 1997, "Potential of CT angiography in acute ischemic stroke," Am J Neuroradiol, vol. 18, pp. 1001-1010
COMPUTED TOMOGRAPHIC AND MAGNETIC RESONANCE VASCULAR IMAGING Kollias, S. S„ Binkert, C. A., Rueseh, S., St Valavanis, A. 1999, "Contrast-enhanced MR angiography of the supra-aortic vessels in 24 seconds: A feasibility study," Neuroradiology, vol. 4 1 , pp. 391-400 Leclerc, X., Godefroy, O., Salhi, A., et al. 1996, "Helical CT for the diagnosis of extracranial carotid artery dissection," Stroke, vol. 27, pp, 461-466 Leclerc, X., Lucas, C, Godefroy, O., et al. 1998, "Helical CT for the follow up of cervical internal carotid artery dissections," Am J Neuroradiol, vol. 19, pp. 831-837 Lenhart, M., Framme, N,, Volk, M., et al. 2002, "Time-resolved contra st-en ha need magnetic resonance angiography of the carorid arteries: Diagnostic accuracy and inter-observer variability compared with selective catheter angiography," Invest Radiol, vol. 37, pp. 535 541 Levy, R. A. & Maki, J. H. 1998, "Three-dimensional contrastenhanced MR angiography of the extracranial arteries: Two techniques," Am J Neuroradiol, vol. 19, pp. 688-690 Leys, D., Moulin, T, Stojkovic, T., et al. 1995, "Follow up of patients with history of cervical carotid artery dissection," Cerebrovasc Dis, vol. 5, pp. 43-49 [Jims;, I.., Korogi, V., Sugahara, T., et al. 2001, "L'.valiiiirioii of the intracranial dural sinuses with a 3D contrast-enhanced MP-RAGE sequence: Prospective comparison with 2D-TOF MR venography and digital subtraction angiography," AJNR Am J Neuroradiol, vol. 22, pp. 481-492 Link, H., Brossman, J., Penselin, V., et al. 1995, "Computed tomography angiography for the evaluation of carotid stenosis," Stroke, vol. 26, pp. 1577-1581 Liu, K., Tanttu, J., Castren, A., & Rutt, B. K. 1999, "Scanning time efficient SLINKY for non-contrast MRA at low field," Magn Resort Imaging, vol. 17, pp. 689-698 Magarelli, N., Scarabino, T., Simeone, A. L., et al. 1998, "Carotid stenosis: A comparison between MR and spiral CT angiography," Neuroradiology, vol. 40, pp. 367-373 Melhem, E. R., Caruthers, S, D., Faddoul, S. G., et al. 1999, "Use of three-dimensional MR angiography for Tracking a contrast bolus in the carotid artery," AJNR Am J Neuroradiol, vol. 20, pp. 263-266 Norris, ]. W. & Rothwell, P. M. 2001, "Noninvasive carotid imaging to select patients for endarterectomy: Is it really safer than conventional angiography?" Neurology, vol. 56, pp. 990-991 Ouanounou, S., Tomsick, T A., Heitsman, C, &£ Holland, C. K. 1999, "Cavernous sinus and inferior petrosal sinus flow signal on three-dimensional time-of-flight MR angiography," AJNR Am J Neuroradiol, vol. 20, pp. 1476-1481 Parker, D. I.., Tsuruda, J. S., Goodrich, K. C, et al. 1998, "Contrast-enhanced magnetic resonance angiography of cerebral arteries. A review," Invest Radiol, vol. i3, pp, 560-572 Polak, J. F., Kalina, P., Donaldson, M. C„ et al. 1993, "Carotid endarterectomy: Preoperative evaluation of candidates with combined Doppler sonography and MR angiography," Radiology, vol. 186, pp. 333-338 Randoux, B., Marro, B., Koskas, F., et al. 2001, "Carotid artery stenosis: Prospective comparison of CT, three-dimensional gadolinium-enhanced MR, and conventional angiography," Radiology, vol. 220, pp. 179-185 Remonda, L., Senn, P., Barrh, A., et al. 2002, "Contrast-enhanced 3D MR angiography of the carotid artery: Comparison with
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conventional digiral subtraction angiography," AJNR Am j Neuroradiol, vol. 23, pp. 213-219 Saloncr, D., van Tyen, R., Dillon, W. P., et al. 1996, "Central intraluminal saturation stripe on MR angiograms of curved vessels: Simulation, phantom, and clinical analysis," Radiology, vol. 198, pp. 733-739 Saraf-Lavi, E., Bowen, B. C, Quencer, R. M., et al. 2002, "Detection of spinal dural arteriovenous fistula with MR imaging arid angiography: Sensitivity, specitieiiv, and prediction of vertebral level," AJNR Am j Neuroradiol, vol. 23, pp. 858-867 Shrier, I). A., Tanaka, II., Nnmaguchi, i., ei al. I <W. "t.T angiography in the evaluation of acute stroke," Am j Neuroradiol, vol. 18, pp. 1011-1020 Stock, K. W., Radue, E. W„ Jacob, A. L., et al, I 995, "Intracranial arteries: prospective blinded comparative study of MR angiography and DSA in 50 patients," Radiology, vol. 195, pp. 451-456 Suwanwela, N. C, Phanthumchinda, K., St Suwanwela, N. 2002, "Transcranial Doppler sonography and CT angiography in patients with atherothrombotic middle cerebral artery stroke," AJNR Am J Neuroradiol, vol. 2 3 , pp. 1352-1355 Turski, P. A., Korosec, F. R., Carroll, T. J., et al. 2001, "Contrastenhanced magnetic resonance angiography of the carotid bifurcation using the time-resolved imaging of contrast kinetics (TRICKS) technique," Top Magn Reson Imaging, vol. 12, pp. 175-181 Villablanca, J. P., Jahan, R., Hooshi, P., et al. 2002, "Detection and characterization of very small cerebral aneurysms by using 2D and 3D helical CT angiography," AJNR Am J Neuroradiol, vol. 2 3 , pp. 1187-1198 Wcntz, K. (J., Rother, J., Schwartz, A., et al. 1994, "Intracranial vertebrobasilar system: MR angiography," Radiology, vol. 190, pp. 105-110 White, P. M., Teasdale, E. M., Wardlaw, j. M., & Easton, V. 2 0 0 1 , "Intracranial aneurysms: CT angiography and MR angiography for detection prospective blinded comparison in a large patient cohort," Radiology, vol. 219, pp. 739-749 Whire, P. M., Wardlaw, J. M., & Easton, V. 2000, "Can noninvasive imaging accurately depict intracranial aneurysms? A systematic review," Radiology, vol. 217, pp. 361-370 Willig, D. S., Turski, P. A., Frayne, R., et al. 1998, "Contrastenhanced 3D MR DSA of the carotid artery bifurcation: Preliminary study of comparison with unenhanced 2D and 3D time-of-flight MR angiography," Radiology, vol. 208, p,-,, 447-451 Wittsack, H. J., Ritzl, A., Fink, C. R., et al. 2002, " M R imaging in acute stroke: diffusion-weighted and perfusion imaging parameters for predicting infarct size," Radiology, vol. 222, pp. 397-403 Wutke, R„ Lang, W., Fellner, C, et al. 2002, "High-resolution, contrast-enhanced magnetic resonance angiography with elliptical centric k-space ordering of supra-aortic arteries compared with selective X-ray angiography," Stroke, vol. 33, pp. 1522-1529 Yamada, N„ Takamiya, M., Kuribayashi, S., ct al. 2000, "MRA of the Adamkiewic/ artery: A preoperative siudy for thoracic aortic a n e u r y s m , " / Comput Assist Tomogr, vol. 24, pp. 362-368
Chapter 37 Neuroimaging C. NEUROANGIOGRAPHIC ANATOMY AND COMMON CEREBROVASCULAR DISEASES Johnny S. Sandhu and Ajay K. Wakhloo Functional Neurovascular Anatomy Branches of the Aortic Arch Common Carotid Arteries External Carotid Artery Internal Carotid Artery Vertebrobasilar System Typical Fetal Remnants
625 625 626 626 629 635 638
Neuroangiography remains the gold standard for diagnostic imaging for most cerebrovascular disorders, even with the advent of magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and three-dimensional (3D) computed tomography (CT) angiography. Despite great advancements in CT and MRA, there are limitations in their sensitivity to detect vascular abnormalities, Although these modalities will undoubtedly improve soon, current indications for diagnostic (catheter) angiography remain extensive (Citron et a). 2000). Furthermore, as other imaging modalities assume a larger role in diagnostic neuroangiography, the applications of neuroendovascular interventions are increasing. Road mapping, digital subtraction angiography, high-resolution flat-panel systems, data acquirement and analysis, and 3D reconstruction (Culham 1996) have all replaced previous methods of acquiring contrast-enhanced images. The importance of understanding normal neurovascular anatomy from an angiographic standpoint remains essential in the diagnosis of neurovascular abnormalities, classification of cerebrovascular pathology, and treatment of disease. The reported success rate of neuroangiography is 9H% (Vitck 1973; Dion et al. 1987; Citron et al. 2000). The potential risks of angiography and interventional procedures include minor and major stroke (140 Variable No flow
End-diastolic velocity (cm/sec) i Variable N/A
ICA/CCA = internal carotid artery/common carotid artery ratio of peak systolic velocity; N/A = not applicable. Source: Reprinted with permission from Tcgeler, C. H. & Ratanakorn, D., 1999, "Ultrasound in cerebrovascular disease," in Neuroimaging; A Companion to Adams and Victor's Principles of Neurology, 2nd cd, ed. J Greenberg, McGraw-Hill, New York.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIF.NCES
^Z9^H
FIGURE 37D.6 Atherosclerotic plaque. Longitudinal gray-scale brightness-mode image of an atherosclerotic plaque {arrow) in the region of the proximal internal carotid artery, with acoustic shadowing.
surface features (smooth, irregular, crater), the echodensity and presence of any calcification producing acoustic shadowing, and the texture (homogeneous, heterogeneous; intraplaque hemorrhage). Hypoechoic plaques and those that are heterogeneous, with prominent hypoechoic regions (complex plaque), indicate an elevated risk of stroke (Polak et al. 1998). High-resolution B-mode imaging is more accurate for defining atherosclerosis of the vessel wall early in the course of the disease than is Dopplcr ultrasound testing. Measurement of the intima-media thickness, which increases in the early stages of plaque formation, is used as a surrogate endpoint for clinical trials assessing whether lipid-lowering medications might slow or reverse atherosclerosis. The sensitivity of B-mode imaging for detecting surface ulceration is estimated at 7 7 % in plaques causing less than 5 0 % linear stenosis and 4 1 % for plaques causing more than 5 0 % linear stenosis, with no significant differences between B-mode carotid imaging and arteriography, Although associated with a somewhat worse outcome, surface irregularity or crater formation appears to be a less important morphological risk factor than echodensity and heterogeneity,
The addition of PDI offers more potential to improve accuracy in some difficult situations. In the setting of highgrade stenosis, PDI improves identification of stenosis and measurement of residual lumen and may improve visualization of plaque surface features, even in the presence of calcification.
Color Plow and Power Doppler Imaging
Volume
There is now widespread use of CFI as part of carotid ultrasound testing. Advantages of CFI include rapid determination of the presence and direction of blood flow, with more accurate placement of the Doppler sample
Conventional criteria for reporting carotid stenosis use flow velocity to estimate the linear percentage of stenosis. But flow velocity may be affected by many other factors besides percentage of stenosis. For example, hyper per fusion can
volume and determination of the angle of insonation. Absence of color filling in what appears Co be the vessel lumen provides clues about the presence of a hypoechoic plaque, and the contour of the color column can provide information about surface features. If a crater or ulcer is open to the lumen, it is filled in by color. Newer instruments with sensitive CFI designed to detect very low flow velocities are able to accurately differentiate critical stenosis from total occlusion (87-100% sensitivity, 84% specificity compared with angiography), obviating the need for conventional angiography (Sitzer, Siebler, and Steinmetz 1996). The addition of CFI improves understanding of many unusual anatomical configurations such as kinks or coils. Although its contribution is difficult to quantify accurately, CFI probably adds approximately 5% to the overall diagnostic accuracy of carotid duplex ultrasound.
Plow Rate
Determination
ULTRASOUND IMAGING OF THE CEREBRAL VASCULATURE increase flow velocity and might be misconstrued as stenosis. Measurement of actual volume flow rate could help avoid mistakes in such situations, and it is the parameter in which most clinicians treating neurological disorders are interested. Color velocity imaging, as previously described, uses time-domain processing to determine flow velocity. With assumption of a circular vessel and flow symmetrical around the axis of its own direction, the data are integrated to yield the volume flow rate in milliliters per minute. It has been shown to be valid and reliable in vitro and reproducible for studying the CCA in volunteers, and expected normal values have been defined (330 ± 60 mL per minute for women and 375 ± 70 mL per minute for men). Use of the CCA volume flow rate in patients with carotid stenosis reveals characteristic decreases in the rate with progressive stenosis. Measurement of CCA volume flow rate is a standard part of the carotid evaluation in some laboratories, being obtained in patients in whom flow velocity suggests 5 0 % or greater carotid stenosis (Plate 37D.II). This method is also being used in other clinical cerebrovascular diseases and offers a new window for understanding cerebral hemodynamic changes (Knappertz, Tegelcr, and Myers 1996; Tan et al. 2002). Other strategies for measuring volume flow rate are available using traditional Doppler ultrasound instruments. Vertebral
Ultrasonography
Because posterior circulation cerebrovascular disease is common, study of the vertebral arteries is considered a part of the routine extracranial duplex examination. The same techniques described for use in the carotid arteries can be used to study the vertebral arteries and the proximal subclavian or innominate arteries. Therefore duplex Doppler and B-mode imaging of these arterial segments should be performed. CFI is also helpful for visualizing the vertebral arteries. The vertebral artery can almost always be evaluated in the pretransverse and intertransverse cervical segment of C5-C6, whereas the origin can be studied on the right in only 8 1 % and on the left in only 65% of patients. Because there is mostly a low-resistance distal vascular bed, the vertebral artery usually shows a low-resistance pattern Doppler spectral pattern, similar to that of the ICA. There are no widely accepted criteria for stenosis in the extracranial vertebral artery. As with the carotid system, spectral analysis provides insight into proximal and distal disease. Technical
Limitations
Potentially important limitations of carotid duplex sonography are relared to the patient, instrumentation, sonographer, and interpreter. Patient factors that can preclude an adequate study include the inability to cooperate, neck swelling or other conditions that limit access to the neck, a high carotid bifurcarion, deeply
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situated vessels, and calcification with acoustic shadowing that blocks the sound beam.
Intracranial Cerebrovascular Ultrasonography Transcranial
Doppler
Ultrasonography
Most commercially available TCD instruments use a 2-MHz probe to allow insonation through the cranium. These pulsed-Doppler instruments have an effective insonation depth range of 3.0-12.0 cm or more that can be evaluated by increments of 2 or 5 mm. At an insonation depth of 50 mm, the sample volume usually is 8-10 mm axially and 5 mm laterally. TCD probes differ from the 4- to 10-MHz transducers used to monitor the progress of intraoperative neurosurgical procedures (Unsgaard et al. 2002). Advantages of TCD include the maneuverability of the small probes, the Doppler sensitivity, and, especially when compared with transcranial color-coded duplex and magnetic resonance angiography, the low price of instruments. Routine TCD testing relies on three natural acoustic windows to study the basal segments of the main cerehral arteries. Insonarion through the temporal bone window allows detection of flow through the middle cerebral artery (MCA) Ml and anterior cerebral artery Al segments. Normal blood flow direction is toward the probe in the MCA and away from it in the anterior cerebral artery. The supraclinoid ICA is also detected, but it may be difficult to distinguish from the MCA. Depending on the position of the window, the probe usually has to be tilted frontally to detect these vessels. A posterior (or occipital) tilt of the probe enables insonarion of the posterior cerebral artery's first segment. The occipital window takes advantage of the foramen magnum's opening into the skull. Flow in the distal vertebral artery and proximal to midporrions of the basilar artery can be detected; it is away from the probe in these arterial segments. The position and caliber of these arteries vary widely, making insonation occasionally difficult. The ophthalmic artery and carotid siphon can be studied through the orbital window. Flow in the ophthalmic arteryis toward the probe and has a high resistance pattern. Flow in the ICA siphon can be either toward or away from the probe, depending on the insonated segment of the siphon. The instrument's power output must be decreased when it is insonating through the orbital window because prolonged exposure to high-intensity ultrasound has been associated with cataract formation. Flow velocities change with age and differ between men and women. Normal values have been reported by several authors. Repeated measurements of flow velocities are highly reproducible. Based on rhe general knowledge of the location of intracranial arteries and flow direction, a comprehensive map of the basal arteries can be generated. This map is
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NF.UROSCIENCES
clinically useful because common pathological conditions affecting the intracranial arteries, such as atherosclerosis, sickle cell disease, and vasospasm associated with aneurysmal subarachnoid hemorrhage, often affect arterial segments that can be insonated. Convexity branches of the cerebral arteries arc beyond the reach of TCD. Transcranial
Color-Coded
Duplex
Ultrasonography
Examinations performed with 2.25-MHz phased array and 2.5-MHz 90-dcgrcc sector transducers enable color-coded imaging of intracranial arterial blood flow in red Aiid blue, respectively, indicating flow toward and away from the probe (Plate 37D.III). The main advantages of transcranial color-coded duplex are the ability to visualize and positively identify the insonated vessel, thus increasing the ultrasonographer's confidence, and the ability to correct for the angle of insonation. In addition, transcranial color-coded duplex provides a limited B-mode image of intracranial structures. Technical
Limitations
A technically adequate study of the anterior circle of Willis cannot be obtained in 2.5-20% of patients studied with TCD. This is due to several factors, including the thickness of the temporal bone. The rate of unsatisfactory studies varies between medical centers and probably relates to the characteristics of the population tested at each neurovascular laboratory. Failure rates are higher in older adults and in African American patients. Restrictions in the emitted power of TCD instruments and limitations secondary to transmission through the skull hone can also result in technically unsatisfactory studies. The immediate cause of this limitation often is an inadequate signal-to-noise ratio. The latter can he improved by enhancing the reflected ultrasound waves with the use of contrast agents. Several echocontrast agents, including lipid-coated microbubbles and galactose microparticlcs, enhance the ultrasound signal in a clinically useful way. A commercially available agent is in use in Germany. Although available for echocardiography, commercial agents are not yet available for TCD testing in the United States. Echocontrast agents are especially useful in patients with inadequate temporal bone windows.
Certification and Accreditation An ongoing program of quality assurance is basic to maintaining the highest quality of testing. Quality assurance is vital to ensure that for specific sonographcrs, using specific equipment, interpreted by specific readers, the criteria arc performing as expected (Gomez et al. 1997; Masdeu 1997; Smith, Anderson, and Gramith 1993). Formal correlation should be sought using any other
modalities available, including catheter angiography, magnetic resonance angiography, pathological specimens, clinical outcomes, and repeat examinations. Certification of sonographcrs and physicians and accreditation of neurovascular laboratories is desirable. In the United States, sonographcrs have access to several certifications that help to demonstrate expertise, The most widely accepted is the registered vascular technologist certification, which requires documented experience in the field, completion of rigorous examinations, and practical application of vascular ultrasound. Guidelines for training physicians have been established by the American Academy of Neurology, the American Society of Ncuroimaging, and other organizations. The Neurosonology Certification offered by the American Society of Neuroimaging is an important mechanism to show additional expertise. It requires documented background training and practical experience. The accreditation offered by the Intersocietal Commission for Accreditation of Vascular Laboratories is the recommended accreditation for neurovascular laboratories and remains the most rigorous of those available. Accreditation is offered for both cerebrovascular extracranial and intracranial testing.
CLINICAL APPLICATIONS Acute Stroke The 1995 introduction of tissue plasminogen activator (t-PA) to treat acute ischemic stroke (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group 1995) focused the attention of the medical community on acute cerebral ischemia as a treatable emetgency. In the National Institute of Neurological Disorders and Stroke trial, all clinically diagnosed subtypes of stroke benefited from t-PA, and brain computed tomography was the only neuroimaging test obtained to rule out intracranial hemorrhage or other unexpected diagnoses. As a result, imaging of the cerebral vasculature is not currently a prerequisite in initiate intravenous t-PA thrombolytic therapy, although perhaps it should be. The association of thrombolytic therapy with a 6.4% (National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group 1995) or higher risk of symptomatic intracerebral hemorrhage has led some investigators to argue for better patient selection. A belief that the treatment of patients with cerebrovascular disease should be specific to the cause of the stroke has prompted the use of technologies such as single photon emission computed tomography, perfusion and diffusion-weighted magnetic resonance imaging, and TCD to better characterize the cause of acute cerebral infarction. TCD studies obtained within hours from the onset of symptoms of cerebral infarction along the vascular territory of the ICA show stenosis or occlusion of the distal
U L T K A S O U M ) [MAC.INK. (>\
intracranial ICA or proximal MCA in 7 0 % of patients. When compared with cerebral angiography, TCD is more than 90% sensitive and specific in detecting supraclinoid ICA or MCA Ml segment lesions. Contrast-enhanced color-coded duplex sonography can he especially useful in this context. Approximately 3 0 % of TCD and cerebral angiography studies show no evidence of arterial occlusions during this acute stage, and it is unlikely that this subgroup of patients benefits from thrombolysis. TCD can monitor the effect of thrombolytic agents. Testing before and after the administration of streptokinase or t-PA o.ni J^SI-SS iIK- agent's efficacy in obtaining arterial patency or ascertain continued patency in the days after treatment (Yasaka et al. 1998). In addition, investigators have adjusted the dosage and duration of intravenous thrombolytic agent administration based on information provided by continuous TCI) monitoring. Rapid arterial I'Lcanalization is associated with better short-term improvement (Alexandrov et al. 2001). Although the current use of thrombolytic therapy in acute stroke does not necessitate rapid evaluation of the carotid arteries, testing might provide information that would alter therapy. Urgent carotid testing has not been widely available, and the exact clinical utility remains to be defined.
Recent Transient Ischemic Attack or Stroke Beyond the 3-hour window, t-PA is not an established treatment option for patients with acute or subacute stroke. Antiplatelet agents and heparin or warfarin anticoagulation are prescribed depending on the immediate cause of cerebral ischemia. Atherosclerotic plaques causing moderate or severe stenosis of the ICA origin and siphon; the proximal segments of middle, anterior, and posterior cerebral arteries; the distal vertebral artery; and the basilat artery constitute approximately 2 0 - 3 0 % of the causes of cetebral infarction. These lesions can be detected with ultrasound techniques. Extracranial
Internal
Carotid Artery
Estimates of how often carotid disease is the primary cause of cerebral infarction vary from 1 5 % to 4 0 % . Although atherosclerosis is by far the most common cause of carotid stenosis or occlusion, other disorders, such as dissection, congenital anomalies, and thrombus that formed locally or arrived from proximal sources, must be sought. In patients with tecent transient ischemic attack or stroke, it is important to identify those with significant carotid stenosis. Not only is carotid endarterectomy (CEA) more effective than the best medical therapy for preventing subsequent stroke in patients with symptomatic tight carotid stenosis (70-99% linear stenosis), but also the absence of significant carotid disease is important in directing further diagnostic
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(KltKHRAI
VASCUI A T U R F ftii
testing and treatment. The North American Symptomatic Carotid Endarterectomy Trial investigators also showed that patients with 5 0 - 6 9 % linear stenosis also have a significant but much lower magnitude of benefit from CEA compared with medical therapy (Barnett et al. 1998). Clearly, although every patient with transient ischemic attack or stroke is not a candidate for CEA, the treating physician must identify those who might reasonably benefit from such treatment. In addition, new treatments, such as angioplasty with stenting, may offer attractive alternatives, even for those who are not good surgical candidates. In the setting of recent transient ischemic attack or stroke, as with other cerebrovascular diseases, several key principles should guide the diagnostic evaluation. The physician must first determine whether any testing is warranted. The basic question is whether testing will help with the diagnosis or affect management. If so, safe, accurate, and less costly modalities should be used first, and more risky, invasive, costly methods should be used only when needed. Physicians also must be aware that the services, resources, expertise, and quality of all types of testing available locally may drastically yet appropriately alter the algorithm for evaluating cetebrovascular disease. Ultrasound testing offers a safe, accurate, noninvasive, and inexpensive way to evaluate for extracranial cerebrovascular disease. It is considered the initial test of choice for identifying significant carotid stenosis in patients with recent transient ischemic attack or stroke (Figure 37D.7; Tegcler and Ratanakorn 1998). For the carotid territory, this should include duplex ultrasonography, with or without CFI. Reports should address the severity of stenosis based on Doppler velocity measurements. They also include information about the presence of any plaque and the morphology, based on high-resolution B-mode imaging. Additional helpful ultrasound tools include PDI and volume flow rate measurement. Results of carotid ultrasound testing must then be integrated with other available testing modalities if additional information is needed. At present, this often means a combination of ultrasound and magnetic resonance angiography or compured tomographical angiography, with conventional angiography reserved for those in whom the noninvasive testing is technically inadequate, equivocal, or contradictory. The combination of ultrasound and magnetic resonance angiography is more cost-effective than the use of routine conventional angiography in this setting. However, the best algorithm for evaluation may vary depending on the services and expertise available at each medical center. Intracranial
Circulation
Intracranial atherosclerotic lesions account for approximately 5 - 1 0 % of all cerebral infarcts. They tend to be more common in African Americans and in Japanese and Chinese populations. Intracranial atherosclerotic lesions are
656
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NF.UROSCIENCES
Extracranial Carotid Ultrasonography in Practice
1
1
i
1
None/Mild
Moderate
Severe
Occlusion
(<S0%)
(50-75%)
(75-99%)
(1%)
- Medical Rx
- Medical Rx
- Consider CEA
- Medical Rx. and
- F/U study optional
• FAJ6-42 months
- MRA. CTA, or Angio
- O A . A C A . & VFR
- Study OA. ACA flow
- Study OA, ACA flow-
- If technically poor.
direction and VFR - If Sx recur, repeat sono and consider MRA. CTA, angio. and CEA
direction and VFR
MRA. CTA, angio
- ""delayed CKA.Rx
- Ongoing Sx. repeat
with AC. repeat sono
sono, angio if none.
before CEA or angio
consider E C l C o r
- If not CEA candidate
contralateral Rx
then medical Rx
* Consider TCD embolus detection with ongoing Sx for any degree of stenosis
* When >75% stenosis, consider TCD cerebrovascular reactivity with CO, or acetazolamldc •Consider TCD with agitated saline study for PFO. especially if no other identified cause FIGURE 37D.7 Extracranial carotid ultrasonography in practice. Practical importance of carotid ultrasound. The category of stenosis severity influences treatment decisions and provides additional diagnostic information. AC = anticoagulation; ACA = anterior cerehral artery; CEA = carotid end antrectomy; C 0 2 = carbon dioxide; CTA = computed tomography angiogram; ECIC = extracranialintracranial bypass surgery; F/U - follow-up; MRA - magnetic resonance angiography; OA = ophthalmic artery; PFO = patent foramen ovale; Rx = treatment; Sx = symptoms; 'LCD = transcranial Doppler; VFR = volume flow rate,
associated with a high risk of cerebral infarction, which varies depending on the location of the lesion. The annual rate of stroke ipsilateral to MCA stenosis is approximately 6-10%. Brain infarction in this setting is caused by occlusion of penetrating arterioles and artery-to-artery embolism {Wong et al. 2002). Pharmacological treatment of vascular risk factors, antiplatelet agents, and anticoagulants often are prescribed to patients with these lesions, but there are no prospective studies showing the efficacy of these regimens. A 1995 retrospective study of symptomatic patients with angiographically demonstrated lesions causing more than 50% stenosis showed that warfarin anticoagulation reduces the risk of recurrent cerebral infarction and has a more favorable risk-to-benefit ratio than aspirin (Chimowitz et al. 1995}. Angioplasty is performed at some centers. ICA distribution stenoses secondary to atherosclerosis, sickle cell disease, moyamoya disease, and dissection are reliably detected by TCD. As in other arteries, a focal increase of flow velocity is the characteristic finding of ICA siphon and supraclinoid segment as well as MCA Ml stenoses (Figure 37D.8). It is often associated with a decrease in velocity in the arterial segment distal to the stenotic lesion, in addition to low-frequency bidirectional signals during systole and arterial wall covibrations. The diagnostically relevant minimal increase in velocity remains a matter of debate, but most investigators concur that
MCA peak systolic and mean velocities exceeding 140 cm per second and 80 cm per second, respectively, are significant. When compared with those of cerebral angiography, TCD findings provide an approximate sensitivity of 8 5 % and specificity of 9 5 % in detecting these lesions. Lower velocity values improve sensitivity, whereas higher values enhance specificity. TCD's accuracy is highest in detecting lesions causing more than 5 0 % stenosis. The technique is less reliable in detecting lesions in the proximal anterior and posterior cerebral arteries, and the MCA M2 segment usually is beyond its reach. The accuracy of cerebral catheter angiography in detecting some itirracranial lesions and in estimating the degree of stenosis has been questioned, however. MCA or basilar artery occlusion is associated with an absence or severe reduction of the Doppler signal at the appropriate depth of insonation at a time when signals from the other ipsilateral basal cerebral arteries arc detectable. Follow-up studies often show spontaneous recanalization of previously occluded segments. The latter can be detected within hours of the onset of symptoms; the majority of symptomatic occlusions are recanalized within 2 days, followed by a period of hyperpcrfusion. Collateral flow patterns associated with severe cervical carotid stenosis or occlusion also can be detected. They include retrograde flow of the ophthalmic artery and
ULTRASOUND IMACIING OF THE CEREBRAL VASCULATURE
657
B FIGURE 37D.8 Middle cerebral artery stenosis. Focal increase in flow velocities. (A) The peak systolic flow velocity is only 82 em per second, a value within the normal range, at a depth of insonation of 56 mm. (B) At 48 mm, however, the peak systolic velocity is markedly increased at approximately 330 cm per second, indicating a severely stenotic lesion of the Ml segment. Continued
anterior or posterior communicating artery flow toward the hemisphere distal to stenosed or occluded ICAs. Lesions causing stenosis of the V4 segment of vertebral artery and the proximal basilar artery also can be imaged by TCD. Focal increases of the peak systolic and mean velocities to, respectively, 120 cm per second and 80 cm per second or more at depths of insonation corresponding to these arterial segments is considered significant (Figure 37D.9). Velocities often exceed 200 cm per second with lesions causing more than 5 0 % stenosis. When compared with angiography, the sensitivity of TCD is approximately 7 5 % in detecting vertebrobasilar stenotic lesions, and its specificity exceeds 8 5 % . The frequent variation in the size and course of the vertebrobasilar trunk and its contribution of collateral flow to the anterior cerebral circulation are the
main reasons for these low figures. Contrast media and transcranial color-coded imaging can be particularly helpful in this setting {Stolz et al. 2002), Usually a benign condition, the subclavian steal syndrome is characterized by the triad of retrograde flow in one vertebral artery, anterograde flow in the other, and biphasic or retrograde flow in the basilar artery (Figure 37D.10), The surge in interest in this condition stems from the use of angioplasty to treat selected patients with severe symptoms. Microemholic signals (Plate 371X1V) detected by 1 CI) correspond to gaseous microbubbles or emboli composed of platelets, fibrinogen, or cholesterol moving in intracranial arteries. In patients with extracranial carotid disease, these signals are associated with a history of recent
658
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
endarterectomy candidates with symptomatic extracranial carotid stenosis diagnosed by duplex scanning, tandem lesions can occasionally coexist and should be ruled out. Therefore duplex and TCD testing should often be obtained together, or in an organized sequence, to answer specific questions or hypotheses developed by the treating physician.
Chronic Ischemic Cerebrovascular Disease Extracranial
FIGURE 37D.8, cont'd. (C) The magnetic resonance angiogram confirms the presence of the stenotic lesion {arrowhead}.
transient ischemic attacks or cerebral infarction in the distribution of the insonatcd artery, and they correlate with the presence of ipsilateral severe stenosis and plaque ulceration. They are detected mainly during the week after symptoms of cerebral ischemia and resolve afterward. Microembolic signals also can be detected in subjects with cardiac prosthetic valves but often correspond to gaseous micro bubbles in that setting. They are less common in adequately anticoagulatcd patients with atrial fibrillation. The clinical impact of microembolus detection studies remains limited. The presence of these signals in an arterial territory is useful in identifying active lesions. This is especially relevant when a symptomatic patient has more than one potential lesion, such as cervical carotid stenosis and atrial fibrillation, or a suboptimal history. In this situation, laboratory data can help identify the specific cause of cerebral infarction. In addition, because the presence of microembolic signals predicts future cerebral ischemic events in the insonated artery's territory (Babikian et al. 1997), the detection of these signals may tilt therapeutic decisions. In the future, microembolus detection studies may be useful in monitoring the effect of antiplatelet agents or anticoagulation. Microemboli monitoring is also useful in the context of CFA and coronary artery bypass surgery. Although at some medical cenrers carotid duplex and TCD testing are performed in different laboratories, they are complementary. The accuracy of TCD studies is improved when the condition of the extracranial carotid and vertebral arteries is known. Similarly, in
Stenotic
Lesions
Ultrasound offers a safe, noninvasive way to serially follow patients with carotid or vertebral artery disorders. Periodic evaluation can be helpful for assessing the progression or regression of existing plaques or the development of new lesions, whether symptomatic or asymptomatic. The timing of follow-up carotid testing must be individualized depending on the severity and types of lesions and the onset of new or recurrent symptoms. Asymptomatic stenosis of less than 5 0 % might be initially restudied in 12-24 months, whereas lesions with 5 0 - 7 5 % stenosis and uncomplicated plaques might wait 6-12 months. For 5 0 - 7 5 % stenosis with complicated plaque features, or for more rh.m 7 5 % stenosis, initial restudy at 3-6 months seems appropriate if CEA is not performed. Lack of progression for several years allows lengthened intervals before restudy. When evidence of asymptomatic progression is present, a shorter interval is recommended. Development of new symptoms should prompt urgent reevaluation. After CEA, repear ultrasound often is done approximately 1 month after surgery and then yearly to look for restenosis. The identification of asymptomatic carotid stenosis has become an important clinical mandate since the Asymptomatic Carotid Atherosclerosis Study showed the benefit of CEA in asymptomatic individuals with 6 0 - 9 9 % stenosis when compared with treatment with 325 mg of aspirin daily (Executive Committee for the Asymptomatic Carotid Atherosclerosis Study 1995). Yet it is not costeffective to screen the entire population, even with ultrasound. Asymptomatic individuals with cervical bruits should be studied, even though bruits often are due to another cause. Patients with multiple risk factors probably warrant study, but the clinical utility of this has not yet been confirmed. If stenosis is identified, intervals for restudy should be similar to those outlined previously, Large population studies, such as the Atherosclerosis Risk in Communities and the Cardiovascular Health Study, have documented the association between risk factors and mtima-media thickening in the wall of the carotid artery on B-mode imaging (Howard et al. 1993; Polak et al. 1998). This may be an early stage in the development of atherosclerosis, and the presence of significant thickening correlates with risk of heart attack and with abnormalities
ULTRASOUND IMAGING OF THE CEREBRAL VASCULATURE
659
FIGURE 37D.9 Basilar artery stenosis. {A, B) The flow velocities are within the normal range in the vertebral arteries. (C) The peak systolic velocity exceeds ISO cm per second, and the end-diastolic velocity exceeds 45 cm per second at an insonation depth of 100 mm, indicating proximal Basilar artery stenosis.
on magnetic resonance imaging of the h t a i n . A l t h o u g h
Intracranial Stenotic
extensive data to confirm the clinical utility of identifying increased intima-media thickness values are lacking, it has been suggested that B-mode imaging to evaluate intima-media thickness should be used clinically to identify patients with high risk for coronary or cerebrovascular events or to assess responses to risk factor modification (Greenland et al. 2000). It is hoped that such early identification of atherosclerotic changes will allow intervention to prevent later development of clinical events.
Lesions
Intracranial atherosclerotic plaques are dynamic lesions. Although some lesions progress, causing increasing degrees of stenosis, others may tegress over short periods of time. TCD enables the noninvasive monitoring of the progtession of these lesions. It is often obtained at baseline, in conjunction with cerebral catheter angiogtaphy or magnetic resonance angiography, and is subsequently repeated during the follow-up period (Figure 37D.11), Monitoring also enables detection of new atherosclerotic plaques.
However, clinical experience is limited, and no published prospective studies exist to make recommendations regarding the frequency and timing of follow-up studies. Cerebrovascular
Reactivity
The annual stroke rate distal to carotid occlusion is approximately 2 - 5 % . Cerebral embolism and hypoperfusion are considered the main causes of recurrent symptoms of cerebral ischemia. Although the ability of abnormal cerebral hemodynamic changes to identify patients at an increased risk of recurrent stroke has been questioned, more recent studies suggest that hemodynamic impairment can be a major cause of cerebral ischemia. In patients with ICA occlusion and impaired cerebrovascular reactivity determined by TCD or xenon computed tomography, the annual rate of distal cerebral ischemic events is approximately 10%. Because a subgroup of patients with impaired cerebrovascular reactivity may benefit from a bypass procedure, a new randomized clinical trial has been organized (Adams et al. 2001).
Both intravenous acetazolamide administration and carbon dioxide inhalation methods are used to assess cerebrovascular reactivity. In patients with exhausted cerebrovascular reactivity, flow velocities fail to adequately increase after the intravenous administration of acetazolamide or have a decreased response to hypercapnia and hypocapnia. TCD testing can provide an estimate of the stroke risk in patients with ICA occlusion. However, the ability of testing to reliably identify patients who might benefit from a revascularization procedure has not been shown. Sickle Cell Disease An occlusive vasculopathy characterized by a fibrous proliferation of the intima often involves the basal cerebral arteries of patients with sickle cell disease. Cerebral infarction is a common complication of this vasculopathy and has a frequency of approximately 5 - 1 5 % . As in all patients with anemia, flow velocities are diffusely increased in patients with sickle cell anemia.
ULTRASOUND IMAGING OF THE CEREBRAL VASCULATURE
661
jfrr" C FIGURE 37D.11 Monitoring of intracranial atherosclerotic lesions. (A) Cerebral angiogram shows an area of stenosis {arrow) in the Ml segment of the right middle cerebral artery, (B) The first transcranial Doppler study obtained within 48 hours of angiography shows a corresponding peak systolic velocity of 188 cm per second. (C) Repeat transcranial Doppler study .34 months later shows a further increase of the peak systolic velocity to approximately 350 cm per second. (Reprinted with permission from Schwarzc, J. J., Babikian, V., DeWitt, L. D., ct al., 1994, "Longitudinal monitoring of intracranial arterial stenoses with transcranial Doppler ultrasonography," ] Neuroimaging, vol. 4, pp. 182-187.)
Additional focal velocity increases in the basal cerebral arteries can be detected in some patients (Plate 37D.V}. These increases correlate with 9 0 % sensitivity and more than 9 5 % specificity with stenotic lesions demonstrated by cerebral catheter or magnetic resonance angiography. A time-averaged mean of the maximum velocity of 200 cm per second or greater in the distal ICA and proximal MCA identifies neurologically asymptomatic children at an increased risk for first-time stroke {Adams et al. 1998). Periodic red blood cell transfusion is associated with a 9 0 % reduction in the rate of stroke. A Clinical Alert from the National Heart, Lung and Blood Institute recommended that children with sickle cell disease between ages 2 and 16 receive baseline TCD testing and that those with normal study results be restudied every 6 months {National Heart, Lung and Blood Institute 1997). Red blood cell transfusions reduce some of the abnormalities seen on cerebral angiography.
Aneurysmal Subarachnoid Hemorrhage Vasoconstriction of intracerebral arteries is the leading cause of delayed cerebral infarction and mortality after aneurysmal subarachnoid hemorrhage. Vasospasm is clinically detected 3 or 4 days after the hemorrhage and usually resolves after day 12. Although the exact cause of vasospasm remains unknown, its presence correlates with the volume and duration of exposure of an intracranial artery to the blood clot. Laboratory and animal models indicate that blood breakdown products can lead to vasoconstriction. The detection of vasospasm is important because it can be treated. Nimodipine, intravascular volume expansion, and pharmacologically induced relative hypertension are some of the prescribed therapies, and balloon angioplasty and intra-arterial papaverine are experimental therapies increasingly provided at some medical centers.
662
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCLS
These treatments are not innocuous, and the ability to noninvasively detect and monitor vasospasm is of clinical interest. Although vasospasm can he angiographically detected in 3 0 - 7 0 % of patients with aneurysmal subarachnoid hemorrhage, only 2CMK)% develop clinical signs of cerebral ischemia. Therefore the presence of vasospasm is not a sufficient condition for developing a clinical focal ischemic deficit, and several factors, including the severity of spasm, presence of collateral flow, condition of patient's intravascular volume, and cerebral perfusion pressure, are considered mitigating factors. TCD studies show an increase in the flow velocities of basal cerebral arteries, usually starting on day 4 after subarachnoid hemorrhage and peaking by days 7-14 (Plate 37D.VI). Although a diffuse increase in velocities often is detected in patients with severe hemorrhage, arterial segments in close proximity to the subarachnoid blood clot usually have the highest velocities. Severe vasospasm in an arterial segment can be associated with reduced regional cerebral blood flow in the artery's distal territory. There is a linear, inverse relationship between the severity of vasospasm and the amplitude of flow velocity increase in an arterial segment. It is valid until the vasoconstriction is so severe that the flow volume is reduced, flow velocities drop, and the TCD signal becomes difficult to detect. The linear relationship can also be affected by several factors including the presence of hyperperfusion. Whether there is a critical threshold of flow velocity for cerebral ischemia remains a matter of debate. Angiographic studies confirm the presence of at least some degree of MCA vasospasm when the mean flow velocities are higher than 100 cm per second, but values below 120 cm per second are considered clinically insignificant. Mean velocities between 120 and 200 cm per second correspond to 2 5 - 5 0 % angiographically determined diameter reduction, and values exceeding 200 cm per second correspond to more than 5 0 % luminal narrowing (Sloan, Wozniak, and Macko 1999). Based on these and other considerations, some investigators initiate hypertensive therapy at a mean velocity threshold of 120 cm per second, but this is not standard practice. The 200 cm per second threshold and rapid flow velocity increases exceeding 50 cm per second on consecutive days are associated with subsequent infarction. The effect of orally administered nimodipine on flow velocities appears to be minimal. TCD is used also to monitor the effects of endovascular treatment of vasospasm. Flow velocities decrease after successful angioplasty or papaverine infusion. Persistent increases after treatment indicate either extension of vasospasm to new arterial segments or hyperemia in the treated arterial segment and may constitute a valid reason for repeat cerebral angiography. The accuracy of TCD in detecting vasospasm depends to some degree on the location of the involved arterial segment. Although TCD criteria are more than 9 0 %
specific in detecting MCA and anterior cerebral artery vasospasm, they are, respectively, 8 0 % and less than 5 0 % sensitive in detecting disease in these arterial segments (Sloan, Wozniak, and Macko 1999). Basilar artery vasospasm is detected with an approximate sensitivity of 7 5 % and specificity of 8 0 % . Several factors, including the effects of hyperemia, increased intracranial pressure and blood pressure changes, the presence of vasospasm in convexity branches not accessible by TCD, and difficulties in assessing vasospasm by angiography, contribute to these findings. Because of these limitations in accuracy, the combined use of TCD and single photon emission computed tomography or xenon-enhanced computed tomography has been advocated, with the expectation that it will provide a more comprehensive and accurate assessment of the clinical condition. Overall, however, TCD is considered to have acceptable accuracy for evaluating vasospasm in aneurysmal subarachnoid hemorrhage. It is a useful tool with limitations that must be taken into consideration in the clinical setting.
Intensive Care Unit and Perioperative Monitoring Cerebral
Circulatory Arrest
A characteristic pattern of changes can be detected by TCD in patients with increased intracranial pressure. Early findings consist of a mild decrease in the diastolic flow velocity and an increase in the difference between peak systolic and end-diastolic velocities. When the intracranial pressure increases further and reaches the diastolic blood pressure level, flow stops during diastole, and the corresponding flow velocity drops to zero; flow continues during systole, and spiky systolic peaks are observed. A further increase of the intracranial pressure is associated with a reverberating flow pattern, with forward flow in systole and retrograde flow in diastole (Figure 37D.12). The net volume of flow decreases and can reach zero. At cerebral perfusion pressure values close to zero, either small systolic spikes are observed (Figure 37D. 12), or no signal at all is detected. This corresponds to a complete arrest of flow as demonstrated by cerebral angiography. The pattern of TCD changes is not specific to a particular neurological disease and can occur in a variety of conditions associated with increased intracranial pressure. The changes described in the preceding paragraphs are also observed in patients clinically diagnosed as brain dead. In one study, a high-resistance waveform pattern consisting of absent or reversed diastolic flow and small early systolic spikes, when present in at least two intracranial arteries, was more than 9 0 % sensitive and 100% specific for brain death. Experience at other centers has been more variable, with some investigators reporting patients who do not
ULTRASOUND IMAGING OF THE CEREBRAL VASCULATURE
satisfy clinical criteria for brain death, even though their TCD studies indicate circulatory arrest in some cerebral vessels. This is not totally unexpected because preserved intracranial circulation has been demonstrated previously in brain-dead patients. Thus although TCD is useful in detecting cerebral circulatory arrest, it cannot be recommended as the sole diagnostic test for diagnosing brain death. The latter must be established based on the clinical presentation and neurological examination findings. TCD and other laboratory tests can help confirm the clinical impression.
Carotid
Endarterectomy
As indicated earlier in this chapter, CEA is more effective than medical therapy when it can be performed with a combined mortality and morbidity of less than 6% for symptomatic and 3% for asymptomatic patients.
663
Unfortunately, these results are not achieved at all medical centers (Wennberg et al. 1998). Monitoring is performed to identify and correct surgical events that can lead to cerebrovascular complications. Monitoring tests currently in use include electroencephalography and stump pressure measurement. These tests are useful in detecting cerebral hypoperfusion or its consequence, cerebral ischemia, but their effectiveness in reducing the perioperative stroke rate has not been demonstrated in prospective studies. TCD monitoring during CEA shows a consistent pattern of flow velocity changes during endarterectomy, The most significant changes occur at the time of carotid clamping, with persistent and severe velocity decreases to less than 1 5 % of prcclamp values in up to 10% of patients (Figure 37D.13). Patients with velocities decreasing to this level usually are considered candidates for shunting. Although definitive TCD criteria for shunting have not yet been established, a postclamp peak systolic
664
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES FIGURE 37D.13 Carotid endarterectomy. At clamp insertion, the peak systolic flow velocity decreases from approximately 175 to 35 cm per second.
or mean flow velocity decrease to less than 3 0 % of t h e preclamp value often is considered an acceptable criterion. T C D also has the u n i q u e ability to detect m i c r o e m b o l i s m as it occurs. This gives T C D an edge over o t h e r m o n i t o r i n g techniques because the majority of perioperative infarcts a r e t h o u g h t to be secondary to cerebral embolism, M t c r o e m h o l i are detected at specific stages of surgery; dissection, c l a m p insertion a n d release, and the immediate p o s t o p e r a t i v e period a r e rhe high-risk periods (Plate 37D.VII). Roth gaseous a n d particulate emboli a r e seen a n d are associated with small cerebral infarcts detected by magnetic r e s o n a n c e imaging a n d with postoperative cognitive d e t e r i o r a t i o n . A relative n e w c o m e t to t h e field of intraoperative m o n i t o r i n g , T C D provides useful information to rhe surgeon. H o w e v e r , the characteristics of microembolism associated with cerebral infarction, such as emboli c o u n t and c o m p o s i t i o n , remain to be determined. A prospective study to assess the technique's effectiveness is needed.
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Barnett, H. J., Taylor, D. W., Eliasziw, M, et a l , 1998, "Eencfit of carotid endarterectomy for patients with symptomatic moderate or severe srenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators," N Engl J Med, vol. 339, pp. 1415-1425 Bluth, E. 1, Sunshine, J. H, Lyons, J. B, et a l , 2000, "Power Doppler imaging: Initial evaluation as a screening examination for carotid stenosis," Radiology, vol. 215, pp. 791-800 Chimowitz, M. I, Kokkinos, J, Strong, J, et a l , for the WarfarinAspirin Symptomatic Intracranial Disease Study Group, 1995, "The warfarin-aspirin symptomatic intracranial disease study," Neurology, vol. 45, pp. 1488-1493 Executive Committee for the Asymptomatic Carotid Atherosclerosis Study, 1995, "Endarterectomy for asymptomatic carotid stenosis," JAMA, vol. 273, pp. 1421-1428 Gomez, C, Kinkel, P., Masdeu, J, et al., 1997, "American Academy of Neurology Guidelines for Credentialing Neuroimaging. Report from the task force on updating guidelines for credentialing in neuroimaging," Neurology, vol. 49, pp. 1734-1737 Greenland, P., Abrams, J., Aurigemma, G. P, et al. 2000, "Beyond secondary prevention: Identifying the high-risk patient fot primary prevention—Noninvasive tests of atherosclerotic burden," AHA Scientific Statement. Prevention Conference V, Circulation, vol. 101, pp. eI6-e22 Griewing, B, Morgenstern, C, Driesncr, F, et a l , 1996, "Cerebrovascular disease assessed by color flow and power Doppler ultrasonography. Comparison with digital subtraction angiography in internal carotid artery stenosis," Stroke, vol. 2 7 , pp. 95-100 Howard, G, Sharrett, R, Heiss, G, et a l , for the ARIC Investigators, 1993, "Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound," Stroke, vol. 24, pp. 1297-1304 Knappertz, V. A, Tegeler, C. H, & Myers, L. G, 1996 "Clinical cerebrovascular applications of arterial ultrasound volume flow rate estimates," / Neuroimaging, vol. 6, pp. 1-7 Krcmkau, F. W, 2002, Diagnostic Ultrasound: Principles and Instruments, 6th cd, Saunders, Philadelphia Masdeu, J. C, 1997, "The American Academy of Neurology workshop on neuroimaging training: American Academy of
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Tan, T. Y., Schminke, U., Lien, L. M., et al., 2002, Extracranial internal carotid artery occlusion: The role of common carotid artery volume flow," / Neuroimaging, vol. 12, pp. 144-147 Tegeler, C. H., Babikian, V. L., & Gomez, C. R. (eds) 1997, Neurosonology, Mosby, St Louis. Tegeler, C. H. &: Ratanakorn, D., 1998, "Neurosonology," in Textbook of Neurology, eds. J. Bogousslavky & M. Fisher, Butterworth-Heinemann, Boston, pp. 101-118 Tegeler. C 11. K Ratanakorn. D., 1999a, "Ultrasound and cerebrovascular disease," in Cerebrovascular Disorders, 5th ed, cd J. F. Toole, Lippineott Williams & Wilkins, Philadelphia, pp. 83-128 Tegeler, C. H. & Ratanakorn, D., 1999b, "Ultrasound in cerebrovascular disease," in Neuroimaging: A Companion to Adams and Victor's Principles of Neurology, 2nd ed, ed J. Greenberg, McGraw-Hill, New York, pp. 645-666 Unsgaard, G., Gronningsaeter, A., Ommedal, S., & Nagelhus Hemes, T, A,, 2002, "Brain operations guided by realtime two-dimensional ultrasound: New possibilities as a result of improved image quality," Neurosurgery, vol. 5 1 , pp. 402-412 Wennberg, D. E., Lucas, F. I.., Birkmeyer, J. D., et al., 1998, "Variation in carotid endarterectomy mortality in the Medicare population," JAMA, vol. 279, pp. 1278-1281 Wong, K. $., Gao, S., Chan, Y. I.., et al., 2002, "Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: A diffusion-weighted imaging and microemboli monitoring study," Ann Neurol, vol. 52, pp. 74-81 Yasaka, VI., O'Kcefe, G. )., Chambers, b. R., el al,, for the Australian Streptokinase Trial Study Group, 1998, "Streptokinase in acute stroke," Neurology, vol. 50, pp. 626-632
Chapter 37 Neuroimaging E. FUNCTIONAL NEUROIMAGING Darin D. Dougherty, Alan J. Fischman, and Scott L. Rauch Functional Neuroimaging Modalities Positron Emission Tomography and Single-Photon Emission Tomography Functional Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Electroencephalography and Magnetoenccphalography Clinical Utility Dementia Seizures
667 667 668 668 668 672 672 672
Structural neuroimaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) have been available for several decades and have become invaluable tools in the evaluation of central nervous system (CNS) disease. Functional neuroimaging modalities have been developed more recently. Although CT and MRI provide static, high-resolution images ol die CNS, functional neuroimaging modalities such as positron emission tomography (PET), single-photon emission CT (SPECT), and functional MRI {fMRI) provide dynamic images of brain function. This chapter reviews the various functional neuroimaging modalities. In addition, the clinical utility of these techniques is reviewed and potential clinical and research applications arc discussed.
FUNCTIONAL NEUROIMAGING MODALITIES Positron Emission Tomography and Single-Photon Emission Tomography PET and SPECT are radiotracer imaging modalities. A biologically relevant radiotracer is introduced into the subject and its actions can be measured in vivo. For example, l 5 0 can be incorporated into either CO2 or H2O, The ' 5 0 radiotracer can be introduced to the subject cither by inhalation or intravenous injection and serves as an in vivo dynamic marker of regional cerebral blood flow (rCBF) in PET studies. PET and SPECT cameras are designed to measure the radiation emitted from radio-
Parkinson's Disease Cerebral Ischemia Neoplasms Research Applications Neutral State Activation Studies Treatment Studies Neurochemistry Conclusion
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tracers in a manner that allows for reconstruction of spatial images (tomographs) that provide both qualitative and quantitative measures of brain function. The typical spatial resolution of these images is 3-5 mm for PET and 7-10 mm for SPECT (although advances in technology may ultimately result in comparable spatial resolutions for both modalities). Single functional images may be collected (i.e., "snapshots" of brain function} or multiple serial images may be acquired (i.e., dynamic, "filmstrip-like" images of brain function). However, the temporal resolution of PET and SPECT docs not approach that of fMRI (discussed later in this chapter). PET and SPECT are primarily used to measure indices of neuronal activity. Regional cerebral metabolic rate (rCMR) and rCBF can be assessed using PET, whereas SPECT can measure only rCBF. IK F-fluorodeoxygIucosc (FDG) is used to measure rCMR and tsO is used to measure rCBF with PET. A number of SPECT radiotracers are available to measure rCBE including yym Tc-hcxamerhylpropyIenearnine oxime (HMPAO), 99m Tc-ethylene cysteinate dimer (ECD), and 12*I-isopropyl iodoamphetamiuc (IMP). Of note, the shorter half-life of l 5 0 (about 2 minutes) allows for multiple measures of rCBE during a single PET study, whereas the longer half-life of the SPECT radiotracers typically allows for only one measure of rCBE during a single SPECT session. Thus paradigms requiring multiple acquisitions require multiple visits on separate days if SPECT is to be used. In addition to the radiotracers designed to measure rCMR and rCBF, there are also a number of agents M>7
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Tabic 37E.1:
Representative radiotracers
Radiotracer Single-photon emission computed tomography "Tc-HMPAO "'"Tc-ECD U, I-IMP l;i I-altropane u, I-0CIT 123
I-epidipride I-IBZM Positron emission tomography C*02, H 2 l s O la F-fluorodcoxyglucosc 11 C-altropane ii/. C-SCH 23,390 U3
u
C-raclo pride
"C-WAY 100635 F-setoperone C-flumazenil C-diprenorphine "C-carfentanil
What it measures
Blood flow liluotl flow Blood flow Dopamine transporter Dopamine transporter/serotonin trans porter Type 2 dopamine (D^) receptor Type 2 dopamine (D2) receptor Blood flow Glucose metabolism Dopamine transporter Type 1 dopamine (D^ receptor Type 2 dopamine 2 (D2) receptor Type 1A serotonin (5-HTIA) receptor Type 2 serotonin (5-HT2) receptor Benzodiazepine receptor Opioid receptor (nonselective) Opioid receptor (mu selective)
designed to measure various aspects of neurochemistry (Table 37E.1). These radiotracers allow for quantification of presynaptic and postsynaptic neuroreceptors and neurotransmitter synthesis. Such neurochemistry studies show promise for assessing conditions in which abnormalities of a single neurotransmitter play a prominent role in the pathophysiology of the disease (e.g., dopamine abnormalities in Parkinson's disease).
Functional Magnetic Resonance Imaging fMRI studies use unique data-acquisition parameters that differ from those used for conducting structural MRI studies. Structural MRI studies involve placing the subject in a strong magnetic field (see Chapter 37A). This strong magnetic field aligns the resonant spin of a fraction of the hydrogen nuclei in the body. Then, the application of a radiofrequency pulse results in these nuclei changing orientation relative to the pre-existing magnetic field. In time, the hydrogen nuclei begin to return to their initial alignment. It is this relaxation of the hydrogen nuclei that provides the data necessary for construction of structural images, fMRI exploits the fact that deoxyhcmoglobin distorts the magnetic field. Because the local concentration of deoxyhemoglobin varies, the amount of distortion also varies. The local concentrations of deoxyhemoglobin provide an indirect measure of oxygen use. These changes in localized blood oxygenation give rise to the fMRI
blood oxygen level-dependent (BOLD) signal change that is related to CBE and cerebral blood volume.
Magnetic Resonance Spectroscopy Magnetic resonance spectroscopy (MRS) also exploits the behavior of endogenous compounds in a magnetic field to measure underlying biological processes. The nuclei of a number of atoms ('H, l y F, 7 Li, 2 i N a , and M P) are excited by the magnetic field. As the energy of these nuclei returns to a baseline state, a "frequency signature" particular to each nucleus can be measured. Simply put, the magnitude of each peak in this "frequency signature" corresponds to the concentration of a particular atom in the brain region being assessed. MRS studies of the different nuclei allow for quantification of a number of compounds in the brain. MRS studies of the hydrogen nucleus allow for the semiquantitative measurement of a number of endogenous compounds including N-acetyl-aspartate (NAA}, choline, creatine, yaminobutyric acid (GABA), glutamate, glutamine, inositol, and phosphocrcatinc. NAA is purportedly a marker of viable neurons. GABA and glutamate are the main inhibitory and excitatory neurotransmitters, respectively, in the human brain. Creatine and phosphocreatine are involved in neuronal energy metabolism. Choline is involved in membrane metabolism, and inositol is involved 111 second-messenger neurotransmission. Phosphorus MRS allows for measurement of molecules involved in energy metabolism such as adenosine triphosphate (ATP) and adenosine diphosphate (ADP). Components of neuronal membranes such as phosphomonoesters (PMEs) and phosphodiesters (PDEs) can also be measured using phosphorus MRS. Fluorine MRS and lithium MRS can be used to measure concentrations of exogenous substances (e.g., drugs) in the brain, i.irhium MRS can be used to measure brain lithium levels, and fluorine MRS can be used to measure the concenttation of fluorinated compounds {e.g., fluoxetine). MRS is being increasingly used to identify neoplasms of brain and to localize areas of tumor involvement (Figure 37E.1).
Electroencephalography and Magneto encephalography Electroencephalography (EEG) involves measurement of cortical activity via scalp electrodes. Conventional EEG has a multitude of clinical applications and is discussed in detail in Chapter 36A. Other EEG-related methodologies include event-related potentials (ERP) and quantitative EEG (QEEG). ERP refers to event-related waveforms in the EEG data that atisc following sensory, motor, or cognitive events. Although HRP lias a wide range ot applications in the research setting, there are currently three major uses of
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FIGURE 37E.1 Grade III astrocytoma, left frontal lobe, evaluated with single-voxel spectroscopy (SVS) and magnetic resonance spectroscopic imaging (MRSI). The results are typical of a high-grade astrocytoma. (A) Postcontrast Tl-weighted axial image used for localization of an 8-mL single voxel ( 2 x 2 x 2 cm) in the left frontal lobe. The voxel is positioned in a region of heterogeneous signal intensity with mild enhancement. There is moderate compression and displacement of adjacent brain, (B) SVS at echo time (TF.) of 135 ms: Point-resolved spectroscopy (PRESS) spectrum demonstrates decreased N-acetyl-aspartate (NAA), increased level of cholinecon raining small molecules (Cho), and increased lactate (Lac, appears as inverted doublet). Compare the peak heights and areas to those in (E), which were acquired from a region of normal-appearing brain. Continued
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FIGURE 37E.1, cont'd. (C) SVS at TE of 20 ms: Stimulated acquisition mode (STEAM) spectrum acquired with shott TE confirms PRESS findings and reveals prominent lipid (Lip) peaks in the 0.6-1.6 ppm region of the spectrum. (D) Same image as in (A) was also used for placement of a 2-cm thick, single-section, mul ti voxel (16 x 16) grid encompassing the brain at this level. Spectra were generated from the center 8 x 8 subvoxels (each 2.5 ml.) and 3 of the 64 spectra are shown in (E), (F), and (G). (E) MRS! at TE of 135 ms; PRESS specttum from a subvoxel located in the same region as used in (B}. Note the similarity in the MRS] spectra and the SVS spectra in (B).
PLATE 37E.I1 L5 0 positron emission tomography (PET) images of a patient experiencing an acute ischemic event. Note that cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO,), and oxygen extraction fraction (OEF) are all decreased at the site of the ischemic event. These are all indices of neuronal activity that can be measured using "0 PET techniques. (Used with permission from Dougherty, D. D., Rauch, S. L., 8c Fischman, A. J. 2003, "Neuropsychiatric applications of PET and SPECT," in Essentials of Nmroimaging for the Practitioner, eds D. D. Dougherty, S. L. Rauch, tk. J. F. Rosenbaum, American Psychiatric Publishing, Washington, DC.)
PLATE 37E.III Illustration of the methodology used for functional neuroimaging activation studies. Data are acquired in a serial manner in both activated and control states. By grouping the activation and control data, one can produce a difference image. Statistical tests can be used to determine which differences are statistically significant. This example shows a robust response to a hemifield stimulation of the visual system with a reversing checkerboard pattern using H 2 1 5 0 as the tracer. The activated visual cortex can be clearly seen, even before subtraction. (Used with permission from Cherry, S. R. & Phelps, M. E. 1996, "Imaging brain function with positron emission tomography," in Brain Mapping: The Methods, eds A. W. Toga & J. C. Mazziotta, Academic Press, San Diego, Calif.)
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Cho
FIGURE 37E.1, cont'd. IF) MRSI at TE of 135 ms: PRESS spectrum from a subvoxel located slightly outside the region of enhancement and necrosis. On routine magnetic resonance imaging (MRI), this area of the hrain might he interpreted as "edema"; however, the elevated Cho, decreased NAA, and evidence of Lac on MRSI suggest that there is tumor infiltration. (G) MRSI at TE of 135 ms: PRESS spectrum from a suhvoxel located in an area of normal-appearing brain. This spectrum serves as a control to which the spectra from abnormal brain can he compared. Note the dominant NAA peak and the similarity of the Cho and Cr peaks in this area of normal brain. (Courtesy Dr. Brian Bowen.)
ERP in the clinical setting. These include brainstem auditory evoked potential, somatosensory evoked potential, and pattern reversal visual evoked potential. QEEG, currently used only in the research setting, involves transforming the LEG data in a manner thai allows for quantitative analysis. Detailed discussion of QEEG and ERP are heyond the scope of this chapter. They are mentioned here because they ate, technically, functional neuroimaging modalities and because they arc increasingly used in conjunction with other functional neutoimaging techniques for research purposes.
Magnetoencephalogtaphy (MEG) is similar to EEG in that it measures surface cortical activity. However, MEG detects the magnetic signal that arises from the electrical current that is measured by EEG. Quantitative and ERP techniques can be applied to MEG data as well. Although fMRI has much better spatial resolution than MEG, the temporal resolution of MEG vastly exceeds that of fMRI. Thus fMRI provides spatial information that allows for refinement of MEG data analysis, whereas MEG provides temporal information that allows for tcfinement of fMRI data analysis. For these reasons, MEG and fMRI
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techniques are increasingly being used in conjunction with each another in the research setting.
CLINICAL UTILITY Although a number of functional neuroimaging modalities are available for assessing the CNS, currently only PET and SPECT have clinical utility. As such, this section focuses on the clinical uses of PET and SPECT. Potential uses for the remaining functional neuroimaging modalities are currently under investigation.
Dementia The potential of PET and SPECT in the diagnosis of Alzheimer's disease and other dementias continues to evolve. In fact, recent studies demonstrate that PET and SPECT have sensitivities and specificities of 9 0 % or more in differentiating Alzheimer's disease from other types of dementia. Typically SPECT studies using a variety of blood flow tracers and/or FDG PET studies are ordered as part of a dementia workup. The characteristic "earmuff" pattern of decreased metabolism or blood flow in bilateral temporoparietal and frontal regions with sparing of the somatosensory cortex is associated with the diagnosis of advanced Alzheimer's disease (Figure 37E.2).
Seizures
FIGURE 37E.2 Fluorodeoxyglucose positron emission tomography (PET) images of a patient with advanced Alzheimer's disease. Note the characteristic pattern of decreased glucose metabolism in all cortical regions except the somatosensory cortex (the "earmuff" pattern). (Used with permission from Dougherty, D. D., Ranch, S. L„, & Fischman, A. J. 2003, "Neuropsychiatry: applications of PET and SPECT," in Essentials of Neuroimaging for the Practitioner, eds D. D. Dougherty, S. L. Rauch, & J. F. Rosenbaum, American Psychiatric Publishing, Washington, DC.)
progresses, binding of these radiopharmaceuticals in the striatum decreases {Plate 37E.I). The clinical use of these techniques is just beginning to emerge. These techniques ultimately may be diagnostically useful not only in situations in which the patient is clinically symptomatic,
Although EEG is the mainstay for detecting seizure foci, this technique is somewhat limited in that EEG is able to measure only corneal surface electrical activity. PET and SPECT are able to measure glucose metabolism or blood flow throughout the brain. Seizure foci demonstrate increased metabolism or blood flow during a seizure and decreased metabolism or blood flow during the interictal period (Figure 37E.3). Thus these functional neuroimaging modalities can be useful in cases with an unclear diagnostic picture, for localization of the seizure focus, and preoperative^ in cases in which neurosurgery is indicated.
Parkinson's Disease Because Parkinson's disease is caused by degeneration of dopaminergic neurons in the substantia nigra, a means for in vivo assessment of dopaminergic function may be of diagnostic value. A number of PET and SPECT radiopharmaceuticals arc available to measure presynaptic dopamine synthesis ( ls E-dopa) and dopamine transporter density (12,I-/SCIT, "C-CFT, ''C-altropane). These measures serve as markers for the number of intact dopaminergic neurons in the striatum. As Parkinson's disease
FIGURE 37E.3 Fluorodeoxyglucose positron emission tomography images ol a patient with temporal lobe epilepsy, fk'tausi' this image was acquired during the interictal period, glucose metabolism is decreased at the site of the seizure focus. (Used with permission from Dougherty, D. D., Rauch, S. L., & Fischman, A. J. 2003, "Neuropsychiatric applications of PET and SPECT," in Essentials of Neuroimaging for the Practitioner, eds D. D. Dougherty, S. L. Rauch, &c J. F. Rosenbaum, American Psychiatric Publishing, Washington, DC.)
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but perhaps even for early diagnosis (before symptoms emerge) so appropriate therapeutic interventions may be initiated earlier in the course of the disease. Another potential use is for quantitative measurement of disease progression, both in the standard clinical setting and in the context of clinical trials.
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or CBF can provide complementary information in the clinical evaluation of cerebral neoplasms. Importantly, tumor metabolism is thought to be proportional to tumor cell proliferation. Thus PET and SPECT studies provide information thai may be used for rumor classification. Lastly, PET and SPECT data may also be used to follow therapeutic response of cerebral neoplasms, as well as for differentiating radionecrosis from tumor recurrence.
Cerebral Ischemia Although PET and SPECT are still not widely used in the evaluation of acute cerebral ischemia, there is growing evidence that PET and SPECT may have significant diagnostic value in these clinical situations. In addition, whereas CT and MRI detect structural changes associated with an ischemic event, PET and SPECT can directly measure cerebral perfusion. Thus PET and SPECT can detect hypoperfusion following an acute ischemic event almost immediately, whereas it may take several hours before corresponding structural changes are detected by CT or MRI (Plate 37E.II). Ongoing studies are being conducted that may help define the role of PET and SPECT in the clinical evaluation of cerebral ischemia.
Neoplasms Most cerebral neoplasms can be detected using CT or MRI. However, because neoplasms typically demonstrate greater metabolism or blood flow than surrounding tissue (Figure 37E.4), PET and/or SPECT studies of glucose metabolism
RESEARCH APPLICATIONS All of the functional neuroimaging modalities discussed in this chapter are being used extensively in neuroscience research. Although each of these modalities is capable of measuring different aspects of brain function, the research paradigms used are relatively universal. In this section, we provide a brief description of some of the ways these functional neuroimaging modalities may be used in the research setting.
Neutral State The simplest type of functional neuroimaging studies involves comparing populations during a resting, or neutral, state. For example, FDG PET studies have been conducted in groups of patients with major depression and in healthy control subjects. These studies have demonstrated that anterior frontal regions, especially on the left side, are hypometabolic in patients with major depression when compared with healthy control subjects. Comparable neutral state functional neuroimaging studies have been conducted in patients with many disorders, including obsessive-compulsive disorder, schizophrenia, and chronic fatigue syndrome.
Activation Studies
FIGURE 37E.4 Fluorodeoxyglucose positron emission tomography image of a cerebral neoplasm demonstrating the increased glucose metabolism associated with the lesions. (Used with permission from Dougherty, D, D., Rauch, S. L., He Fischman, A. J. 2003, "Neuropsychiatric applications of PET and SPECT," in Essentials of Neitroinhigiiii; for the l'rtiititiancr, etls D. D. Dougherty, S. L. Ranch, & J. F. Rosen ha uni, American Psychiatric Publishing, Washington, DC.)
Although neutral state functional neuroimaging studies have provided valuable information regarding the pathophysiology of a number of disorders, functional neuroimaging studies conducted during specific tasks may have even greater research use. In functional neuroimaging activation studies, individuals perform tasks designed to assess a particular function (e.g., cognitive, affective, and visual) or to probe the functional integrity of a specific brain region. Brain function during the performance of these tasks is compared with brain function during a neutral condition and the difference is attributed to the performance of the task (Plate 37E.III). This methodology may be more robust than neutral state functional neuroimaging studies. For example, although neutral state functional neuroimaging studies demonstrate minimal abnormalities in patients with attention-deficit/hyper-
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activity disorder (ADHD), functional neuroimaging activation studies assessing attention in patients with this condition have demonstrated marked abnormalities in patients with ADHD when compared with healthy control subjects.
chapter. Thus functional neuroimaging technologies can be used to study indices of neuronal activity, as well as neurochemistry using any of these paradigms.
CONCLUSION Treatment Studies Functional neuroimaging techniques (eirher neutral state or activation studies) can also be used to assess treatment. There are generally two approaches to these types of studies. The first type, predictors of treatment response studies, involves performing functional neuroimaging studies in patients before initiating a course of treatment. After treatment, correlates between baseline brain function and subsequent treatment response can be ascertained. In this ni.miu • •.;• iv possibk' to detect baseline brain function profiles that predict subsequent treatment response. Secondly, functional neuroimaging studies can be performed before and after treatment. Predictors of trearment response analyses can be performed using the baseline functional neuroimaging data. Moreover, a comparison of pretreatment and posttreatment functional neuroimaging data may help to elucidate the mechanism of action of the treatment in question.
Neurochemistry As described previously PET, SPECT, and MRS can be used to assess neurochemistry in vivo. Essentially any functional neuroimaging paradigm that assesses neuronal activity (e.g., neutral state studies, activation studies, and treatment studies) can also be performed using these neurochemistry imaging techniques. Thus dopamine function, for example, can be measured at rest, before and during a specific task, or before and after treatment, and the data can be analyzed using methods similar to those described earlier in this
In summary, the application of functional neuroimaging technologies in the clinical evaluation of patients continues to evolve. In addition, functional neuroimaging is a powerful tool for neuroscience research. In the coming years, rhe clinical use of functional neuroimaging technology should continue to expand rapidly.
FURTHER READING Bonte, F. J., Weiner, M. F., Bigio, E. H., et al. 2001, "SPECT imaging in dementias," J Nucl Med, vol. 42, pp. 11311132 Cherry, S. R. Ec Phelps, M. E. 1996, "Imaging brain function with positron emission tomography," in Brain Mapping: The Methods, eds A. W. Toga &c J. C. Mazziotta, Academic Press, San Diego, Calif Dougherty, D. D. & Ranch, S. L. 2001, Psychiatric Neuroimaging Research: Contemporary Strategies, American Psychiatric Publishing, Washington, DC Dougherty, D. D., Rauch, S. L., & Rosenbaum, J. F. 2003, Essentials of Neuroimaging for the Practitioner, American l'sychinrrie Publishing, Washington, DC Krausz, Y., Bonne, O., Marciano, R., et al. 1996, "Brain SPECT imaging of neiiropsychuuric disorders," I'.ur I ILntioL vol. 21, pp. 183-187 Silverman, D. H., Small, G. W., Chang, C. Y., et al. 2001, "Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome," JAMA, vol. 286, pp. 2120-2127 Theodore, W. H. & Gaillard, W. D. 2000, "Positron emission tomography in neocortical epilepsies," Adv Neurol, vol. 84, pp. 435-446
Chapter 38 Neuropsychology Jane S. Paulsen and Karin Ferneyhough Hoth
Goals of Neuropsychology Neuropsychological Assessment The Brief Mental Status Examination Mini-Mental State Examination Dementia Rating Scale Additional Bedside Evaluation Draw a Clock Neuropsychological Characteristics of Neurological Disease Mild Cognitive Impairment
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The assessment of cognitive functioning is a critical part of a complete neurological examination. Whereas the cluneal neurological examination often focuses on the motor and sensory system, the neuropsychological examination focuses on the psychometric assessment of cognition and behavior. The cognitive evaluation can significantly contribute to neurological diagnosis, treatment planning, and monitoring over time. A wide range of intellectual abilities are assessed, and neuropsychological information complements information from electrophysiological techniques and neuroimaging. In this chapter we describe the neuropsychological evaluation process, including methodological issues that must he considered in test administration, examine the contribution of a comprehensive neuropsychological assessment, and describe the typical patterns of cognitive impairments that are associated with a variety of neurological disorders. Guidelines for brief mental status assessment are also included.
GOALS OF NEUROPSYCHOLOGY When potential cognitive deficits are noted clinically or during a brief mental status examination, an extended neuropsychology assessment is appropriate. Although the specific goals of a neuropsychological assessment differ depending on the referral question and the context in which the examination is given, several overarching aims can be identified {Table 38.1). The primary goal oi neuropsychological assessment is to identify and describe the patient's cognitive strengths and weaknesses and characterize impairments and deficits in patients with brain damage. Approximately 30 years ago,
Alzheimer's Disease Vascular Dementia and Vascular Cognitive Impairment Fron to temporal Dementia Parkinson's Disease Huntington's Disease Tourctte's Syndrome Multiple Sclerosis Epilepsy Human Immunodeficiency Virus Traumatic Brain Injury
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the main role of neuropsychology was lesion localization. Although this remains useful, the advent of neuroimaging techniques in the 1970s and 1980s shifted the emphasis of neuropsychology toward describing the patient's cognitive and behavioral profile. Nonetheless, tests of neuropsychological functioning often are able to detect subtle cognitive deficits that are undetected by electrophysiological or neuroimaging methods. Other major goals of neuropsychological assessment concern differentiation between intellectual changes associated with brain damage, cognitive and behavioral impairments resulting from psychiatric illness, and cognitive changes secondary to normal aging. In addition to offering information regarding diagnosis and neuroanatomical localization of dysfunction, the neuropsychological assessment is unique in its ability to address the patient's functional abilities. Clinicians often are called on to assess a patient's ability to make financial and health care decisions, to drive a car, and to live independently. These decisions can also determine when a patient is able to return to work after injury or what type of job the patient is suited for. A neuropsychological assessment may be used to determine appropriate adjustments to the patient's treatment and develop recommendations regarding activities of daily living. Repeated neuropsychological evaluation can be invaluable in monitoring cognitive change over time. Repeated assessments can track cognitive decline in a progressive illness, such as dementia or multiple sclerosis, or monitor recovery after acute injury, such as stroke or traumatic brain injury. Evaluating the effectiveness of medical procedures and neurological surgery also entails repeated comprehensive assessment ot cognitive abilities. A comparison ol preand post-treatment data offers information about changes in the patient's level of functioning after medical intervention. 675
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Table 38.1: Goais of n euro psycho logy To identify cognitive strengths and weaknesses To detect cognitive deficits not evident on the neurological, imaging, and physiological evaluations To differentiate cognitive impairments due to age, education, socioeconomic status, race, psychiatric symptoms, and personality factors To predict functional ability in work, driving, and self-care To monitor cognitive changes associated with recovery, disease progression, and treatment
NEUROPSYCHOLOGICAL ASSESSMENT The neuropsychological assessment generally involves a clinical interview, review of patient records, test selection, test administration and scoring, test interpretation, diagnosis, and treatment and rehabilitation recommendations. The clinical interview may vary in length given the presenting concerns of the patient. However, a complete interview typically covers the patient's developmental background, personal medical and psychiatric history, family medical history, academic performance, vocational achievements, psychosocial functioning, and activities of daily living. Information obtained from collateral sources such as caregivers or spouses about the patient's medical and psychosocial history often is critical. Behavioral observations of the patient during the examination are an important source of information that can influence test selection and the interpretation of test scores. One of the primary goals of the interview is to develop hypotheses about the patient's cognitive status and guide test selection. Many measures of cognitive functioning are available, and they differ in format, length, complexity, standardization, and quality of normative data. Different tests may be appropriate in different cases, and the test selection process is essential in gathering meaningful information about the patient. In the fixed battery approach, the same tests are given to every patient in a standardized manner. One of the most commonly used fixed batteries is the Halstead-Reitan Battery (Table 38.2}, for which comprehensive norms were published by Heaton and colleagues. An advantage of the fixed battery is that the information gathered is comprehensive and systematically assesses multiple domains of cognitive functioning. Additionally, if repeated assessments are available, test scores can be directly compared with baseline information. Drawbacks of the fixed battery approach involve its length (typically X hours! because it may be too long for some patients to tolerate and is difficult to afford with limited reirnbursement schedules in managed care. Finally, a comprehensive assessment may not be necessary to address the referral question. In contrast with a fixed battery, in the flexible (or hypothesis-driven) approach, test selection differs based on the referral question, the patient's history, and the clinical interview. Most neuropsychologists' approach falls
Table 38.2: Heaton adaptation of Halstead-Reitan neuropsychological battery Tactual Performance Test Finger Oscillation Test Category Test Seashore Rhythm Test Speech Sounds Perception Test Aphasia Screening Test Sensory-Perceptual Examination Strength of Grip Test Tactile Form Recognition Test WVdisliT Adult Intelligence Scale-Revised Wcchsler Memory Scale-Revised Source: Adapted from Heaton, R, K., Grant, I., &c Matthews, C. G. 1991, Comprehensive Norms for Expanded Halstead-Reitan Battery: Demographic Corrections, Research Findings, and Clinical Applications, Psychological Assessment Resources, Odessa, FL.
somewhere between the use of a set battery and a completely individualized examination. Often called the flexible battery, a brief set of basic tests is initially administered and additional tests of more specific abilities are used to meet each particular patient's needs. Test interpretation requires the integration of neuropsychological test scores with findings from the clinical interview, the patient's history, the neurological examination, and neurophysiology and neuroimaging data. Before this can be accomplished, however, the raw test scores must be interpreted in the context of an appropriate comparison standard. Several approaches are used in interpreting neuropsychological test scores including the use of normative data, cutting scores, and comparisons with baseline data. Neuropsychological test scores are interpreted most often through the use of normative data obtained by collecting information about test performance from a standardization sample. For instance, Table 38.3 shows the percentage of variance in test raw scores accounted for by the demographic variables age, education, and sex. The test chosen for this example is the Wechsler Adult Intelligence Scale (WAIS), one of the most commonly administered assessments of intellect. As shown in the table, some tests share 3 8 % variance with age (Digit Symbol), others share 4.)'X> variance with education (Information), and others differ with sex (Arithmetic). Interpreting performances on these tests without correcting for demographic characteristics of the person of interest would result in inappropriate conclusions. Normative data provide information about the expected test performance of individuals within a particular group, often stratified based on age or level of education. An individual raw score is compared with the distribution of scores from the person's peer group to determine where it falls within the range of performances. Figure 38.1 and Table 38.4 show guidelines for use in neuropsychological interpretation. The usefulness of normative data depends
NEUROPSYCHOLOGY Tabic 38.3: Percentage of variance in test scores accounted for by demographic variables
performance of an 82-year-old man with 8 years of education by comparing his test score with those of a group of 40-year-olds with an average of 12 years of education. .Significant limitations exist in some normative data including the absence of suitable norms for older adults and heterogeneity of education, ethnicity, and health variables among some standardization samples. Furthermore, it is important to use the most recent norms available because cohort effects may lead to differences between current patients and those from whom data were collected years ago. When appropriate norms are not available, there is a danger of overdiagnosis or undcrdiagnosis of cognitive impairment. Thus the accurate intetprctation of neuropsychological test performance necessarily incorporates information about the sample from which the norms for each test were developed.
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Another approach to test interpretation is the use of cutting scores to identify people who demonstrate pathological cognitive symptoms. Some tests ate designed to measure abilities that are largely intact in normal subjects but are impaired in disordered patients. For example, most people are able to bisect a line without difficulty, but patients with left-sided visuospatial neglect typically identify the midpoint of the line to be to the right of the centet. Tests that rely on cutting scores tend to measure performances with low base rates or deficits that very few people demonstrate. An important component of test interpretation is the comparison of current performance with past test scores. Often no previous data have been collected. Clearly, when one is attempting to identify cognitive decline, a patient's
A = age; E = education; S = sex. Source: Adapted from Heaton, R. K., Grant, 1., & Matthews, C. G, 1991, Comprehensive Norms for Expanded Haistead-Reitan Battery: Demographic Corrections, Research Findings, and Clinical Applications, Psychological Assessment Resources, Odessa, FL.
strongly on the size and representativeness of the standardisation sample. Clinical utility can be greatly affected by the goodness of the fit between the individual and the sample and the extent to which the norms take demographic factors into account. For example, it would not be appropriate to make determinations about the test
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8
9
4% 7% 12% 17% 20% 17% 12% 7% 4%
Percent of scores in each stanine
1
677
i
i
l_
J
L
10 20 30 40 50 60 70 80 90 99
The normal curve and its relationship to derived scores.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCFS
Table 38.4: Qualitative
Descriptive terms associated with performance within various ranges of the normal distribution terms
Severely impaired Moderately to severely impaired Moderately impaired Mildly to moderately impaired Mildly impaired Below average or atypical Average Above average High average Superior Very superior Amazingly superior God-like
Standard deviation
+3.0
-2.51 2.01 -1.51 -1.01 -0.51 +0.51 +0.99 +1.49 +1.99 +2.99 +2.99
score
Percentile rank
T score
99
80
Note: The patient's educational history and premorbid level of functioning should be taken into consideration in applying any qualitative label.
previous performance is an ideal c o m p a r i s o n s t a n d a r d . W h e n no previous test scores a r e available, evidence of the patient's p r e m o r b i d intellectual functioning is used to m a k e an estimate. D e m o g r a p h i c factors such as e d u c a t i o n level can he useful indicators of p r e m o r b i d level of ability. O n e rural neuropsychologist used n u m b e r of acres o w n e d to estimate I Q . A c o m m o n a p p r o a c h to estimating p r e m o r b i d intellectual functioning is to rely on specific characteristics of the patient's neuropsychological test p e r f o r m a n c e that arc considered stable, or " h o l d " tests. R e a d i n g ability often is used as an estimate of overall p r e m o r b i d intellectual ability because it is t h o u g h t to be resistant to m a n y processes t h a t cause declines in cognitive functioning. Some c o m m o n measures of reading ability a r c the N a t i o n a l American Adult Reading Test (Nelson 1982), which measures the ability to read irregularly spelled w o r d s , and the Wide R a n g e Achievement T c s t - 3 (Wilkinson 1V93), which m e a s u r e s the ability to read a l o u d . Because d e m o g r a p h i c variables a c c o u n t for a significant p r o p o r t i o n of t h e variance in neuropsychological test p e r f o r m a n c e , a n u m b e r of regression e q u a t i o n s have been developed using intelligence test standardization samples. T a b l e .38.5 lists s o m e of the d e m o g r a p h i c regression m o d e l s used to estimate premorbid intellect. C o n t e m p o r a r y neuropsychologists use a c o m b i n a t i o n of these strategies to arrive at the best estimate of p r e m o r b i d ability. Factors other t h a n the cognitive ability of interest, including d e m o g r a p h i c and clinical characteristics, can
Table 38.5:
Premorbid verbal IQ estimations
Wilson: V1Q = 0.18 (age) - 2.02 (sex) - 8.99 (race) + 3.09 (education) + 0.97 (occupation) + 70.8 Barona: VIQ = 54.23 + 0.49 (age) + 1.92 (sex) + 4.24 (race) + 5.25 (education) + 1.89 (occupation) + 1.29 (region) Reynolds: VIQ = 127.85 - 3.7 (parental SES) - 8.86 (race) - 2.40 (sex) - 0.16 (region) - 1.16 (urban or rural residence)
influence a p a t i e n t ' s test scores. Subject characteristics such as a g e , e d u c a t i o n , sex, a n d ethnicity h a v e been s h o w n to affect test b e h a v i o r (see T a b l e 3 8 . 3 ) . Overall, increasing age is associated with m o r e adverse c o n s e q u e n c e s of brain d a m a g e , a l t h o u g h the relationship is c o m p l i c a t e d . In terms of test p e r f o r m a n c e , aging has different effects on different cognitive d o m a i n s . Aging h a s its m o s t p r o n o u n c e d effects on n o n v e r b a l , timed tests, a n d a l t h o u g h ovcrlearned material typically is stable into late life, a generalized slowing of response is the most u b i q u i t o u s c h a n g e . Educ a t i o n level can also influence test p e r f o r m a n c e , which is not surprising given t h a t several neuropsychological tests were developed with t h e intent to m e a s u r e intelligence and predict a c a d e m i c success. As m e n t i o n e d earlier, n o r m s are c o m m o n l y divided based on age a n d e d u c a t i o n . Sex differences on neuropsychological tests of spatial abilities, strength, m o t o r speed, a n d certain verbal abilities have been o b s e r v e d , a l t h o u g h males a n d females a p p e a r to be equivalent in general intelligence. Finally, a l t h o u g h research suggests t h a t ethnicity influences p e r f o r m a n c e on s o m e n e u r o p s y c h o l o g ical tests, it is clear t h a t m o r e research on the topic is w a r r a n t e d . T h e clinical m y t h t h a t ethnicity is i m p o r t a n t only on verbal or k n o w l e d g e based tests a n d n o t on " c u l t u r e free" tests such as s o m e a b s t r a c t reasoning m e a s u r e s is o u t d a t e d . M o r e recent evidence suggests t h a t this distinction is unclear, a n d a l t h o u g h research on the effect of ethnicity on test p e r f o r m a n c e h a s been increasing, we still do n o t u n d e r s t a n d the c o m p l e x relationship. M e d i c a t i o n a n d t r e a t m e n t side effects c a n c o m p l i c a t e the interpretation of test scores. Often patients w h o a r e referred for n e u r o p s y c h o l o g i c a l assessment a r e t a k i n g medications or a r e being treated for a medical d i s o r d e r . In fact, the action of s o m e d r u g s or t r e a t m e n t s can be t h e source of a patient's presenting cognitive p r o b l e m s . G a t h e r i n g treatm e n t i n f o r m a t i o n and assessing the potential influence of medications or o t h e r inrerventions on cognitive functioning is essential. O l d e r a d u l t s and patients with brain d a m a g e
NEUROPSYCHOLOGY
may he particularly susceptible to adverse drug reactions, winch can impair cognitive functioning. For example, anticholinergic drugs used to treat Parkinson's disease can interfere with memory functions and present as exaggerated cognitive dysfunction. When relevant, a neuropsychological examination can help to elucidate potential interactions between brain damage and treatment effects.
THE BRIEF MENTAL STATUS EXAMINATION zBefore neuropsychological referral the neurologist typically has either clinical or historical evidence of cognitive concerns. The ability to rapidly and reliably assess the nature and extent of cognitive impairments is important in all clinical settings. An important component of the neurological examination is the brief mental status examination. Although the mental status examination often is conducted in a nonstandard manner, neurologists are encouraged to develop a standardized method of mental status examination so that interpretations across time and patients can be made reliably (Table 38.6). Recommended standard examinations arc briefly described in this section.
Mini-Mental State Examination Although a variety of standardized mental status examinations have been used, a few scales are used more widely than others. One popular mental status examination often administered by neurologists is the Mim-Mcntal State Examination (MMSE; Folstein et al. 1975), an 11-item standardized method assessing orientation, attention, immediate and short-term recall, naming, and the ability to follow simple verbal and written commands. The MMSE has been used with different cultural and ethnic subgroups and has been translated into several different languages. Using a cutoff of 23, the sensitivity and specificity of the MMSE have been reported to he 8 7 % and 8 2 % , respectively, for detecting delirium or dementia in hospitalized patients (Anthony et al. 1982), More recent research
Tabic 38.6:
Utility of menta! status assessments
Benefits
Drawbacks
Standardized format Brevity Sensitivity to advanced dementia
Reliance on total score Emphasis on verbal tasks Disproportionate weight orinitiition In sensitivity with above average IQ Perceptual deficits = wrong answers No consideration of gender, education, or ethnicity
Test-retest reliability
679
has documented the significant associations between MMSE performances and age [r — -.38) and education (r = .50), suggesting that the utility of the instrument varies greatly depending on demographic factors. The best norms published to dare involve dara from rhc Epidemiologic Catchment Area household surveys and are presented in Table 38.7. Longitudinal studies suggest that people with Alzheimer's disease (AD) show an average annual rate of change of 2.81 points, although change rates are not uniform across illness stages. The item most often missed by people with AD is item 5 (recall three items), whereas the most sensitive item for "subcortical" dementias is item 4 (serial 7s) (Figure 38.2). Despite its widespread use, the validity and reliability of MMSE administration and interpretation have received little attention. There are three primary threats to the internal validity of the MMSE: nonorthogonal wotd stimuli allowed fot recall, nonstandard scoring of serial 7s, and nonstandard inclusion of spelling world backwards in MMSE total. Because learning and then teaching standard scoring instructions can alleviate the latter two threats, we have included structured scoring criteria in the MMSE shown in Figure 38.3. The primary threat to the internal validity of the MMSE is that most practitioners simply use whatever words come to mind or whatever words they were trained with for the recall of three items. Even the standard MMSE sold by Psychological Assessment Resources (PAR) has only two sets of words. This practice is unsatisfactory for several reasons. Firsr, older adults in a community or hospital quickly learn the local stimuli. For instance, all residents at one university teaching hospital were using "apple, orange, airplane," and many patients had been examined by a medical student, a resident, a fellow, and an attending physician at various times throughout their care. The test is not a measure of learning and memory if the patient has heard it before. In addition, the wotd stimuli used cannot be associated with one another. For instance, the words in the aforementioned example can easily be associated with one another, such as "orange and apple" (both fruits) or "orange airplane" (a color modifying the airplane). The rest is not a uniform measure of three items if some items are associated with others. Another common problem is the use of words with varying degrees of imageability. For instance, the words "red," "ball," and "happy" are not equivalent in their evocation of images. It may be easy to picture a red ball but more difficult to recall that it is happy. In an effort to encourage residents to vary the word stimuli and avoid "chunked" or "grouped" stimuli, we have selected a list from which words can be selected. We have selected imageablc words with a standard frequency index of U > 60 (approximately 100 per million) that require a reading level not greater than sixth grade. We encourage practitionets to return to the list petiodically and select a new version of three unrelated words to practice standard administration of the MMSE (Table 38.8).
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NEUROI.OGICAI, INVESTIGATIONS AND RELATED CLINICAL NF.UROSCIENCES
Table 38.7: Mini-Mental State Examination score by ago and educational level, number of participants, mean, standard deviation, and selected percentiles Age (years) Educational level 18-24 25-29 30-34 .;> 39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 >85 Total 0-4 yr Mean SD 5-8 yr Mean SD 9-12 yr or high school diploma Mean SD College experience Mean SD Total Mean SD
208 26 2,9 525
88 23 1.9 310 26 2.3 626
126 22 1.9 633 26 1.7 814
1W 22 1.7 533 26 1.8 550
112 21 2.0 437 25 2.1 315
105 in 2.2 241 25 1.9 163
61 19 2.9 134 23 3.3 99
892 22 2.3 3223 26 2.2 8240
28 2.2 220
28 2.2 231
28 1.7 270
28 1.4 358
27 1.6 255
27 1.5 181
25 2.3 96
26 2.0 52
28 1.9 5701
29 1.9 870 28 2.4
29 1.5 101 1 28 2.5
29 1.3 1294 28 2.0
29 1.0 1931 27 1.6
28 1.6 1477 27 1.8
28 1.6 1045 26 2.1
27 0.9 605 25 2.2
27 29 1.3 1.3 346 18,056 24 28 2.9 2.0
17 22 2.9 94 27 2.7 1326
23 25 2.0 83 27 2.5 958
41 25 2.4 74 26 1.8 822
33 23 2.5 101 26 2.8 668
36 23 2.6 100 27 1.8 489
28 23 3.7 121 26 2.5 423
34 23 2.6 154 27 2.4 462
49 2:
29 2.2 783
29 1.3 1012
29 1.3 989
28 1.8 641
28 1.9 354
28 2.4 259
29 1.3 2220 29 2.0
29 0.9 2076 29 1.3
29 1.0 1926 29 1.3
29 1.0 1443 29 1.8
29 1.7 979 28 2.0
29 1.6 831 28 2.5
ir
Source: Data from the Epidemiologic Catchment Area household surveys in New Haven, Connecticut; Baltimore, Maryland; St Louis, Missouri; Durham, North Carolina; and Los Angeles, California, between 1980 and 1984. The data are weighted based on the 1980 U..S. population census by age, sex, and race. Adapted from Crum, R. M., Anthony, J. C, Bassett, S. S., & Eolstein, M. F. 1993,/>1M,4, vol. 269, no. 18, pp. 2386-2391.
FIGURE 38.2 Mini-Mental State Examination profiles for patients with Alzheimer's disease (AD) and Huntington's disease (1 ID) with total Mini-Mental scores between 20 and 24. (Double asterisk indicates that the difference is significant at p < .001.) (Adapted from Brandt, J., Flostein, S. F„, & Folstein, M. F. 1988, "Differential cognitive impairment in Alzheimer's disease and Huntington's disease," Ann Neurol, vol. 23, pp. 555-561.)
NEUROPSYCHOLOGY
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FIGURE 38.3 Mini-Mental State Examination. (Adapted from Folstein, M. F., Folstein, S. E., & McHugh, P. R. 1975, "Mini-mental State: A practical method for grading the cognitive state of patients for the clinician," / Psychiatr Res, vol. 12, no. 3, pp. 189-198.)
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Table 38,8:
Mini-Mental State Examination Word Sets For Item #3
hand, snow, telephone eyes, river, newspaper mountain, door, baby garden, drink, teacher car, moon, breakfast window, boat, sheep
city, nose, salt boy, wheel, meat bag, kitchen, child ball, sand, animal radio, dinner, hill farm, ice, children
school, cotton, lake house, cross, rock Face, valley, dollar Food, wind, stick milk, tools, plants water, chair, road
Dementia Rating Scale The Dementia Rating Scale (DRS; Mattis 1976) is a 36-item measure of cognitive status with five subscales: Attention, Initiation, Construction, Conceptualization, and Memory. Although administration of the DRS can take 15 minutes for healthy older adults (and up to 40 minutes for people with severe impairment), the scale has clear advantages over the MMSE in some situations. The DRS assesses a greater number of cognitive domains and is less likely to miss impairment. The DRS has a greater range, so measures of change are better documented and interpreted. Finally, the DRS is successful in differentiating between various types of dementia, even in later stages of disease (Paulsen e t a l . 1995; Figure 38.4). Using a cutoff of 129, the sensitivity and specificity of the DRS have been reported to he 9 8 % and 9 7 % , respectively, for detecting AD (Monsch et al. 1995). To better account for demographic influences, the following formula is used to determine whether performance is impaired: 0.09 (age) - 0.06 (education) + 0.59 (initialion/petseveration subscale score) + 1.25 (memory subscale score) = x. A value of x below zero suggests impairment (98% of AD),
eggs, paper, sky mouth, wood, key bread, Floor, leaf desk, fish, sugar horse, world, truck teeth, Flowers, ship
grass, arm, book bus, dog, stone dust, sun, hair map, fire, bed foot, machine, lunch girl, star, bird
whereas a score value above zero suggests normal performance (98% of normal controls [NC]). Norms for older adults are provided in Table 38.9. Longitudinal studies suggest that people with AD show an avetage annual rate of DRS change of 11.38 points. The Initiation/ Perseveration subscale is most sensitive for subcortical and white matter dementias, whereas the Memory subscale is most sensitive for AD.
Additional Bedside Evaluation Despite its advantages, the DRS takes longer to administer and is unlikely to be used at the bedside by neurologists. The 5-minute MMSE is more likely to remain the scale of choice for cognitive screening. Although the MMSE identifies AD, the most prevalent cause of dementia, it does not identify subtle cognitive impairments associated with white matter, subcortical, and cerebellar changes. Because the executive functions involve the most complex forms of human behavior, mild disturbances in their resolution can have significant impact on daily living. It is recommended that bedside executive tasks and careful
FIGURE 38.4 Dementia Rating Scale (DRS) category scores by Huntington's disease (HD) impairment level. The mean percentage of the maximum possible score obtained on each subscale of the Mattis DRS by the severely impaired patients with HD and Alzheimer's disease (AD). The asterisk (*) indicates significant differences between the groups {p < ,01). (Adapted from Paulsen, J., Butters, N., Sadek, B. S., et al. 1995, "Distinct cognitive profiles of cortical and subcortical dementia in advanced illness," Neurology, vol, 45, pp. 951-956.)
NEUROPSYCHOLOGY
Table 38.9: Group means and standard deviations of dementia rating scale scores for older adults Age ranges DRS scales
62-79
80-95
Total score
M = 133.8 SD = 6.3 M = 35.3 SD = 1.3 M = 33.9 SD = 3.3 M = 5.5 SD = 1.3 M = 35.5 SD = 2.8 M = 23.4 SD = 1.8
M = 128.2 SD = 8.2 M = A5.1 5D = 2.0 M = 31.7 5D = 4.9 M = 5.1 SD = 1.8 M = 34.7 SD = 2.8 M = 20.7 SD = 3.5
Attention Initiation/perseveration Construction Concept ualization Memory
Source: Adapted from Vangel and Lichtenberg 1995, "'Mattis Dementia Rating Scale: Clinical utility and relationship with demographic variables," Clin Neurol, vol. 9, pp. 209-213.
clinical interview accompany the MMSE to provide a comprehensive cognitive screening. Any indication of poor decision making, disinhibition, inflexibility, or slowed processing may warrant a complete neuropsychological assessment. To identify possible weaknesses in this area, many neurologists use fluency, clock drawing, or an evaluation of alternating sets. Healthy older adults should be able to produce about 20 first names in 1 minute, and performances below this cutoff watrant additional evaluation by a neuropsychologist. The alternating patterns shown in Figure 38.5 may be used to document inability to smoothly switch sets. Other bedside mental status examinations include executive items such as proverb interpretation and conceptual teasoning. For example, patients are asked to interpret the meaning of "Rome wasn't built in a day" and "A golden hammer can break down an iron door,"
683
stimulus-bound errors while demonstrating better performance when asked to copy a drawing of a clock rather than construct a clock on command (Figure 38.6; Rouleau et al. 1996). Longitudinal study of CDT performance in AD indicates that stimulus-hound errors increase with disease progression. The CDT can effectively differentiate between certain types of dementia syndromes. For instance, people with Huntington's disease (HD) commit more planning errors and tend to have more graphic difficulties than patients with AD (Figure 38.7), whereas people with Parkinson's disease (PD) make a greater proportion of visuospatial errors. Although bedside cognitive examinations have included the clock drawing test for years, little use has been made of the clocks produced in terms of scoring and interpretation. Although originally conceived as a specific test of visuospatial and constructional ability, the CDT has recently gained favor as a quick and easily administered screening instrument for general cognitive dysfunction. The use of the CDT emerged from the realization that the test is sensitive to many fotms of brain dysfunction because it draws on multiple cognitive processes, including auditory comprehension of the instructions, access to the semantic reptesentation of a clock, conceptualization and planning abilities, and visuoperceptual, visuospatial, and visuomotor skills. Numerous studies uniformly demonstrate that patients with AD perform significantly worse than control subjects on the CDT and that the test has clinical utility for detecting dementia. Qualitative analysis of the performance of mildly demented patients indicates that poor performance may be mediated by semantic knowledge deficits tesulting in conceptual errors in AD (e.g., misrepresenting the clock by drawing a face without numbers or with an incorrect use of numbers,
10 r-
9
.
.
•
35
,,
18-
Command
Copy Condition
FIGURE 38.6 Scores obtained in the command and copy conditions as a function of diagnostic groups. NC = normal controls; DAT = dementia of the Alzheimer's type; HD = Huntington's disease. (From Rouleau, L, Salmon, D. P., & Burtcrs, N. 1996, "Longitudinal analysis of clock drawing in Alzheimer's disease patients," Rmin Cngn, vol. 31, pp. 17-34.)
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NEUROLOGICAL INVESTIGATIONS AND RLLATED CLINICAL NEUROSCIENCES
FIGURE 38.7 Distribution of error types in Alzheimer's disease (AD) patient groups in the command condition of the Clock Drawing Test. HD = Huntington's disease. (Adapted from Rouleau, I., Salmon, D. P., Sc Butters, N. 1996, "Longitudinal analysis of clock drawing in Alzheimer's disease patients," Brain Cogn, vol. 31, pp. 17-34.) misrepresenting the time by failing to include the hands, incorrectly using the hands, or writing the time in the clock face; Figure 38.8) or planning or graphic errors in subcortical dementias (Figure 38.9). Conceptual errors on the CDT occur early in AD and increase over time. In addition, the performance of patients with AD often is much worse when they are asked to draw a clock from memory than when they are asked to copy a drawing of a clock.
NEUROPSYCHOLOGICAL CHARACTERISTICS OF NEUROLOGICAL DISEASE In this section we briefly address the ncuroeognitive sequelae of some of the major neurological disorders. Reference is made to appropriate chapters in this text and to other review articles where appropriate.
Mild Cognitive Impairment The field of aging and dementia research is increasingly focusing on characterizing the earliest period of cognitive impairment before the development of dementia. Growing evidence points to a long prodromal period in the
development of disease, with research suggesting that biochemical and neuropathological changes may occur up to 20 years before the clinical manifestation of disease. Mild to moderate impairment in cognitive functioning, typically memory, with otherwise intact performance has been called mild cognitive impairment (MCI; Petersen et al. 1999). MCI typically refers to a clinical presentation between normal aging and dementia, with greater than expected memory loss in the absence of other cognitive deficits (Figure 38.10). MCI should be differentiated from normal aging and other terms such as "ageassociated memory impairment" and "age-associated memory decline," which generally refer to extremes of normal aging rather than a precursor to a pathological condition. Diagnostic criteria for MCI have been formulated by the Mayo Clinic Alzheimer's Research Center (Table 38.10). Estimates of the prevalence of MCI suggest that approximately 5-8% of people in community samples meet criteria for MCI. Several large-scale clinical trials arc under way to identify drugs that can slow cognitive decline among people with MCI, so identifying patients with MCI is imperative. The clinical outcome of patients with MCI has been investigated in longitudinal follow-up studies. Several reviews of the literature have concluded that patients with MCI are at an elevated risk for developing clinically
NEUROPSYCHOLOGY
pt2188: HD (command)
pt2095: DAT {command)
pt 2038: HD (copy)
pt2145: DAT (command)
FIGURE 38.8 Sample of command and copy errors observed on the Clock Drawing Test in patients with Alzheimer's disease (dementia of the Alzheimer's type [DAT]) and Huntington's disease (HD). Graphic difficulties; (A) moderate; (B) severe, stimulus-bound response, (C) associated with visuospatial deficit; (D) associated with a conceptual deficit in representing the time on the clock. (Adapted from Rouleau, I., Salmon, D. P., & Butters, N. 1996, "Longitudinal analysis of clock drawing in Alzheimer's disease patients," Brain Cogn, vol. 31, pp. 17-34.)
diagnosed AD. Estimates suggest that approximately 1 0 1 5 % of patients with MCI will progress to AD per year. Studies have also found that MCI is associated with increased morbidity and a decline in selected cognitive
685
abilities including episodic memory, semantic memory, and perceptual speed. The heterogeneity of MCI has been acknowledged in the literature. Recently, several subtypes of MCI have been proposed including an amnestic subtype, which emphasizes memory loss, a subtype in which a single nonmemory domain is affected, and a subtype in which multiple domains arc slightly affected (Figure 38.11). The criteria for MCI require both subjective and objective memory impairment in the presence of normal general cognitive functioning. Overall, deficits on measures of verbal episodic memory and new learning arc reported in patients with MCI, whereas other cognitive functions including language and executive functioning are largely intact (Petersen et al. 2001). The objective memory impairment typically is documented with neuropsychological testing using a cutoff of performance approximately 1.5 standard deviations below the average performance of people of a similar age and education. However, although other aspects of cognitive functioning in these people are largely intact, they may not be completely normal. A study comparing patients with MCI, normal control subjects, and patients with mild AD (characterized by a clinical dementia rating of 0.5 and 1) demonstrated that although the jyucral cognitive function of these subjects was normal, the level of cognitive functioning in other nonmemory domains was somewhat below normal (Petersen 2000). Several predictors of subsequent cognitive decline among people with MCI and mild AD have been examined. An investigation at the Mayo Alzheimer's Disease Research Center longitudinally examined 155 people with MCI and found that apolipoprotein E4 carrier status, poor performance on a cued recall test, and atrophic hippocampi on magnetic resonance imaging (MRI) predicted more rapid FIGURE 38.9 Samples of visuospatial and planning errors observed on the Clock Drawing Test in patients with Alzheimer's disease (dementia of the Alzheimer's type [DATJ) and Huntington's disease (HD): (A) neglect of the left hemisphere; (B, C) planning deficit; (D) deficit in the spatial layout of numbers; (E) numbers written outside the clock face; (F) numbers written in counterclockwise direction. (Adapted from Rouleau, I., Salmon, D. P., &c Butters, N. 1996, "Longitudinal analysis of clock drawing in Alzheimer's disease patients," Brain Cogn, vol. 31, pp. 17-34.)
686
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Alzheimer's Disease Neuropsychological tests, formal or informal, have always been the hallmark of the clinical diagnosis of AD. The recent development of pharmacological treatments for AD and the introduction of new therapies make assessing dementia at its different stages an even greater scientific and public health challenge. Neuropsychological tests at present are the only in vivo screening and diagnostic tools fot AD and related disorders that can establish deficits in more than one domain of cognition. This is required for the diagnosis of dementia and AD by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (American Psychiattic Association 1994) and the National Institute of Neurological and Communicative Disorders and Srroke/Alzheimer's Disease and Relared Disorders Association (NINCDS-ADRDA) (McKhann et al. 1984) criteria. Although the MMSE is excellent fot identifying AD in mid-stages (i.e., total score of 23), it is insufficient to identify early AD. Several cognitive tasks have been developed to sctccn for AD. Among these additional tests are the Neurobehavioral Cognitive Status Examination (Kiernan et al. 1997) and the 7 Minute Screen (Solomon etal. 1998). Tabic 38.10:
Criteria for amnestic mild cognitive impairment
Memory complaint, preferably corroborated by an informant impaired memory function for age and education Preserved general cognitive function Intact activities of daily living Not demented Source; Peterson, R. C, Doody, R., et al. 2001, "Current concepts in mild cognitive impairment," Arch Neurol, vol. 58, pp. 19851992.
AD results in a global disorder of intellectual functioning that affects a wide variety of cognitive processes. Memory impairment usually is the earliest and most salient fcatute of the disorder, but the particular cognitive processes that are initially affected and the relative seventy of various cognitive impairments can vary from patient to patient. The neuropsychological evaluarion of AD must include a thorough assessment of a wide range of cognitive abilities, including verbal and nonverbal memory, language and semantic knowledge, attention and executive functions, visual perception, and spatial abilities. Numerous studies have shown that measures of the ability to learn and retain new information arc effective in differentiating between mildly demented patients with AD and normal adults. For example, Welsh and colleagues (1991) found that the accuracy of word list recall after a 10-minute delay differentiated patients with very early AD (MMSE > 25) from healthy controls with bettet than 9 0 % accutacy. The abnormally rapid forgetting exhibited by patients with AD on clinical memoty tests suggests that their memory impairment is caused by ineffective consolidation of information (i.e., difficulty transferring information from shortterm to long-term memoty). Because AD results in widespread cortical damage and affects a wide variety of cognitive functions, the memory impairment of these patients may be exacerbated by a number of ancillary deficits. For example, poor attention and weakened semantic memory associations may adversely affect memory performances. One recent report suggests that attention is the first nonmemory domain to be affected in AD, before language and visuospatial functions. Divided attention and aspects of selective attention, such as set-shifting and response selection, are particularly vulnerable, whereas sustained attention is largely preserved in the early stages of AD.
NEUROPSYCHOLOGY
NORMAL ELDERLY CONTROLS
687
ALZHEIMER'S DISEASE PATIENTS
FIGURE 38.12 The cognitive map of normal older adults {left) and patients with Alzheimer's disease (right) obtained from multidimensional scaling analysis and clustering analysis. (Adapted from Chan, A., Butters, N., Paulsen, J. S., et al. 1993, "An assessment of the semantic network in patients with Alzheimer's disease," J Cogn Neurosci, vol. 5, pp. 254-261.)
The nature of language deficits exhibited by patients with Al) Mifi^ests thai these patients MI iter deterioration in the organization of semantic knowledge or a degradation of the knowledge itself. For example, several studies using verbal fluency tests have shown that patients with AD are more impaired when required to generate exemplars from a particular category (e.g., animals) than words beginning with a particular phoneme (e.g., FAS). Chan and her colleagues (1993) used multidimensional scaling analyses to show the distorted semantic network of the patient with AD (Figure 38.12). Deficits in visuoperceptual abilities and constructional praxis occur in patients with AD, although they usually emerge after the early stages of the disease and may have little to contribute to the differentiation of early dementia from normal aging. Convergent findings from neuropathology, neuroimaging, and neuropsychology indicate that early memory impairments in AD are specifically related to early stage limbic-diencephalic pathology and that nonmnemonic impairment is specifically related to later-stage tcmporal-neocortical pathology.
Vascular Dementia and Vascular Cognitive Impairment Current estimates of the prevalence of vascular dementia suggest that it accounts for 10-50% of all dementia cases, making it the second most common cause of dementia after AD {see Chapter 72 for a review of the clinical aspects of vascular dementia). The development of the diagnostic criteria for vascular dementia has been heavily based on AD research. This has resulted in a focus on symptoms of memory impairment, progression, and severity of symptoms. Vascular dementia is treated as a largely unitary condition and either implicitly or explicitly includes dementia caused by stroke {see Chapter 72). Several authors argue that this focus is inadequate to capture
the range of cognitive impairments that can result from cardiovascular disease (Bowler and Hachinski 2002). Bowler and Hachinski proposed the broader term vascular cognitive impairment (VCI) to encompass the array of cognitive deficits resulting from cerebrovascular disease. Those who may be diagnosed with VCI include patients with early cases of cognitive impairment associated with cardiovascular disease and exclude those with nonischemic cases and major stroke. Future research on VCI may help characterize the range of cognitive impairments that are typically associated with cerebrovascular disease. In the meantime, it is important to recognize that vascular lesions that produce cognitive impairments can have many different origins, including ischemia, incomplete infarction, and major stroke. Although numerous studies have attempted to identify patterns of cognitive deficits that arc typically associated with cerebrovascular disease, the recognition of characteristic cognitive impairments is influenced by the manner in which the patients are diagnosed. The particular pattern of cognitive deficits varies with the subtypes of vascular dementia, which include subcortical vascular dementia, multi-infarct dementia, hypoperfusion dementia, and single cortical or subcortical infarcts {Desmond and Pasquicr 2002). Given such a wide range of dementias, a comprehensive description of the corresponding deficits is beyond the scope of this chapter (see Chapter 72). Nonetheless, several commonalities, including an emphasis on impairment of executive functioning with largely intact performance in several aspects of memory, have emerged in the literature. The most common neuropsychological impairment in patients with cerebrovascular disease, particularly those without a history of major stroke, is subcortical and frontal lobe functioning deficits. Planning and sequencing, speed of mental processing, performance on unstructured tasks, and attention tend to be impaired in vascular dementia
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
(Desmond and Pasquier 2002). Subcortical lacunar infarctions in the territory near the thalamus, caudate, and globus pallidus may disrupt frontal-subcortical circuits and account for the prevalence of executive dysfunction in these patients. The presence of memory impairment in vascular dementia is somewhat controversial. Memory impairment is considered a defining feature of AD, and many studies have found more significant memory impairments in AD than in vascular dementia. However, several studies have found evidence of memory impairment in vascular dementia as well. For example, one study found that tests of memory were among those that differentiated between patients with ischemic stroke and control participants. Findings of memory impairment associated with cerebrovascular disease may result from comorbid cerebrovascular disease and Alzheimer's dementia. Memory impairment may also be a secondary manifestation of cerebrovascular disease from infarcts in the medial temporal lobe or a consequence of executive functioning deficits such as inattention and disorganization (Desmond and Pasquier 2002), Using positron emission tomography, Reed et al. (2000) found that episodic memory failure in patients with subcortical cerebrovascular disease was associated with prefrontal lobe metabolism, whereas memory performance in patients with AD was correlated with left hippocampal and temporal lobe metabolism. The authors suggest that different pathogenic mechanisms underlie episodic memory failure in subcortical vascular disease and AD. Given the current criteria for vascular dementia, which emphasize memory impairment and global cognitive deterioration, it has also been suggested the observed memory deficits in patients diagnosed with vascular dementia may be influenced by selection bias.
Historically, a patchy, stepwise pattern of cognitive deficits has been associated with vascular dementia, particularly multi-infarct dementia. There is recent evidence that patients with vascular dementia have a higher prevalence of fluctuating cognitive functioning than those with AD. Although this may be the case in some instances, it is clear that the course of cognitive decline may also be continuous and slowly progressive in many patients with multiple vascular disorders,
A recent review of the literature indicated that patients with AD have greater deficits than patients with vascular dementia in functions mediated by posterior cortical areas including memory deficits (e.g., faster rate of information decay, reduced ability to benefit from retrieval cues, and greater intrusion errors) and particular language deficits such as naming impairment (Desmond and Pasquier 2002). Greater deficits in syntax in vascular dementia, and in accessing lexicon in AD, have also been reported. One study examined the performance of 114 people with probable AD and subcortical ischemic vascular dementia on a variety of tests purported to measure executive abilities. The authors found that patients with AD had more self-monitoring problems than patients with subcortical vascular disease, whereas patients with subcortical vascular disease demonstrated more executive memory search deficits, pointing to differences in the types of executive functioning deficits manifested by the dementia groups (Yuspeh et al. 2002). Despite these observed differences, other recent research has found evidence of similar patterns of deficits when comparing patients with AD and vascular dementia on several neuropsychological tests.
There are three main histological types: microvacuolar, Pick's, or motor neuron disease. It is important to note that each of these FTD syndromes can be associated with motor neuron disease (amyotrophic lateral sclerosis), although the neurological symptoms and signs commence after the development of the dementia and lead to death within 3 years. Although it has been suggested that FTD disorders should be regarded as tauopathies on the basis of the tau pathology seen in a number of cases and the mutations in the tau gene in some familial cases, recent studies have documented only 3 7 % of FTD with tau pathology and 1 0 % with mutations in the tau gene, suggesting that FTD is not a unitary etiological disorder.
Fro n to temp oral Dementia Focal degeneration of the frontotemporal lobes is a common cause of dementia, accounting for about 2 0 % of cases of dementia with presenile onset. Frontotemporal dementia (FTD) encompasses a clinically heterogeneous group of syndromes determined by the distribution of pathological change within the brain. Cases of FTD do not have a common molecular basis, however, and highlight the importance of defining patients on clinical, anatomical, histological, and biological grounds. Three ma]or syndromes can be identified: (1) frontal lobe degeneration of non-Alzheimer type, in which changes in social behavior and personality predominate, reflecting the orbitobasal frontal lobe focus of the pathology; (2) semantic dementia, also known a progressive fluent aphasia, in which there is a breakdown in the conceptual database that underlies language production and comprehension and is associated with asymmetrical anterolateral temporal atrophy with relative sparing of the hippocampal formation; and (3) progressive nonfluent aphasia, the most rare of these syndromes, in which the phonological and syntactic components of language are affected in association with left perisylvian atrophy.
Simple cognitive screening tests, such as the MMSF, are unreliable for detecting and monitoring FTD. Performance on the MMSE can remain intact even when institutionalization is needed. Early personality or functioning complaints must be regarded seriously, and a neuropsychological assessment should emphasize executive and social tasks, The clinical presentation of primary FTD is one of profound alteration in social conduct and personality.
NEUROPSYCHOLOGY Patients may show a disinhibited, overactive, and restless change reminiscent of orbitofrontal dysfunction or akinesia and apathy accompanied by a lack of concern and insight (Table 38.11). In many patients, stereotypic, ritualistic behaviors are the dominant clinical feature. Such patients may develop elaborate rituals for dressing or toileting, adhere to a rigid daily routine, and experience significant difficulty shifting from one activity to the next. Performances on executive tasks reveal profound abnormalities in abstraction, planning, sequencing, organization, and regulation. Patients with semantic dementia typically complain of loss of memory for words. They are often painfully aware of their shrinking expressive vocabulary but are strangely oblivious to their impaired comprehension. Caregivers note the increased use of substitute words and phrases such as "thing" and "you know." Patients with primary right-sided atrophy may present with difficulty recognizing and naming faces and become severely prosopagnostic. Dayto-day episodic memory and orientation remain intact. Progressive nonfluent aphasia presents with a decline in language expression in the relative absence of other cognitive deficits. Speech becomes nonfluent and effortful and may involve stuttering. Word retrieval difficulties are prominent, and repetition is impaired. Spoken and written comprehension remains largely preserved, as do visual perception, spatial abilities, and memory. Social skills typically are well preserved in the early stages, although behavioral changes akin to frontal lobe degeneration emerge later in the disease.
Parkinson's Disease In addition to motor symptoms, PD is associated with elevated levels of depression and cognitive impairments, Clinical ratings based on the level of clinical disability have become the standard method of measuring PD-related functioning. The Unified Parkinson's Disease Rating Scale {Fahn et al. 1987) is the most widely used scale today and incorporates the Hoehn-Yahr clinical disability stages and the Schwab and Kngland activities of daily living into scores that are used to assess treatments and measure disease stages. Because cognitive and emotional Tabic .18.11:
6S9
functioning can have a significant impact on functional capacity, these assessments must be a central component of the PD evaluation. Although cognitive impairment is the rule rather than the exception in PD, there is heterogeneity in presentation and progression of cognitive deficits. The neuropsychological profile of PD includes cognitive slowing, memory impairment, visuospatial deficits (e.g., problems with pattern completion and facial recognition), and a range of executive deficits including impairments in decision making, planning, shifting, and monitoring of goal-directed behaviors. Nearly all patients with PD suffer from a general cognitive slowing, or bradyphrenia. Several studies suggest that changes in executive functioning may be one of the earliest signs of cognitive decline in PD. Patients with PD often report problems with decision making, planning, and monitoring of goal-directed behaviors. On traditional and computerized neuropsychological tests, even nondemented patients with PD show impaired ability to shift between sets. Up to 8 0 % of patients with PD experience speech problems beyond production problems related to motor symptoms. They experience problems comprehending and producing syntactically complex sentences. Unlike patients with AD, those with PD generally do not experience problems with name finding. Memory problems are also commonly reported among patients with PD. In particular, they report difficulty in recalling effortful information but exhibit intact recognition. Several studies have demonstrated that learning and retrieval deficits exist in patients with PD without frank dementia. Dementia occurs in up to 2 5 % of patients with PD. A number of factors have been implicated as risk factors for dementia in PD, including older age, lower education, and the presence of depression and confusion or psychosis after levodopa treatment. There is no consensus regarding the effect of pharmacological treatment on cognition in PD. It is clear that for some patients with PD, the gold standard treatment, levodopa, may exert a highly selective and deleterious effect on cognitive function. This is particularly salient given that the cognitive decline observed in PD remains a major source of disability and mortality in PD.
Differentiating Alzheimer-type dementia from frontal lobe dementia
CI mica I variables
Alzheimer's disease
frontal lobe dementia
Personality Social skills Kliivcr-Bucy syndrome Language Naming Drawing Calculation Memory
Passive, largely intact Spared early Late Fluent aphasias Lexical anomia Impaired early Impaired early Impaired early, not helped by cues
Apathetic, disinhibited, sometimes eccentric Early deterioration Early Decreased output, mute Semantic anomia Largely spared Largely spared Variable, helped by cues
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSC1LNCES
Huntington's Disease HD is a genetically transmitted neurodegenerative disease of the basal ganglia that is characterized by a triad of clinical symptoms: choreoathctosis, cognitive decline, and psychiatric features. The diagnosis of HD is based on a neurological evaluation and requires the presence of an unequivocal movement disorder, although the cognitive and behavioral alterations are the most debilitating aspect of the disease and place the greatest burden on HD families. In manifest HD, the most striking cognitive deficit is executive dysfunction (e.g., strategies in planning and problem solving, self-monitoring, and attentional and cognitive flexibility). As expected, cognitive deficits reported in people who are presymptomatic for HD but have the gene mutation also emphasize executive dysfunction. In a meta-analytic review, Zakzanis (1998) concluded that patients with HD are most deficient in the acquisition of new information, delayed recall, cognitive flexibility, manual dexterity, attention, speed of processing, and verbal skill. Several studies have demonstrated that patients with HD are impaired on tests that require executive functions, such as the Wisconsin Card Sorting Test, the Stroop Color Word Test, and clinical rating scales of executive dyscontrol. In fact, brief tests of executive functions have been suggested as sensitive tools for identifying subcortical dysfunction. That is, the Serial Sevens item on the Mini-Mental State Examination, the Initiation and Perseveration subtest of the Dementia Rating Scale (Mattis 1976), and an abbreviated battery of frontal lobe tests have been demonstrated to be distinctly sensitive to patients with HD. Some recent research has evaluated the performance of patients with HD on clinically relevant, face-valid tests of judgment and decision making. Stout and colleagues (2001) used a simulated gambling task to quantify decision-making deficits in patients with I ID, Findings showed that patients with HD made fewer advantageous selections than age- and education-matched healthy controls and dementi a-severity-matched patients with PD. Impairments on tasks requiring decision making may result from various cognitive decrements, including learning, attention, inhibition, and appreciation for future consequences. Findings can also be interpreted as further evidence that patients with HD are less able to benefit from feedback and have difficulty varying output based on performance. Despite evidence of explicit knowledge for the tasks, patients with HD were unable to update existing programs based on new experience and to alter their responses. Numerous wide-ranging consequences of these types of executive deficits are self-evident. Early neuropsychological studies reported that patients with HD perform poorly on subtests requiring attention and working memory. More recent studies have emphasized dysfunction in unique aspects of attention, including resource allocation, response flexibility, and vigilance. For
instance, one study reported that patients with HD are able to maintain attention for a previously learned response set but have difficulty shifting attention to a new set. Others have reported that patients with HD are able to maintain alertness when the task involves an external cue but fail when internal self-generated vigilance is required. The clinical implications of the attentional impairment in HD are significant. Many people with HD perform better when they avoid tasks involving divided attention. Patients and families agree that trying to divide the already-compromised attentional resources can contribute to discomfort and increase safety risks. For instance, driving a car while listening to the radio, talking to people in the back seat, or talking on the cell phone is not recommended. To reduce choking risk, the environment should be quiet and calm at mealtimes to emphasize concentration on chewing and swallowing. Deficits in learning and memory are the most frequently reported cognitive complaints from people with HD and their family members. Patients with HD exhibit verbal learning deficits even in the earliest stages of the illness. The majority of studies describe the memory impairment as a primary encoding and retrieval deficit because recognition memory often is preserved. That is, most studies show that people with HD consistently have problems learning new information and also experience difficulty when asked to use free recall to remember what they have learned; in contrast, they perform near normal when a less-effortful memory strategy is used, such as offering choices of or recognizing possible learned items. Patients with HD manifest intact retention over a delay period, indicating no abnormal forgetting or rapid loss of information. When tested on memory for information acquired long ago, they demonstrate no temporal gradient in performance, indicating that memory performance is equivalent for all periods of their lives. The memory impairment of HD is characterized by a mild encoding deficit (probably caused by impaired organization of the to-be-learned information and ineffective working memory) and moderately impaired retrieval in the context of largely intact memory storage when measured with a less-effortful strategy (i.e., recognirion). Skill learning can be acquired when external feedback is allowed, but motor programs are not stored for later use, possibly because of the dependence of the striatum in "chunking" components of the motor program. Several studies have shown olfaction impairments in HD using the University of Pennsylvania Smell Identification Test (Doty 1991). The most comprehensive research to date assessed absolute detection, intensity discrimination, quality discrimination, short-term recognition memory, and lexical- and picture-based identification for odor, using taste and vision as comparison modalities. Results suggested that although odor recognition memory is not affected in patients with I ID, absolute detection, intensity discrimination, quality discrimination, and identification
NEUROPSYCHOLOGY
were significantly impaired. Poor detection sensitivity explained performance on several other olfactory tasks where odor identification was the function most impaired. Deficits in the ability to copy simple geometric designs, to copy block designs, and to put together puzzles are evident in HD. Although some of these impairments probably reflect motor abnormalities, performance is also impaired on motor-free untimed perceptual tasks. Mohr and colleagues (1997) recently examined whether visuospatial deficits in basal ganglia disease are a nonspecific function of dementia severity or whether they reflect disease-specific impairments. Findings suggested that general visuospatial processing capacity is impaired as a nonspecific dementia effect in both HD and PD, whereas only patients with HD showed specific impairment in person-centered spatial judgment. For instance, people with HI) (but not PD) experience difficulty with map reading, directional sense, and varying their motor responses after alterations in space. People with HD typically misjudge distances and the relationship of their body to walls, curbs, and other potential obstacles. One of the most prominent features of HD is the motor speech impairment, or dysarthria, that is characteristic of the illness. Early speech changes may include insufficient breath support, varying prosody, increased response latencies, and mild misarticulations. As HD progresses, phrase length decreases, and pauses in speech output lengthen. Performances on tasks of letter and category fluency are impaired early in the disease, although the integrity of word associations remains largely intact, with little evidence of intrusion or perseveration errors. Despite significant impairments in verbal fluency, speed of output, and complexity, syntactic structure remains intact, and speech content usually is appropriate. Although there are some reports in late-stage HD of mild deterioration in semantic knowledge structure, several other studies have shown that errors in confrontation naming are more likely to be caused by visual-perceptual deficits and retrieval slowing. Speech output becomes severely impaired as the disease progresses, typically resulting in a profound communication deficit. Several studies have relied on the Total Functional Capacity (TFC) scale to quantify disease stages and functional dependence associated with HD. Research has been largely consistent, with most studies demonstrating an average decline of 0.63 ± 0.75 units/year on the TFC. Although controversial, there is some evidence that rate of progression is more rapid in juvenile onset and more gradual in late onset. Marder and colleagues (2000) recently examined the annual rate of functional decline in 960 prospective patients with HD followed an average of 18 months at 43 sites in the Huntington Study Group. Findings were consistent with previous research, suggesting TFC decline of 0.72 units per year and independent-scale decline of 4.52 units per year. Better cognitive status at baseline, lower baseline TFC, and longer disease duration
691
were associated with a less rapid rate of decline, whereas depressive symptoms were associated with more rapid functional decline. Rich and colleagues (1999) assessed flexibility and language functions over 5 years and reported stable semantic clustering (language) performances in patients with HD despite a progressive reduction in shifting. Findings are consistent with a cross-sectional study of 75 patients with HD divided into three stages of illness: early, middle, and advanced. These findings suggested that memory, receptive language, and simple attention remain largely intact throughout the stages of HD. It is important for professionals and family members to educate staff at care facilities regarding the pattern of impaired and preserved cognitive functions in later stages of HD, when verbal output is severely limited.
Tourette's Syndrome Tourctte's syndrome (TS) is an inherited neuropsychiatric disorder characterized by motor and phonic tics (Jankovic 2001). Diagnostic criteria for TS include the presence of multiple motor tics and one or more vocal tics, both of which must exceed a year's duration. Onset of this disorder occurs in childhood, with an average onset age of 6 to 7 years. AI tin High evidence suggests a genetic transmission of TS, a gene has not yet been identified. Illness course is variable, with some patients experiencing spontaneous remission or significant decrease of symptom severity whereas others experience lifelong presence of symptoms. Up to 6 8 % of children with TS function below expectations in school. The neuropsychology of TS is incomplete, however, in part because there have been insufficient experimental studies of primary psychological systems and in part because most studies that have been carried out have included a mix of subjects. Because comorbidity in TS is high, subject samples often are heterogeneous with regard to obsessive-compulsive symptoms, attention deficit hyperactivity disorders, mood disorders, coprolalia, age, medication usage, illness duration, and age of onset. In addition, TS children sometimes are distracted by their various motor and vocal tics or use a great deal of resources to suppress these tics, taking attention from their studies. Motor tics may interfere with homework, note taking, or performance on written examinations. Children with TS are clearly seen as different from other children in the classroom and often experience psychological and emotional burdens associated with being perceived as different. Despite these iinutations, some preliminary conclusions may be drawn. Although some findings suggest that children with TS have executive dysfunction, other reports show that children with pure TS (no comorbid diagnoses) have normal performances on neuropsychological measures or nearly normal performances with only subtle slowing or disinhibition. When considered together, findings suggest
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCF.S
that cognitive impairments in pure TS are mild and not easily captured with gross measures. More comprehensive executive evaluations and novel study designs (Cirino et al. 2000) probably are needed to better differentiate the core cognitive component of TS from the cognitive deficits associated with its comorbid disorders. Children with TS and a comorbid diagnosis of attention deficit hyperactivity disorder (ADHD) demonstrate dysexecutive performances and increased perseverative errors as well as increased incidence of learning disability. Primary cognitive dysfunction associated with frontal systems may impait the planning, organization, and execution of behavioral output for children with TS and ADHD. Compensatory sttategics that might be useful involve increased structure fot problem solving. Children with TS and comorbid obsessive-compulsive symptoms show dysexecutive petformances as well, but performance is mosr severely impaired in children with TS, ADHD, and obsessivecompulsive symptoms. Even after controlling for tic severity, IS children with comorbid ADHD and obsessivecompulsive disorder demonsrrated the most severe cognitive impairments and poorer academic achievement.
Multiple Sclerosis Cognitive dysfunction is a significant cause of disability in patients with multiple sclerosis (MS). Estimates of the prevalence of cognitive impairment in MS range from 4 5 % to 6 5 % . Cognitive deficits can develop at any time during the course of the disease and can occur in the presence or absence of neurological disability. Although some research suggests that only certain domains of cognition are initially affected and that more widespread cognitive deficits emerge later in the disease, the course of cognitive impairment in MS remains controversial. Although cognitive deficits vary among patients with MS, perhaps because of the interindividual variability in the nature of the microscopic and macroscopic pathology of MS, several patterns of impairment are evident in the literature {Table 38.12). Patients with MS who have cognitive impairmenr mosr commonly have deficits in memoty, learning, attention, speed of information processing, and verbal fluency. Deficits in conceptual thinking and problem solving, functional language abilities, and spatial reasoning have also been reported in the literature. As mentioned earlier, memory deficits are one of the most commonly observed cognitive impairments in MS. A meta-analysis of 36 published papets on memoty impairment in MS suggested that patients had significant abnormalities in all aspects of memory functioning, Nonetheless, individual studies have focused on different aspects of the memory deficit. Early studies of memory impairmenr in MS identified rettieval deficits as being important. More recently, several studies have suggested that the memory impairment in MS results primarily from
Table 38.12: sclerosis
Cognitive
Relative frequency of cognitive deficits in multiple
deficits
Attention Information processing Encoding memory Free recall memory Verbal fluency Auditory and visual span Recognition memory Executive function Conceptual reasoning Visuoperceptual function Loss of stored factual knowledge Motor learning Apraxia Agnosia
Aphasia
Frequency \n multiple sclerosis
+-H-
+++ +4 +++ +++
++ ++ ++ ++ ++ + + + + +
Note: + indicates frequency from rare ( + ) to common (+++). Source: Adapted from Bagart et al. 2002, "Cognitive dysfunction in multiple sclerosis," CNS Drugs, vol. 16, pp. 445-455.
deficits in acquisition rather than recall per se. For example, although people with MS need significantly more learning trials to meet criteria on memory tasks, after a delay they recall similar amounts of information to healthy controls (Demaree et al. 2000). Other studies have suggested that deficits in working memory underlie the short-term memory deficits and verbal dysfluency observed in MS (Janculjak et al. 1999). Slowed information processing speed among patients with MS has been observed in several studies independent of slowed sensorimotor processing. A recent study compared the neuropsychological performance of 55 inpatients with MS with that of 42 norma) controls (Janculjak et al. 2002). Findings suggested that the major cognitive deficit in MS caused by demyclination is the slowing of information processing, which was found to be related to focused attention and the simplest forms of explicit memory. The transfer of information between hemispheres has also been shown to be slow in patients with MS, and imaging studies have revealed corpus callosum atrophy in MS. Four subtypes of MS have been defined based on an international survey of specialists: (1) relapsing-remitting, (2) secondary progressive, (3) primary progressive, and (4) progressive-relapsing courses. Primary progressive MS involves continual progression from the onset of the disorder, whereas the relapsing-remitting subtype involves initial petiods of remission that later develop into secondary progressive MS. Some studies on the neuropsychology of MS have attempted to identify differing patterns of cognirive deficits among the subtypes. For example, a study examining explicit and implicit memory found that patients with primary progressive MS exhibited a pattern of memory impairment that was distinct from that of patients
NEUROPSYCHOLOGY with relapsing-remitting and secondary progressive MS (Figure 38.13}. Furthermore, a recent meta-analysis of 34 studies comparing patients with MS and healthy controls found that cognitive impairment was evident generally and that distinct patterns of neurocognitive deficits characterized chronic progressive and relapse-remitting subtypes of MS (Kakzanis 2000). Patients with chronic progressive MS presented with more frontal executive impairment, whereas patients with relapsing-remitting MS presented with more memory-related dysfunction.
693
A meta-analysis of research on neuropsychological functioning in patients with MS over a 20-year period suggested that interhemispheric transfer, general cognitive ability, and learning and memory were more highly associated with MS than visuoperceptual, visuospatial, and visuoconstructional ability, language, and conceptual ability (Table 38.13). Effect sizes comparing MS and healthy control groups on variables grouped by neuropsychological domain were generally small to moderate. However, in contrast with many previous reports, disease subtype was not related to neuropsychological functioning, Several studies suggest that lesion burden as measured by brain imaging, including MRI, correlate with cognitive disability. Deficits on neuropsychological measures have been correlated with lesion load, atrophy of the corpus callosum, and magnetization transfer ratio. One study that used MRI found that right and left superior frontal lobes arc the regions of the cortex most susceptible to atrophy and resulting cognitive changes in verbal and spatial learning, attention, and conceptual reasoning (Benedict et al. 2002). Another study examined 28 patients with MS and matched healthy controls using MRI and neuropsychological testing at baseline and 1-year and 4-year follow-up (Sperling et al. 2001). Results of this study suggest that MS lesions demonstrate a propensity for frontal and parietal white matter. Patients with MS showed significant impairments on tasks of sustained attention, processing speed, and verbal memory as compared with the control subjects, which was correlated with MS lesion volume in frontal and parietal regions. The authors concluded that disruption of frontoparietal subcortical networks might underlie the observed pattern of neuropsychological impairment observed in these patients. In contrast, the authors of a study of cognition using MRI in patients with rare forms of MS (primary progressive and transitional progressive MS) observed modest correlations between MRI lesion measures and a global cognitive impairment index. They concluded that cognitive functioning in primary progressive and transitional progressive MS is multifactorial and is not adequately explained by pathology as demonstrated by conventional MRI (Camp et al. 1999). These authors suggest that advances in imaging and the development of more sensitive cognitive tests will help elucidate the pathophysiology of MS in these subtypes of the disease.
Epilepsy PPMS
RRMS
SPMS
Control
FIGURE 38.13 Free recall performance, word fragment completion priming, and exemplar generation priming in primary progressive multiple sclerosis (PPMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and control subjects. (Adapted from Blum, D,, Yonelinas, A. P., Luks, T., et al. 2002, "Dissociating perceptual and conceptual implicit memory in multiple sclerosis patients," Brain Cogn, vol. 50, pp, 51-61.)
An epileptic seizure, by definition, involves abnormal activity of the brain; therefore it is commonly acknowledged that the ictal period, before, during, and immediately after a seizure, is associated with cognitive changes including confusion and alterations of consciousness. However, it is important to recognize that epilepsy is also associated with interictal alterations in cognitive abilities {see Chapter 73 for a review of epilepsy).
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCLS
Table 3S.13:
Effect sizes of differences between patients with multiple sclerosis and control subjects
Neuropsychological
domain
Interhemispheric transfer Mood Lind psychological status General cognitive ability Learning and memory Attention/executive ability Sensory and motor ability Visuoperceptual ability Language Conceptual ability
k
N
Mr (SD)
r,r
Q„
7 14 29 85 55 35 30 45 22
798 1157 3269 7575 5479 3260 3991 4736 2733
.46 .37 36 .35 .34 .34 .26 .26 .22
.43*
23.8 71.9 s 182.7* 414.1* 437.6* 109,8* 159.3* S0.6* 42.4*
(.15) (.21) (.20} (.18) (.26) (.19) (.21) (.21) (.13)
. 3 - 1 •>
.33* ,32* .28* .30* .24* .23* .23*
k — number of effect si7.es; N = number of subjects per effect size; Mr — effect size; rsu — weighted r; Q — homogeneity statistic; Qw — Q within.
Source: Adapted from Wish art, H. &c Sharpc, D. 1997, "Neuropsychological aspects of multiple sclerosis: A quantitative review," } Clin Exp Ncuropsychol, vol. 19, pp. 810-824.
There is no one cognitive profile associated with epilepsy, perhaps because the condition has a variety of origins and clinical manifestations. Nonetheless, a substantial body of research suggests that a range of cognitive deficits is related to epilepsy and its treatment, One of the most often studied neuropsychological variables in epilepsy is overall intellectual functioning. The early clinical literature suggested that epilepsy was commonly associated with overall cognitive deterioration, and several recent studies have also found evidence of overall decrements in intellectual functioning in patients with epilepsy. However, other research suggests that epilepsy does not necessarily lead to overall reductions in cognitive functioning. Research examining the relationship between overall cognitive status and particular clinical characteristics has provided useful information. For example, patients with more generalized seizure activity tend to show more significant and widespread cognitive deficits, There is evidence that people with convulsive seizures have poorer cognitive functioning, whereas generalized nonconvulsive and partial seizures are not associated with significant losses in overall intellect. Research on the age of onset shows that the earlier the epilepsy begins, the greater the impact on cognitive abilities. Furthermore, the longer the duration of epilepsy, the lower the patient's overall cognitive functioning. Findings regarding the relationship between the frequency of seizures and cognitive functioning have yielded mixed results. It appears that the type of seizures experienced by the patient, including their cause and whether the patient experiences status epilepticus with repeated seizures concentrated in time, may be more predictive of losses in overall cognitive functioning than seizure frequency alone. Focal seizures typically involve just one side of the brain and are more likely to show a circumscribed pattern of cognitive deficits than more generalized epilepsy. Focal seizures usually are associated with patterns of cognitive performance typically seen with damage to the area of the seizure focus in the absence of epileptic activity.
Memory dysfunction is the most commonly reported cognitive complaint associated with temporal lobe epilepsy (TLE; Ogden-F.pker and Cullum 2001). Verbal memory deficits typically are reported to be associated with left temporal lobe epilepsy, whereas verbal memory deficits have been emphasized in association with right temporal lobe epilepsy. However, findings regarding the relationship between epilepsy and memory functioning are mixed, and some studies have not found a relationship between the laterality of TLE and material specific memory deficits. Nonetheless, there is evidence that self-reported memory is an important predictor of quality of life in patients with TLE (Giovagnoli and Avanzini 2000). Language disorders are also associated with epilepsy. One study examined language function in 60 patients with epilepsy and found that more than 3 0 % of the patients had language impairments, with greater deficits in receptive than in expressive abilities. The language abilities of patients with unilateral TLE were studied using a large battery of neuropsychological language tests. Results showed that patients with left temporal lobe epilepsy performed significantly worse on tests of naming, repetition, and language comprehension than patients with right temporal lobe epilepsy. The authors concluded that language problems occur in TLE generally but are more pronounced in left temporal lobe epilepsy. Deficits of the ability to name objects have also been shown to be associated with intractable mesial temporal lobe. For example, one study examined whether object-naming deficits in TLE were associated with semantic knowledge deficits (Bell et al. 2001; Figure 38.14). The findings suggested that patients with early-onset TLE have a semantic knowledge deficit that contributes to their confrontation naming problems. Several studies have demonstrated that deficits in executive functioning are associated with frontal lobe epilepsy. Recently, one study compared the neuropsychological profiles of children with frontal lobe epilepsy and TLE (Culhane Shelburne et al. 2002), Children with frontal lobe
NEUROPSYCHOLOGY
695
FIGURE 38.14 Boston Naming Test (BNT) results by group (temporal lobe epilepsy [TLF.| versus normal controls). (Adapted from Bell, B. D., Hermann, B. P., Woodard, A. R. 1997, "Object naming and semantic knowledge in temporal lobe epilepsy," Neuropsychology, vol. 15, pp. 434-443.)
Group
epilepsy had deficits with planning and executive functions with intact verbal and nonverbal memory, whereas the children with TLE showed the opposite pattern. Another study examined children with TLE, frontal lobe epilepsy, and generalized epilepsy (Hernandez et al. 2002). Findings indicated that children with frontal lobe epilepsy had deficits in planning and impulse control and more coordination problems and motor rigidity than children in the other groups. A complicating issue in identifying cognitive deficits associated with epilepsy is the fact that the main treatment approaches, including anticonvulsant medications and neurosurgery for intractable seizures, commonly have additional, independent effects on neuropsychological functioning. Therefore treatment must balance seizure relief with adverse side effects of the treatment. Many patients with epilepsy remain on antiepileptic medication for years. Awareness of the potentially harmful effects of anticonvulsant medications on cognitive functioning is increasing. Many of the older anticonvulsants have been associated with adverse effects on cognition, although their specific patterns of impairments may vary. Reviews of the literature suggest that antiepileptic drugs can decrease performance on tests of motor speed, attention, memory, perceptual functions, and motor coordination. Antiepileptics can also affect cognition by increasing drowsiness and dizziness. However, there is some suggestion in the literature that newer antiepileptic medications such as oxcarbazepinc and vigabatrin have less of an impact on cognitive functioning than older drugs, although this has not been comprehensively studied (see Brunbech and Sabers 2002 for a review). Historically, several methodological problems including selection factors, statistical problems, and inappropriate use of cognitive tests complicate the research. However, it is clear that the consideration of
potential side effects of antiepileptic medication is important in treatmenr and that further research as new medications arc developed will be valuable. The surgical resection of epileptogenic brain tissue can be an effective treatment for inrractable epilepsy; however, preoperative localization of the seizure origin and assessment of cognitive abilities are essential to minimize the adverse consequences that can be associated with the surgery. Surgical resection typically is performed to treat TLE that is resistant to pharmacotherapy and is used less commonly for intractable frontal lobe epilepsy. Neuropsychological evaluation provides important information about localization of seizure onset, lateralization of important cognitive functions, and the risks of surgery to essential psychological functions such as language and memory. Neuropsychological assessment also provides information about psychosocial and cognitive changes after surgery. The most common neuropsychological finding after surgical resection is a decline in verbal memory after dominant temporal lobe resection and deficits in visual memory after nondominant temporal lobe resection. However, some research suggests that the neuropsychological performance of many patients improves after surgical treatment for TLE. Postoperative improvement appears to be influenced by the reduction in the frequency of seizures after surgery (Wachi et al. 2 0 0 1 ; Table 38.14). Engman et al. (2001) found significant variability between individuals in their postoperative cognitive change. The authors point to the importance of considering interindividual and ultraindividual variability. Several factors have been shown to be associated with favorable postoperative outcomes, including interictal electroencephalographic localization to the operated lobe and the absence of secondarily generalized seizures.
696
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Table 38.14:
Neuropsychological results of seizure-free and not-seizure-free groups before surgery and 1 year after surgery Seizure free
Test Wechsler Adult Intelligence Scale-Revised Verbal IQ Performance IQ Full-Scale IQ Wechsler Memory Scale-Revised Verbal General Delayed Paired Associates Raven Progressive Matrices
Not seizure free
Before surgery
1 yr after surgery
Before surgery
1 yr after surgery
86.1 (15.3) 89.2(16.8) 86.3(15.9)
87.8 (14.8)* 98.7(17.8)** 91.4(15.4)**
83.4 (10.9) 88.6(14.9) 84.1(12.5)
82.8 (13.3) 89.7(18.0) 84.1(16.2)
81.4 (14.7) 88.6 (16.3) 90.6 (17.7) 32.6(3.7)
91.3 (14.9)** 96.1 (18.2)** 103.7 (17.7)** 34.3(2.3)**
80.4 (17.3) 85.9 (11.2) 89.9 (11.0) 32.8(2.4)
88.4 (20.6) 92.0(18.0) 97.7 (18.3) 34.2 (1.9)1'
Note: Values represent the means with the standard deviation indicated in parentheses. *p < 0.05, **p < 0,01 compared with presurgical scores. Source: Adapred from Wachi, M., Tomikawa, M., et al. 2002, "Neuropsychological changes after surgical treatment for temporal lobe epilepsy," Epilepsia, vol. 42, suppl. 6, pp. 4-8.
Human Immunodeficiency Virus Overall estimates of the number of people infected with human immunodeficiency virus (HIV) who experience neurocognitive complications of infection range from approximately 3 0 % to 5 0 % . Neuropsychological impairment in HIV-infected patients can be classified into three subgroups (Grant et al. 1999). Patients with subsyndromic neuropsychological impairment show deficits in at least two neuropsychological domains with no evidence of functional impairment. A second ncurobehavioral disorder in HIV has been called mild neurocognitive disorder or minor cognitive/motor disorder and involves deficits in at least two ability domains, confirmed by neuropsychological testing, and impairment sufficient to affect the patient's daily functioning. The most severe neurocognitive manifestation of infection is HIV-1-associated dementia, which is characterized by moderate to severe cognitive and psychomotor slowing, impaired concentration and attention, memory disturbances, and often motor incoordination and weakness. The neuropsychological profile of patients with HIV, particularly in the later stages of the disease, has been associated with the deficits seen in subcortical dementias (e.g., Huntington's disease), including slowed information processing, reduced fluency, impaired motor skills, and impaired free recall of recently learned information. Indeed, there is evidence that the greatest brain abnormalities occur in subcortical structures and white matter regions. However, the neuropsychological deficits observed in HIV can vary greatly across individuals. Cognitive impairment can be associated with the direct effects of HIV infection or secondary complications, including those resulting from immunodeficiency (e.g., opportunistic infections) and the treatment of the disease. Although the majority of studies provide evidence of neuropsychological impairments in a subset of patients in the later stages of HIV infection, the prevalence of cognitive
symptoms early in the course of HIV infection is more controversial. A meta-analysis of 41 studies examining the neuropsychological sequelae of HIV infection found that cognitive deficits in the early stages of HIV are small and increase in the later phases of the illness (Reger et al. 2002). Overall, the authors concluded that the cognitive decline with disease progression resembled a subcortical pattern; the greatest declines were in motor functioning, executive skills, and information-processing speed. A literature review of 57 articles on neuropsychological functioning in asymptomatic HIV-infected patients points to inconsistencies in the literature (White et al. 1995). Thirty-two percent of the studies reported increased neuropsychological impairment in HIV-positive subjects, 2 1 % had equivocal results, and 4 7 % found no significant differences in neuropsychological functioning between HIV-infected subjects and seronegative controls. Interestingly, the authors of the review article found that the comprehensiveness of the neuropsychological battery used in the studies was strongly associated with the likelihood of finding group differences, underscoring the importance of a comprehensive assessment approach. The domains of neuropsychological functioning that were most often impaired were attention and speed of information processing, learning, verbal abilities, and motor functioning. Researchers at the San Diego HIV Neurobehavioral Research Center (HNRC) have been longitudinally assessing the neurocognitive functioning of over 500 HIVpositive men. Findings ftom this group suggest that asymptomatic HIV-positive men have twice the rate of neuropsychological impairment of HIV-negative control subjects and that cognitive impairment increases with disease progression (Figure 38.15). Neuropsychological impairment was found to be more prevalent in later stages of infection, and when it occurred, it affected more cognitive domains than in the asymptomatic stage. Additional research from the HNRC group suggests that
NEUROPSYCHOLOGY
attention and learning arc the areas impaired in the greatest proportion of HIV-positive men, a finding that is consistent with previous research (Figure 38.16).
Traumatic Brain Injury Traumatic brain injury (TBI) is one of the most common forms of acquired neurological damage in the United States, particularly in young adults. Cognitive deficits after injury are common. In cases of moderate to severe injury, where head trauma is sufficient to cause loss of consciousness and post-traumatic amnesia, impairment in several cognitive
697
domains including attention, memory, communication skills, and executive functioning may occur. Although more controversial, in some cases mild head injury can also produce alterations in cognitive status (see van der Naalt 2001 for a review of recovery after mild to moderate TBI). The psychological consequences of injury depend on how the injury occurred, the severity of the injury, the site of the lesion, premorbid personality, and the treatment received after the injury. Therefore the range of deficits that can result from brain injury vary significantly. Brain damage after trauma may involves penetrating or closed injuries, and consequences of both the primary injury and secondary effects influence the clinical presentation. The fact that
fi'JS
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Table 38.15:
Common neurocognitive sequelae of moderate to severe traumatic brain injury
Cognitive domain
Clinical manifestation of the impairment
Attention
Difficulty with sustained attention Poor concentration Psychomotor impersistence Problems with acquiring and retaining new verbal or nonverbal information Problems in retrieving verbal and nonverbal memories Slowed sensorimotor skills and information processing Problems in convergent and divergent reasoning Poor judgment Difficulty planning Problems in self-monitoring and self-correcting behavior Difficulty recognizing deficits Unrealistic expectations concerning the recovery of functions Problems related to poor treatment compliance Problems in word comprehension Impaired reading, spelling, and writing ability Tendency to become fragmented in free speech Problems in adequate or time efficient execution of various pcrccptual-motor-spatial-sequential tasks
Memory
Speed of information processing Executive functioning
Awareness of symptoms Language and communication
Impaired integrative functions
brain injury often involves both focal injuries to the brain and diffuse damage (e.g., shearing effects and edema} contributes to variability in the presentation of cognitive impairment. Despite individual clinical variability, several common neurobehavioral sequelae of moderate to severe TBI can be identified (Table 38.15). For example, damage to the orbital and polar aspects of the frontal lobe and the temporal poles is likely to result from head trauma given the anatomy of the skull (e.g., orbital plate of the frontal bone and sphenoidal ridge). These injuries can be associated with executive dysfunction and memory deficits. Immediately after injury, patients may experience loss of consciousness and post-traumatic amnesia. Early recovery is characterized by resumption of basic attentional processes and a return of speech. Patients may go through a period nt confusion during which they confabulate and tail to retrieve new, and often remote, memories. Although attention gradually improves, mental slowness with decreased information-processing speed often persists. Patients may complain of confusion, inability to think clearly, and disorientation. They tend to be distractiblc and unable to maintain focused attention. After the acute confusional state and post-traumatic amnesia ends, the most common cognitive deficits that persist include disturbances of memory, attention, language, and executive dysfunction. Memory disturbance is one of the most common complaints of patients after TBI and is related to the severity of TBI and the diffuse nature of the injuty. Patients may show problems with acquisition and retention of new verbal and nonverbal information and problems with retrieval. Retrograde memory deficits, for events occurring before the injury, often show a memory gradient so that the most temporally proximate events are the most likely to be forgotten.
After frontal lobe damage, deficits in judgment, planning, organizing and sequencing, concept formation, set shifting, self-monitoring, and self-correcting behavior may occur. The sequelae of moderate to severe traumatic brain injury can also include disturbances in the balance between excitatory and inhibitory processes including impulse control problems, reduced stamina or energy levels, and lowered tolerance for frustration and irritability. Inadequate awareness of deficits may be present such that the patient has difficulty assessing the severity of his or her deficirs, sometimes leading to unrealistic expectations for recovery and poor treatment compliance.
REFERENCES American Psychiatric Association, 1994, Diagnostic and Statistical Manual of Mental Disorders—Revised ed. American Psychiatric Press, Washington, D.C. Anthony, J. C, I^eResehe, L., Niaz, U., et al. 1982, "Limits of the 'Mini Mental State' as a screening test for dementia and delirium among hospital patients," Psycho! Med, vol. 12, pp. 397-408 Bell, B. D., Hermann, B. P., Woodard, A. R., et al. 2001, "Object naming and semantic knowledge in temporal lobe epilepsy," Neuropsychology, vol. 15, no. 4, pp. 434-443 Benedict, R. H. B., Bakshi, R., et al. 2002, "Frontal cortex atrophy predicts cognitive impairment in multiple sclerosis," ] Neuropsychiatry Clin Neurosci, vol. 14, no. 1, pp. 44-.51 Bowler, J. V. Sc Hachinski, V. 2002, "The concept of vascular cognitive impairment," in Vascular Cognitive Impairment, eds T. Erkinjuntti & S. Gauthier, Martin Dunitz, Ltd., London, pp. 9-26 Rrunbech, L. & Sabers, A. 2002, "Effect of antiepileptic drugs on cognitive function in individuals with epilepsy: A comparative review of newer versus older agents," Drugs, vol. 62, no. 4, pp. 593-604
NEUROPSYCHOLOGY Camp, S. J., Stevenson, V. L., Thompson, A. J., et al. 1999, "Cognitive function in primary progressive and transitional progressive multiple sclerosis: A controlled study with MR1 correlates," Brain, vol. 122, no. 7, pp. 1341-1348 Chan, A., Butters, N., Paulsen, J. S.,et al, 1993, "An assessment of the semantic network in patients with Alzheimer's disease," } Cogn Neurosci, vol. 5, no. 2, pp. 254-261 Cirino, P., Chapieski, M., & Massman, P. 2000, "Card sorting performance and ADHD symptomatology in children and adolescents with Tourette syndrome," / Clin Exp Neuropsychol, vol. 22, pp. 245-256 Culhane-Shelburne, K., Chapieski, I.., Hiscolk, M., & Glaze, D. 2002, "Executive functions in children with frontal and temporal lobe epilepsy," ./ Iiu Ncttrupsythnt Soc, vol. S, no. \ pp. 623-632 Demaree, H. A., Gaudino, E. A„ DcLuca, J., & Ricker, J. H. 2000, "Learning impairment is associated with recall ability in multiple sclerosis," / Clin Exp Neuropsychol, vol. 22, no. 6, pp. 865-873 Desmond, D. W. & Pasquier, F, 2002, "Global cognitive syndromes," in Vascular Cognitive impairment, eds T. Erkinjunttc & S. Gauthier, Martin Dunitz, Ltd., London, pp. IK9-204 Doty, R. L. 1991, "Olfactory dysfunction in neiitodegenerative disorders," in Smell and Taste in Health and Disease, eds T. V. Getchell, R. L. Doty, L. M. Bartoshuk, & J . B. Snow, Jr., Raven, New York Engman, E., Andersson-Roswall, L., & Malmgren, K. 2 0 0 1 , "Preand postoperative general neurocognitive status and memory in 70 epilepsy surgery patients," Acta Neurol Scand, vol. 103, no. 6, pp. 351-359 Fahn, S„ R. Elton, L„ Committee Mot UD 1987, "The Unified Parkinson's Disease Rating Scale," in Recent Developments in Parkinson's Disease, eds S. Fahn, C. D. Marsden, C, D. B. Calne, & M. Goldstein, Macmillan, Florham Park, NJ, vol. 2, pp. 153-163,293-304 Folstein, M. F., Folstein, S. E., & McHugh, P. R. 1975, " M i n i Mental State; A practical method for grading the cognitive state of patients for the clinician," / Psychiatr Res, vol. 12, pp. 189-198 Giovagnoli, A. R, &c Avanzini, G. 2000, "Quality of life and memory performance in patients with temporal lobe epilepsy," Acta Neurol Scand, vol. 101, no. 5, pp. 295-300 Grant, I., Marcotte, T. D., Heaton, R. K., & Group H. 1999, "Neurocognitive complications of HIV disease," Psycho! Sci, vol. 10, no. 3, pp. 191-195 Hernandez, M. T., Sauerwem, H. C, et al. 2002, "Deficits in executive functions and motor coordination in children with frontal lobe epilepsy," Neuropsychologia, vol. 40, no. 4, pp. 384-400 Janculjak, D., Mubrin, Z., Brzovic, S., et al. 1999, "Changes in short-term memory processes in patients with multiple sclerosis," Eur ] Neurol, vol. 6, pp. 663-668 Janculjak, D., Mubrin, Z., Brinar, V., & Spilich, G. 2002, "Changes of attention and memory in a group of patients with multiple sclerosis," Clin Neurol Neurosiirg, vol. 104, pp. 221-227 Jankovic, J. 2001, "Tourette's syndrome," N Engl J Med, vol. 345, pp. 1184-1192 Kakzanis, K. K., 2000, "Distinct neurocognitive profiles in multiple sclerosis subtypes," Arch Clin Neuropsychol, vol. 15, no. 2, pp. 115-136 Kiernan, R. J., Mueller, J., Sc Van Dyke, C. 1987, "The Neurobehavioral Cognitive Status Examination: A brief but
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differentiated approach to cognitive assessment," Annals of Internal Medicine, vol. 197, pp. 484-485 Marder, K., Zhao, R, Myers, R. H., et al. 2000, "Rate of functional decline in Huntington's disease," Neurology, vol. 54, no. 8, pp. 1712 Mattis, S. 1976, "Mental status examination for organic mental syndrome in the elderly patient," in Geriatric Psychiatry, eds L. Bellak He T. B. Karasu, Grune Sc Stratton, New York, pp. 77-122 McKhann, G., Drachman, D,, Folstein, M., et al, 1984, "Clinical diagnosis of Alzheimer's disease: report of the N1NCDS-ADRDA work group," Neurology, vol. 34, no. 7, pp. 939-944 Mohr, E., Glaus, J. )., & Browcrs, P. 1997, "Basal ganglia disease and visuospatial cognition: Arc these disease-specific impairments?" Bchav Neurol, vol. 10, no. 2-3, pp. 67-75 Monsch, A. U., Bondi, M. W., Salman, D. P., et al. 1995, "Clinical validity of the Mattis Dementia Rating Scale in detecting dementia of the Alzheimer type," Arch Neurol, vol. 52, pp. 899-904 Nelson, H. E. 1982, The National Adult Reading Test (NART) test manual, NFER-Nelson, Windsor, UK Ogden-F.pker, M. & Cullum, C. M. 2001, "Quantitative and qualitative interpretation of neuropsychological data in the assessment of temporal lobectomy candidates," Clin Neuropsychol, vol. 15, no. 2, pp. 183-195 Paulsen, J., Butters, N., Sadek, J. R., et al. 1995, "Distinct cognitive profiles of cortical and subcortical dementia in advanced illness," Neurology, vol. 45, pp. 951-956 Petersen, R, C. 2000, "Aging, mild cognitive impairment, and Alzheimer's disease," Neurol Clin, vol, 18, no. 4, pp. 789-805 Petersen, R. C, Doody, B., Kurz, A., et al. 2001, "Current concepts in mild cognitive impairment," Arch Neurol, vol. 58, pp. 1985-1992 Petersen, R. C, Smith, G. E., Waring, S. C, et al. 1999, "Mild cognitive impairment: Clinical characterization and outcome," Arch Neurol, vol. 56, pp. 303-308 Reed, B. R., Eberling, J. L., Mungas, D., et al. 2000, "Memory failure has different mechanisms in subcortical stroke and Alzheimer's disease," Ann Neurol, vol. 48, no. 3, pp, 275-284 Reger, M., Welsh, R., Razani, J., et al. 2002, "A meta-analysis of the neuropsychological sequelae of HIV infection," j Int Neuropsychol Soc, vol. 8, pp. 410-424 Rich, J. B., Troyer, A. EC, Bylsma, F. W., & Brandt, J. 1999, "Longitudinal analysis of phonemic clustering and switching during word-list generation in Huntington's disease," Neuropsychology, vol. 13, no. 4, pp. 525-531 Rouleau, L, Salmon, D. P., &c Butters, N. 1996 "Longitudinal analysis of clock drawing in Alzheimer's disease patients," Brain Cogn, vol. 3 1 , no. 1, pp. 17-34 Solomon, P. R., Hirschoff, A., Kelly, B., et al. 1998, "A 7 minute neurocognitive screening battery highly sensitive to Alzheimet's disease," Arch Neurol, vol. 55, no. 3, pp. 349-355 Sperling, R. A., Guttmann, C. R. G., Hohol, M. J., et al. 2001, "Regional magnetic resonance imaging lesion burden and cognitive function in multiple sclerosis," Arch Neurol, vol. 58, pp. 115-121 Stout, J. C, Rodawalt, W. C, & Siemers, E. R. 2001, "Risky decision making in Huntington's disease," / Int Neuropsychol Soc, vol. 7, no. 1, pp. 92-101 van der Naalt, J. 2001, "Prediction of outcome in mild to moderate head injury: A review," / Clin Exp Neuropsychol, vol. 2 3 , no. 6, pp. 837-851
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Wachi, M., Tomikawa, M., Fukuda, M., et al. 2 0 0 1 , "Neuropsychological changes after surgical treatment for temporal lobe epilepsy," Epilepsia., vol, 42, suppl. 6, pp. 4-8 Welsh, K., Butters, N., Hughes, J-, et al. 1991, "Detection of abnormal memory decline in mild cases of Alzheimer's disease using CERAD neuropsychological measures," Archives of Neurology, vol. 48, pp. 278-281 White, D. A., Heaton, R. K., Monsch, A. U., & Group H. 1995, "Neuropsychological studies of asymptomatic human immunodeficiency virus type-1 infected individuals," / bit Neuropsycbo! Soc, vol. 1, pp. 304-315
Wilkinson, G. S. 1993, Wide Range Achievement Test-3, Wide Range, Inc, Delaware Yuspeh, R. L„ Vanderploeg, R. D., Crowell, T. A., &: Mullan, M. 2002, "Differences in executive functioning between Alzheimer's disease and subcortical ischemic vascular dementia," / Clin Exp Neuropsychol, vol. 24, no. 6, pp. 745-754 Zakzams, K. K. 1998, "The subcortical dementia of Huntington's disease," J Clin Exp Ncuropsycbol', vol. 20, no. 4, pp. 565-578
Chapter 39 Neuro-Ophthalmology: Ocular Motor System Patrick J. M. Lavin and Sean P. Donahue
Generation and Control of Eye Movements Ocular Motor Subsystems Horizontal Eye Movements Vergence Eye Movements Vertical Eye Movements Development of the Ocular Motor System Supranuclear Gaze Disturbances Ocular Motor Apraxia Spasm of Fixation Familial Horizontal Gaze Palsy Acquired Horizontal Gaze Palsy Wrong-Way Eyes Periodic Alternating Gaze Deviation
701 703 704 709 709 710 711 714 714 715 715 715 716
Neuro-ophthalmology bridges the disciplines of ophthalmology and neurology. Despite sophisticated technological advances in neuroimaging, competence in neuro-ophthalmological diagnosis still requires basic clinical skills. These include attentive listening; timely, probing questions; knowledge of neuroanatomy and of disorders that affect the afferent and efferent visual pathways; skill in examination of the visual system and the cranial nerves; and experience and expertise in evaluating supplementary investigations, including perimetry, fluorescein angiography, and neuroimaging. Often, a thorough clinical examination and careful thought preempt uncomfortable, invasive, and expensive procedures. The old adage "ears and eyes first and most, hands least and last," still holds true. This chapter discusses central control mechanisms and disorders of the ocular motor system. Diplopia, nystagmus, and other ocular oscillations are discussed in Chapter 16, and disorders of the ocular motor nerves are discussed in Chapter 76.
GENERATION AND CONTROL OF EYE MOVEMENTS A reasonable understanding and interpretation of gaze disorders require an appreciation of the anatomy and physiology of eye movement control. In the words of Hughlmgs Jackson, "The study of the cause of things must be preceded by the study of things caused." Normal visual behavior is accomplished by a continuous cycle of visual fixation and visual analysis interrupted by saccades (Schall and Thompson 1999). Individuals with
Ping-Ponj; Gaze • Saccadic Latcropulsion Torsional Saccades Slow Saccades Prolonged Saccadic Latency Square Wave Jerks Internuclear Ophthalmoplegia One-and-a-HalF Syndrome Disorders of Vertical Gaze Disorders of Convergence Disorders of Divergence Eye Movement Recording Techniques
716 716 716 716 716 717 718 718 718 722 722 724
intact sensory visual systems (optical and afferent) are capable of discerning small details, comparable to Snellen acuity of 20/13, provided the fovea is maintained on target. However, 10 degrees from fixation, the resolving power of the retina drops to 20/200. Although the peripheral retina has poor spatial resolution capabilities, it is exquisitely sensitive to movement (temporal resolution). The image of an object entering the peripheral visual field stimulates the retina to signal the ocular motor system to make a rapid eye movement (saccade) and fixate it on the fovea: In the words of the American psychologist, William James "The peripheral retina is like a sentinel and when an object of regard falls upon it, it shouts 'hark, who goes there' and calls the fovea to the spot," Visual information concerning spatial resolution (fine detail) and color travels via retinal ganglion (P) cells to the parvocellular layers of the lateral geniculate nucleus (LGN), whereas information concerning temporal resolution (movement) travels via retinal ganglion (M) cells to the magnocellular layer of the LGN. In turn, neurons in the LGN project via the optic radiations to the primary visual area (VI), the striate cortex (area 17). Visual processing in the cortex begins in the primary visual area from which issues two processing streams (Figure 39.1A). One stream (ventral), responsible for form and object recognition and emphasizing foveal representation, projects to the temporal lobe via occipital areas V2 and V4. The second stream (dorsal), responsible for movement recognition, guiding actions in space, and emphasizing peripheral visual field representation, projects to the prestriate cortex. It then relays to the superior temporal sulcus region, which contains cortical areas MT (middle temporal) and MST (middle superior temporal) in monkeys, roughly equivalent
7(11
702
NEUROLOCICAI, INVESTIGATIONS AND RELATED CMNICAI NEIIROSCIENCFS
FIGURE 39.1 (A) Overview of the visuo-ocular motor system, (Redrawn from Sruphorn and Schall 2002.) (B) Areas in the human brain that are believed to be important in generating saccades and pursuit. BSG = brainstem saccadic generator; CN = caudate nucleus; ESC = extra striate cortex; FFF = frontal eye field; LGN = lateral geniculate nucleus; IJP = lateral intraparietal area; MST —medial superior temporal visual area; MT = middle temporal visual area; PEF = parietal eye field; PFC = prefrontal cortex; PPC = posterior parietal cortex area; PPRF = paramedian pontine reticular formation; PTO = pa rie to-tempore-occipital junction; SC = superior colliculus; SEF = supplementary eye fields in the supplementary motor area; 7a = area 7a; SN = substantia nigra. to the parieto-temporo-occipital junction (PTO) in humans, and encodes for location, direction, and velocity of objects. Both streams converge on the FEF (frontal eye field) and are involved in controlling saccades (see later). The prcmotor substrates for conjugate gaze and vergence eye movements are in the brainstem. The substrates specific for vertical gaze, vergence, and ocular
counter-rolling are in the mesodiencephalic region, whereas those for horizontal eye movements are mainly in the pons. The mechanisms for horizontal eye movements are better understood than those for vertical eye movements and are based on clinicoparhological and radiological correlation as well as animal and bioengi nee ring experiments. With the exception of reflexive movements, such as the
NEURO-OPHTHALMOLOGY; OCULAR MOTOR SYSTEM
vestibulo-ocular reflex (VOR) and fast phases of nystagmus, cerebral structures determine when and where the eyes move, whereas brainstem mechanisms determine how they move: in other words, voluntary eye movements are generated in the brainstem, but are triggered by the cerebral cortex.
Ocular Motor Subsystems Six ocular motor subsystems enable the fovea to find and fixate a target, stabilize an image of the target on each retina, and maintain binocular foveation during head or target movement, or both. The saccadic system moves the eyes rapidly (up to 800 degrees per second) to fixate new targets (Figure 39.2A). Saccades may be generated voluntarily or in response to verbal commands in the absence of a visible target. Reflex saccades may occur in response to peripheral retinal stimuli, such as visual threat or retinal error signals, or to sound. Saccades are also the fast components of nystagmus. The pursuit system enables the eyes to track slowly moving targets (up ro 70 degrees per second) to maintain the
B FIGURE 39.2 Simulated eye movement recordings, By convention for horizontal movements, upward deflections represent rightward eye movements, and downward deflections represent leftward eye movements. (A) Saccades. A target moves rapidly 10 degrees to the right. After a latency of about 200 ms, the eye follows. When the target returns to the center, the sequence is repeated in the opposite direction. (B) Pursuit. The target moves in a sinusoidal pattern in front of the patient. The eye follows the target after a latency of about 120 ms, but pursuit movements to the right are defective, resulting in the rightward "cogwheel" (saccadic) pursuit. Pursuit to the left is normal.
703
image stable on the fovea. Specially trained subjects are capable of smooth pursuit eye movements as fast as 100 degrees per second. Pursuit eye movements are limited more by the target's acceleration than by its velocity. If the target moves too quickly or abruptly changes direction, or if the pursuit system is impaired, the eyes are unable to maintain pace with the target and fall behind. Consequently, the image moves off the fovea, producing a retinal error signal that provokes the saccadic system to make a catch-up saccade to refixate the target. The cycle then repeats itself, resulting in saccadic ("cogwheel") pursuit (see Figure 39.2B). Bidircctionally defective pursuit eye movements, a normal finding in infants, are nonspecific and occur under conditions of stress or fatigue, or with sedative medication. Impaired tracking in one direction, however, suggests a structural lesion of the ipsi lateral pursuit system (see Figure 39.2B). Fixation allows the eyes to maintain an image of a stationary target on each fovea at rest. The fixation subsystem shares neural circuitry with the optokinetic (OKN) and pursuit systems (Leigh and Zee 1999). The vestibular eye movement subsystem maintains a stable image on the retina during head movements. The semicircular canals respond to rotational acceleration of the head by driving the VOR to maintain the eyes in the same direction in space during head movements. The otoliths (utricle and saccule} are gravity receptors that respond to linear acceleration and static head tilt (gravity), that is, with ocular counter-rolling. The vestibular system is discussed further in Chapter 4 1 . The optokinetic system uses visual reference points in the environment to maintain orientation. It complements the vestibulo-ocular system, which becomes less responsive during slow or sustained head movements, to stabilize images on the retina in situations such as spinning. When the eyes reach their limit of movement in the orbits, a reflex saccade allows refixation to a point further forward in the direction of bead rotation. The sequence repeats itself, resulting in OKN (see Chapter 16). In humans, the optokinetic system responds predominantly to fixation and pursuit of a moving target (immediate component), and to a lesser extent velocity storage (delayed component), which involves neural circuitry in the vestibular system. (Velocity storage is a mechanism by which the central nervous system, predominantly the vestibular system including the vestibuloeerebellum, prolongs or perseverates short signals generated by the vestibular end-organ to enhance orientation in space. Velocity storage is largely involuntary.) The vergence system enables the eyes to move disconjugarely (converge and diverge) in the horizontal plane to maintain binocular fixation on a rarget moving toward or away from the Subject. Vergence movements are essential for binocular single vision and stereoscopic depth perception.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NHJKOSCILNCES
T h e different types of eye m o v e m e n t s Table 3 9 . 1 .
are
listed
in
H o r i z o n t a l Eye M o v e m e n t s W h e n gaze is redirected from o n e p o i n t to a n o t h e r , a saccade moves the eyes conjugatcly. To enable t h e small, strap-like e x t r a o c u l a r muscles to move the relatively large globes and overcome the elastic recoil of the viscous orbital Tabic 39.1:
Types of eye movements
A. Saccades (moving eyes from one target to another) Intentional saccades (internally triggered, with a goal) Visually guided saccades Memory-guided saccades (with visual/vestibular input) Predictive saccades Target-searching saccades Antisaccades"' Reflexive saccades (externally triggered) Visually guided saccades Auditory saccades Spontaneous saccades (internally triggered, without a goal) During another motor activity At rest When sleeping Quick phases of nystagmus Physiological nystagmus Vestibular nystagmus Optokinetic nystagmus End-point nystagmus Pathological nystagmus (see Chapter 16) B. Eye movements stabilizing the image of the target on the fovea Smooth pursuit Eoveal pursuit Full-Held pursuit (slow phase of optokinetic nystagmus) Vesti bu I o-ocular reflex (horizontal, vertical, torsional) Convergence C. Ocular oscillations that may interfere with vision Double saccadic pulses Macrosaccadic oscillations Ocular bobbing Ocular dysmetria Ocular hypometria Ocular by per m err ia Ocular lateropnlsioii Ocular torsi pulsion Ocular flutter Ocular neuromyotonia Ocular tics (myoclonic jerks) Oculogyric crisis Opsoclonus Saccadic pulses Square wave pulses (previously designated macrosquare wave jerks) Square wave jerks Superior oblique myokymia Torsional saccades (blips) * Antisaccades are fast eye movements deliberately made away from a new target. It is a laboratory procedure used to investigate frontal lobe or cognitive function.
c o n t e n t s , the yoked a g o n i s t muscles require a surge or hurst of innervation (pulse) at the s a m e time their yoked a n t a g o n i s t s a r e reciprocally inhibited (Figure 3 9 . 3 A ) . For a leftward s a c c a d e , rhe left lateral rectus a n d t h e right medial rectus muscles each receive a pulse of innervation while their a n t a g o n i s t s , the left medial and right lateral rectus muscles, a r e reciprocally inhibited. Excitatory b u r s t n e u r o n s (EBNs) c o n t a i n e d in t h e ipsilateral p a r a m e d i a n p o n t i n e reticular formation (PPRF), just rostral to the a b d u c e n s n u c l e u s , generate the pulse to initiate the saccade. T h e E B N s a r e m e d i u m - lead hurst cells t h a t discharge a b o u t 10 ms before, a n d d u r i n g , all horizontal saccadic eye m o v e m e n t s ; they preferentially discharge for ipsilateral saccades and create the i m m e d i a t e p r e m o t o r c o m m a n d g e n e r a t i n g pulse activity for saccades. A b o u t half the n e u r o n s in the a b d u c e n s nucleus a r e i n t e r n e u r o n s (with different m o r p h o l o g i c a l a n d p h a r m a c o l o g i c a l features t h a n the n e u r o n s of the a b d u c e n s nerve) t h a t relay, via t h e medial longitudinal fasciculus
FIGURE 39,3 Ocular motor events on gaze left. (A) After the appearance of a stimulus 20 degrees to the left of fixation (-20 degrees), the eyes move to the target with a saccade after a latency of 200 ms. Idealized electromyography of the left extraocular muscles shows the activity of the agonist (the left lateral rectus [LLR|), and the antagonist (the left medial rectus |I.MR] muscles). (B) The pulse originates in the excitatory burst neurons (EBNs) and is mathematically integrated by the neural integrator (NI); both signals are added to produce the pulse-step of the innervation to the ocular motor neurons. (C) The pause cells (P) discharge continuously, suppressing the hurst cells (B), except during a saccade, when they "pause," allowing the burst cells to discharge and generate a pulse. (Reprinted with permission from P. j. M. Lavin. 1985, "Conjugate and disconjugate eye movements," in Neitro-opbthaimofoxy: Clinical signs and symptoms, ed T. J. Walsh, Lea &c Febiger, Philadelphia.)
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GAZE LEFT
FIGURE 39.4 A lateral head turn induces movement of the cndolymph, in the ipsilatcral horizontal semicircular canal, toward the ampulla (as would warm water caloric stimulation of an ear), and thus excites the contralateral abducens nucleus and inhibits the ipsilateral abducens nucleus via the vestibular nuclei (VN). Each abducens nucleus innervates the ipsilateral lateral rectus muscle via the abducens nerve and the contralateral medial rectus muscle via the abducens nucleus inremeurons, the medial longitudinal fasciculus (MLF), and the neurons for the medial rectus (part of cranial nerve [CN] ill nucleus). Neurons in each paramedian pontine reticular formation (PPRF) also have an excitatory input to the ipsilateral abducens nucleus and an inhibitory input to the contralateral abducens nucleus, for saccades and quick phases of nystagmus, (LE = left eye; RE = right eye. (Adapted from Lavin, P. J. M. 1985, "Conjugate and disconjugate eye movements," in Neuro-opbtbalmvlogy; Clinical signs and symptoms, cd T. j. Walsh, Lea Sc Febiger, Philadelphia.)
(MLF), to the contralateral medial rectus neurons in the oculomotor nuclear complex (Figure 39.4). The KBNs are tonically suppressed, except just before and during a saccade, by pause cells located in the nucleus raphe inter positus rostral to the abducens nucleus. Thus the pause cells, which receive input ftom the cerebrum, cerebellum, and superior colliculus (SC), mediate the command for a saccade when they cease discharging and allow the burst cells to fire (Figure 39.5). At the same time the EBNs discharge, a group of inhibitory cell-burst neurons that lie caudal to the abducens nucleus in the medial rostral medulla and project across the midline to the contralateral abducens nucleus, discharge during the saccade to reciprocally inhibit the yoked antagonist muscles (Leigh and Zee 1999). To maintain the eyes on target in an eccentric position at the end of a saccade, the agonist muscles for a leftward movement (left lateral and right medial recti) now require a new level of tonic innervation—a position command— achieved by a gtoup of neurons referred to as the neural integrator (NI). (An integrator converts phasic input to tonic output, mathematically, by using reverberating collateral circuits to rc-excite neurons. The efficiency of an integrator
FIGURE 39.5 Electrophysiological events during an eye movement. P represents an intraneuronal recording from a pause cell and demonstrates a constant discharge, which ceases, allowing an excitatory burst neuron (iJ) to discharge during pulse. T represents the discharge in a tonic neuron, which increases after the pulse as a result of integration of the pulse to a step. Both the pulse [P) and the tonic output (T) of burst-tonic neurons inncrvare the ocularmoror neurons (Oc). The rcsuir is a rapid contraction of the extraocular muscle, which moves the eye from primary position and holds it in an eccentric position (£).
depends on its time constant, that is, the duration it can prolong the activity of the input. The effective time constant is the period necessary for the output to decay to 3 7 % of its initial value after the input signal stops.) The NI for horizontal gaze, thought to be partly in the rostral perihypoglossal nuclear complex and the adjacent rostral medial vestibular nucleus {Leigh and Zee 1999), receives the velocity command signal (pulse) from the EBNs. The NI then mathematically integrates the pulse to a "tonic" position command (step) before relaying it to the ipsilateral abducens nucleus (see Figures 39.3B and 39,4). The cerebellum and the PPRF maintain the output of this NI by controlling the gain, via a positive feedback loop, to keep the eyes on target (Figure 39.6). The gain of a system is the ratio of its output to its input. In this case, the output is the innervation required to maintain eccentric fixation, and the input is the pulse signal (see Figure 39.3C). If the NI is unable to maintain the gain at unity (output/input = 1),
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FIGURE 39.6 The time constant of the brainstem neural integrator (Nf), and therefore the fidelity of its output (innervation for gaze holding), is controlled predominantly by the cerebellum. Dysfunction of the gain control (K) may cause the integrator output to fall (a shortened time constant causes the signal to decay), allowing the eyes to drift back toward primary position. Conversely, an increase in K may result in an unstable integrator and Cause the eye to drift eccentrically with an increasing velocity waveform. EBN = excitatory burst neuron. (Adapted from Lavin, P.J. M. 1985, "Conjugate and disconjugate eye movements," in Neuro-ophtbalmology: Clinical signs and symptoms, eds T. J. Walsh, Lea &c Fchigcr, Philadelphia. Reprinted by permission of the author and the publisher.) the output falls, causing the eyes to drift off target toward primary position. A corrective saccade then refixates the target, resulting in gaze-evoked (gaze-paretic) nystagmus (see Chapter 16). Current evidence suggests that all conjugate eye-movement commands, including saccades, pursuit, the slow phases of OKN, and the VOR, are initiated as velocity commands and mediated by a final common integrator (Figure 39.7), Although its anatomical borders are not clear, the PPRF is defined functionally with the medial aspects of the nuclei gigantoeellularis, or pontis centralis oralis and caudalis, and is located just ventral and lateral to the MLF, extending from the level of the abducens nucleus almost to the trochlear nucleus. The PPRF innervates the ipsilateral abducens nucleus, the rostral medulla (part of the NI),
FIGURE 39.7 The final common integrator hypothesis. All conjugate eye movements (£) are initiated as eye, velocity commands (£') that are converted to eye position (E) by the neural integrator (N/). Both eye velocity and eye position commands arc relayed to the motor neurons, (Adapted from Cannon, S. C. & Zee, D. S. 1988, "The neural integrator of the oculomotor system," in Current Neuro-ophthalmalogy, eds S. Lessell & J. T W. van Dalen, Year Book, Chicago.)
and the midbrain reticular formation (MRF) to coordinate horizontal and vertical eye movements. The PPRF receives direct input from the medial vestibular nucleus, the contralateral frontal eye fields (FEFs), the ipsilateral posterior parietal region, the SC, and the cerebellum. A lesion of the abducens nucleus produces paralysis of all ipsilateral versional eye movements. Pontine lesions outside the abducens nucleus may selectively involve certain classes of eye movements while sparing others, demonstrating that the neural signals encoding subclasses of eye movements (e.g., saccades, pursuit, VOR, tonic position) project independently to the abducens nucleus (Halmagyi 1994). The PPRF also plays a role in generating vertical eye movements; acute bilateral injury may cause a transient vertical and horizontal gaze palsy. A unilateral lesion, in addition to impairing ipsilateral horizontal saccades, may also cause slowing and oblique misdirection of vertical saccades away from the side of injury (Johnston et al. 1993). With rare exceptions (Miller et al. 2002), lesions of the abducens nucleus that cause an acquired ipsilateral gaze palsy almost always involve the facia! nerve fasciculus as it loops around the abducens nucleus, and result in an associated facial nerve palsy. The vestibular system stabilizes the direction of gaze during head movements by virtue of changes in its tonic input to the ocular motor nuclei. This is most clearly illustrated by the horizontal VOR (see Figure 39.4). Each horizontal semicircular canal innervates the ipsilateral medial vestibular nucleus to inhibit the ipsilateral and excite the contralateral abducens nucleus. The ampulla of the right horizontal semicircular canal is stimulated by turning the head to the right (or warm caloric stimulation). This mechanical information is transduced by the vestibular end organ to electrical signals and transmitted to the ipsilateral vestibular nucleus. Excitatory information is then relayed to the contralateral abducens nucleus, and inhibitory information to the ipsilateral abducens nucleus, causing the eyes to deviate in the direction opposite to head rotation, thus maintaining the direction of gaze. Saccades (sec Tabic 39.1), or fast eye movements, are iniriated mainly in the contralateral frontal lobe and may be classified into four broad groups: 1. Internally triggered saccades, which are voluntary (intentional) and include target-searching, memoryguided, predictive (where the appearance of the target is anticipated), intentional visually guided saccades to an existing target in the peripheral visual field, and antisaccades. 2. Externally triggered saccades are reflexively activated by the appearance of a new target or a sound. 3. Spontaneous saccades, which occur in the absence of a target and are triggered internally, by both the FEF and the SC, to repetitively scan the environment; they occur at rest, during other motor activities, and during rapid-eye-movemenr sleep.
NEURO-OPHTHALMOI.OGY: OCULAR MOTOR SYSTEM
4. The quick phases of nystagmus (see Chapter 16). A number of specialized areas in the cerebral cortex, identified by both experimental and pathologic lesions, and by neurophysiological studies, particularly in monkeys, and by transcranial magnetic stimulation, play a major role in controlling saccades (see Figure 39.IB): 1. The FEF, in the prcccntral gyrus and sulcus (Brodmann's area 6 in humans, and area 8 in monkeys). 2. The supplementary eye field (SEF) on rhe dorsomedial aspect of rhe superior frontal gyrus is anterior to the supplementary motor area. 3. The parietal eye field (PEF), in the lateral intraparietal area (LIP) in monkeys, is equivalent to an area in the intraparietal sulcus near the angular gyrus region (Brodmann's areas 39 and 40) in humans. Other cortical areas that have a role in controlling saccades include the posterior parietal cortex (PPC), located in Brodmann's area 39 in the upper angular gyrus in humans, equivalent to 7a in monkeys; the prefrontal cortex (PFC), area 46; the vestibular cortex in the posterior aspect of the superior temporal gyrus; and the hippocampus in the medial temporal lobe (Pierrot-Dcscilligny et al. 1995). These cortical areas, and the superior colliculus, are parts of a network that collectively produce saccades and determine when different types of saccades occur and where they go; that is, they calculate their direction and amplitude (accuracy). In summary, this network determines where potential targets for orienting are located; where, whether, and when gaze will shift; and coordinates saccades with visually guided reaching and head movement-,. The FEF is heavily interconnected, topographically, with areas in both the dorsal and ventral streams of the extrastriate visual cortex (see Figure 39.1A) and participates in the transformation of visual signals into saccadic motor commands (Schall et al. 1995). Being extensively connected with extrastriate visual cortical areas, many neurons in the FEF respond to visual stimuli. The FEF and SC are both activated in the same way at the same time in response to visual stimuli before and during saccades. The FEF also plays a direct role in producing saccades. Low-intensity microstimulation of the FEF" elicits saccades; this direct influence is mediated by a subpopulation of neurons in FEF that discharge specifically before and during saccades. These neurons that trigger movementrelated activity innervate the deeper layers of the SC and neural circuits in the brainstem that generate saccades. The FEF projects to the SC mainly by three pathways: a direct pathway through the posterior aspect of the anterior limb of the internal capsule near the genu, an indirect pathway via the thalamus, and another indirect pathway via the caudate nucleus to neurons in the substantia nigra pars reticulata (SNr), These neurons in the SNr project,
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in turn, to the SC and tonically suppress saccades by a yaminobutyric a d d (GABA)-ergic mechanism. Controlled d is inhibition of this basal ganglia system is important for normal visually and auditory-guided saccades and is probably essential for saccades to remembered targets (Stell and Bronstein 1994). Saccades of different amplitudes and directions are encoded in neurons in the FEF and SC in a retinotopic fashion (i.e., rhe size and direction of a saccade is determined by which neurons are stimulated). The SC also has some role in reflexive and orienting saccades. The basal ganglia are involved in sequencing complex memory-guided saccades and perhaps predictive saccades (Picrrot-Deseilligny et al. 1995). The SEF parallels the FEF in several respects, and also innervates ocular motor centers in the SC and brainstem. However, the SEF seems to play a less essential or less potent role in saccade production, as ablation of SEF causes only minimal and short-lasting gaze impairment. The role of the PEF (area LIP in monkeys) is uncertain. Although neural activity in the PEF precedes saccades, the PEF docs not directly control the initiation of saccades, but signals areas such ay the FEE and SC with the location of potential targets for orienting {Colby and Goldberg 1999; Snyder et al. 2000). The SC has seven alternating fibrous and cellular layers that are broadly divided into a superficial sensory (dorsal) and a deep, predominantly motor (ventral) division. The superficial sensory division receives a direct orderly input from the retina via the accessory optic tract, bypassing the lateral geniculate body, such that the visual field may be mapped on the surface of the SC (retinotopic). Only about 10% of the retinal ganglion cells project to the SC, the remainder project to rhe lateral geniculate bod\ to subserve conscious vision. The deep motor division receives visual input from the striate cortex (area 17) and projects to motor areas in the subthalamic region and brainstem. The deeper division also receives input directly from the FEE and PPC and indirectly via the basal ganglia, as well as somatosensory and auditory input. Stimulation of the SC drives the eyes contralateral^ to a point in the visual field corresponding to the retinal projection lo that site. Thus the SC is essentially a sensory map overlying a corresponding motor map and represents the visual fields (Leigh and Zee 1999). The SC may also play a role in relaying excitatory information from part of the inferior parietal lobule (1PL), which has some influence in initiating saccades. Isolated lesions of the SC produce minimal, but specific, defects of saccades; when combined with experimental lesions of the FEFs; however, significant contralateral saccadic defects result. Purely vertical saccades require bilateral, simultaneous stimulation of corresponding points of the SC or of the FEFs. Control of smooth pursuit eye movements is also complex (see Figure 39.1) but essentially consists of three components: sensory, motor, and attcntional-spatial. The stimulus for pursuit is movement of an image across the
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
fovea at velocities greater than 3-5 degrees per second. The sensory component includes the striate cortex (area 17), which receives information from the retinal ganglion (M) cells via the magnocellular layer of the lateral geniculate body (nucleus) and the optic radiations. The striate cortex projects to the prestriate cortex (parieto-occipital areas 18 and 19) and then to the superior temporal sulcus region, which contains cortical areas MT (middle temporal) and MST (middle superior temporal) in monkeys, equivalent to the pariero-temporo-occipital junction (PTO) in humans (Barton et al. 1995). This sensory subsystem encodes for location, direction, and velocity of objects moving in the contralateral visual field and is the major afferent input driving smooth pursuit; it projects bilaterally to the pursuit motor subsystem, which is also located in the PTO region, as well as to the FEF and SFF. This pursuit pathway is indirect and focuses attention on small moving targets. A direct pathway, bypassing the attentional-spatial subsystem, enables large, moving objects, such as fullfield OKN stimuli, to generate smooth pursuit contralaterally even when the subject is inattentive. The SC also contributes to pursuit drive. The PTO projects via the internal sagittal stratum and the posterior limb of the internal capsule to the ipsilateral dorsolateral and lateral pontine nuclei (Gaymard et al. 1993). The pursuit
pathways control ipsilateral tracking and so must either remain on the same side or undergo a double decussation at least once. In 1992, Johnston and coworkers suggested the pursuit pathways project from the pontine nuclei to the contralateral flocculus and medial vestibular nucleus and then back to the ipsilateral abducens nucleus (Figure 39.8). Pursuit defects fall into four categories (Morrow and Sharpe 1993): 1, Retinotopic defects: Lesions of the geniculostriatc pathway cause impaired pursuit in both directions in the contralateral visual field defect. Defects also occur with lesions of areas MST or MT; these patients have apparently normal visual fields but selective "blindness" for motion. 2. Impaired pursuit, worse in the ipsilateral direction in both hemifields, occurs with lesions in the lateral aspect of area MST and the foveal representation of area MT in monkeys, similar to a focal PTO lesion in humans. Lesions in the FEFs, posterior thalamus, midbrain, ipsilateral pons, contralateral cerebellum, contralateral pontomedullary junction, and the ipsilateral abducens nucleus can also impair pursuit in both hemifields worse in the ipsilateral direction.
PONTINE NUCLEI
FIGURE 39.8 Postulated double decussation of pursuit pathways in the brainstem and cerebellum. The first decussation consists of excitatory mossy fiber projections from the pontine nuclei to granule cells, which excite basket cells and stellate cells in the contralateral cerebellar flocculus. The basket and stellate cells inhibit Purkinje cells, which in turn inhibit neurons in the medial vestibular nucleus (MVN). The second decussation consists of excitatory projections from the MVN to the opposite abducens nucleus (VI). (Reprinted with permission from Johnston, J. L., Sharpe, J. A., Et Morrow, M. J. 1992, "Paresis of contralateral smooth pursuit and normal vestibulat smooth eye movements after unilateral brainstem lesions," Ann Neurol, vol. 31, pp. 495-502.)
NEURO-OI'HTHALMOLOGY: OCULAR MOTOR SYSTEM 3. Symmetrically impaired pursuit in both horizontal directions occurs with focal lesions in the parietooccipital region {area 39). Medication (e.g., anticonvulsants, sedatives, and psychotropic agents), alcohol, fatigue, inattention, schizophrenia, encephalopathy, a variety of neurodegenerative disorders, and age (infants and the elderly) also cause symmetrically impaired pursuit. 4. An acute nondominant (e.g., parietal or frontal) hemisphere lesion associated with a hemispatial neglect syndrome causes transient loss of pursuit beyond the midline into contralateral hemispace. The cerebellum coordinates the ocular motor system to drive the eyes smoothly and accurately and is richly supplied by afferent fibers conveying ocular information (such as velocity, position, and neural integration) from the vestibular system, the afferent visual system, the PPRF, and the MRF. The dorsal vermis and fastigial nuclei determine the accuracy of saccades by modulating saccadic amplitude; they also adjust the innervation to each eye selectively to ensure precise conjugate movements. Lesions of the dorsal vermis and fastigial nuclei result in saccadic dysmctna (often, overshoot dysmetria that is greater centripetally) and macrosaccadic oscillations (see Chapter 16). Selective cerebellar lesions have differential effects on eye movements. Bilateral lesions of the fastigial and globose (interpositus) nuclei cause hypermetria of externally triggered saccades but do not affect internally triggered saccades (Straube et al. 1995). Bilateral lesions of the posterior vermis (lobules VI and VII) cause hypomctric horizontal and vertical saccades and impaired pursuit. Unilateral lesions of the posterior vermis cause hypometric ipsilateral and hypermetric contralateral saccades, whereas unilateral lesions of the caudal fastigial nucleus cause hypermetric ipsilateral and hypometric contralateral saccades (Biittner and Straube 1995; Vahedi et al. 1995). The flocculus, part of the vestibulocerebellum, is responsible for matching the saccadic pulse and step appropriately and for stabilizing images on the fovea. It adjusts the output of the NI and participates in long-term adaptive processing to ensure that eye movements remain appropriate to the stimulus. For example, the amplitude (gain) and even the direction of the slow phases of the VOR are adjusted by the flocculus. Lesions of the flocculus result in gaze-holding deficits, such as gazeevoked, rebound, and downbeat nystagmus. Floccular lesions also impair smooth pursuit, cancellation (suppression) of the VOR by the pursuit system during combined head and eye tracking, and the ability to suppress nystagmus (and vertigo) by fixation. The nodulus, also part of the vestibulocerebellum, influences vestibular eye movements and vestibular optokinetic interaction. Lesions of the nodulus in monkeys and humans produce periodic alternating nystagmus (PAN).
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Vergence Eye Movements In humans and other animals capable of binocular fusional vision, dysconjugatc (vergence) eye movements are necessary to maintain ocular alignment on an approaching or retreating object (convergence and divergence, respectively). Electromyography demonstrates that divergence is an active movement, although not as dynamic or as much under voluntary control as convergence. The principal driving stimuli for vergence movements, relayed from the occipital cortex, are accommodative retinal blur (unfocused) and fusional disparity (diplopia). Each of these stimuli can operate independently. During convergence, each eye also extorts, more so in downgaze, to facilitate stereoscopic perception (Brodsky 2002), In addition, the pupils change size, synkinetically, as part of the near reflex to increase the depth of field and to improve the focus of the optical system. Although the precise locations of the convergence and divergence centers are unknown, two areas, the midbrain prctcctum and the nucleus reticularis teg men ti pontis (NRTP), are important. Lesions in the pretectal region cause accommodative and vergence abnormalities (Ohsuka et al. 2002), and there is a group of neurons that fire in relation to the angle of convergence just lateral ro the third cranial nerve nuclear complex. The NRTP is contiguous with the PPRF and forms part of a feedback loop by relaying visual information to the cerebellum via a cerebroponto-ccrcbellar pathway; the NRTP may also function as a vergence integrator. Experimental lesions of the NRTP in monkeys can cause sustained convergence or pendular convergence-divergence oscillations. Unilateral stimulation of areas 19 and 22 of the preoccipital cortex caused bilateral convergence, accommodation, and miosis in macaque monkeys. The occipitomesencephalic pathway, involved in vergence, travels more vcntrally in the dienccphalon and midbrain than does the light reflex pathway and is less susceptible to compression by extrinsic lesions (dorsal midbrain syndrome) (see Chapter 22).
Vertical Eye Movements The pathways involved in controlling vertical gaze arc not fully known, and some of the neural connections discussed below arc speculative. The third and fourth cranial nerves innervate the extraocular muscles responsible for both vertical and torsional eye movements (see Chapter 16). The pre motor substrate for vertical and torsional eye movements lies in the midbrain reticular formation (MRF); however, some vertical saccades are programmed in the PPRF and relayed to the MRF via a juxta-MLF pathway, presumably to coordinate horizontal, vertical, and oblique trajectories, and head movement. The rostral interstitial nucleus of the medial longitudinal
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fasciculus (riMLF) on each side contains EBNS for both upward and downward saccades but only for ipsilateral torsional saccades. The KBNs for upward saccades are probably caudal, ventral, and medial in the riMLF and project to the elevator muscles (superior rectus and inferior oblique) bilaterally, with axons crossing within the oculomotor nucleus (Figure 39.9A) and not in the posterior commissure (PC) as previously thought (Bhidayasiri et al. 2000). The EBNs for downward saccades are more rostral, dorsal, and lateral in the riMLF, and project only to the ipsilateral depressor muscles (inferior rectus and superior oblique) (Figure 39.9B). The EBNs for vertical saccades also project to the interstitial nucleus of Cajal (INC), which plays a major role in neural integration for vertical and torsional gaze (see below) (Bhidayasiri ct al. 2002). From the INC, the pathways project dorsally and laterally to cross in the PC before turning vcntrally to the oculomotor and trochlear nerve nuclei (see Figure 39.9). The axons to the elevator muscles travel more dorsally and thus are more susceptible to extrinsic compression, such as from a pinealoma.
interstitial nucleus of Cajal (INC). Burst-tonic and tonic neurons in the region of the INC discharge in relation to vertical eye position and play a role in vertical pursuit and eye position. These neurons project to the contralateral INC and the ocular motor nuclei via the PC, which plays a critical role in vertical gaze (see Figure 39.9). Injury to the PC limits all types of vertical eye movements, particularly upward movements, although the vertical VORs and Bell's phenomenon may be relatively spared. Retinal slip, the sensory stimulus for vertical pursuit, is encoded by the dorsolateral pontine nuclei and relayed to the flocculus and posterior vermis before converging, via the INC, on the midbrain (see Figures 39.8 and 39.9). The commands for vertical pursuit pass through the pons and cerebellum before turning rostrally to reach the relevant ocular motor neurons in the midbrain.
DEVELOPMENT OF THE OCULAR M O T O R SYSTEM
While the riMLF is key for vertical saccades, the MRF also has a role because of its reciprocal connections with the SC. Each riMLF also receives input from the nucleus of the posterior commissure, the FEF, the SC, the fastigial nucleus of the cerebellum and the contralateral riMLF; the latter fibers cross in a commissure ventral to the aqueduct (see Figure 39,9). Each riMLF is supplied by a branch of the proximal posterior cerebral artery, the posterior thalamosubrhalamic paramedian artery; a single anomalous posterior thalamo-subthalamic paramedian artery (the arrery of Pcrchcron) may supply the riMLF bilaterally. Vertical saccades require bilateral supranuclear innervation from the FEF or SC, or both.
At birth, the vestibular system is the most developed of the ocular motor subsystems and is easily tested by rotating the infant, held at arm's length, with the head tilted 30 degrees forward. In normal neonates, the eyes tonically deviate in the same direction as head movement; reflex saccades develop by 2 - 3 weeks. Smooth pursuit movemenrs may be detected in neonates but only with large targets (such as a human face) at low velocities. These findings, although not well quantified, are consistent with histological maturation of the fovea after at least 8 weeks of age. Neonates can also generate the smooth pursuit component of OKN with full-field stimulation.
The neural integrator (NI) for vertical and torsional eye movements (Halmagyi et al. 1994) is located in the
Fixation is not well developed until about two months, although some infants younger than 1 month can fixate
A
UPGAZE
UPGAZE
FIGURE 39.9 Hypothetical pathways involved in controlling vertical eye movements, (A) Upward eye movements. Burst neurons for upward saccades are shown projecting from the medial rostra] interstitial nucleus of the medial longitudinal fasciculus (riMLF) to the elevator muscles, superior recti and inferior obliques bilaterally, with axons crossing within the oculomotor nucleus. Continued
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FIGURE 39.9, cont'd. (B) Burst neurons for downward saccades are shown projecting only to the ipsilateral depressor muscles, the inferior rectus and superior ohlique. The axons of the burst neurons for upward saccades also project to the interstitial nucleus of Cajal (INC), which plays a role in tun nil integration tor vertical and torsional gaze. From the INC, the axons project dorsally and laterally to cross in the posterior commissure before turning ventrally to the oculomotor and trochlear nerve nuclei. (CN-II1 = third nerve nuclear complex; CN-IV = fourth nerve nucleus; INC = interstitial nucleus of Cajal; IO — inferior oblique subnucleus; IR = inferior rectus subnucleus; PC = posterior commissure; nMLF = rostral interstitial nucleus of the medial longitudinal fasciculus; RN = red nucleus; SN = substantia nigra; SO = superior oblique nucleus; SR = superior rectus subnucleus.) (Redrawn from Bhidayasiri, R., Plant, G. T„ & Leigh, R. J. 2000, "A hypothetical scheme for the brainstem control of vertical gaze," Neurology, vol. 54, pp. 19851993.)
targets, provided the stimuli are engaging and the infant is alert. By nine weeks, 90% of full-term infants can fixate and follow the human face. Full-field OKN and larger targets stimulate the parafoveal retina, which matures earlier than the fovea. Stimulation of the saccadic system, also immature in the neonate, is influenced by the infant's attention as well as by the size and appropriateness of the target. Vertical saccades mature more slowly than horizontal saccades and may not he detected for the first month after birth. Vergence movements are also slow to mature but are seen after about the first month. Ocular alignment in the newborn is usually poor, with transient shifts from esotropia to exotropia during the first few weeks. In most infants, ocular alignment is established by 3-4 weeks but may be delayed as late as five months. Small angle esotropia and intermittent esotropia may spontaneously resolve in infants less than 20 weeks of age; constant esotropia greater than 40 prism diopters is unlikely to resolve spontaneously. Esotropia after 3 months and exotropia after 5 months are considered abnormal and require appropriate evaluation. Large-angle exotropia may be associated with craniofacial, genetic, or other neurological abnormalities. Paroxysmal phenomena are common in infancy and may be as widespread as one in four (Reerink et al. 1995).
Ocular motor anomalies may occur in the neonate without any pathological significance. About 2% of newborns have a tendency for tonic downward deviation of the eyes in the waking state; during sleep, however, the eyes assume the normal position, and the VORs are intact. Other uncommon abnormalities seen in newborns include opsoclonus, which may regress through a phase of ocular flutter, skew deviation, apparent bilateral internuclear ophthalmoplegia; transient downbeat nystagmus; and tonic upward deviation. These findings likely represent delayed maturity of the ocular motor system in neonates.
SUPRANUCLEAR. GAZE DISTURBANCES Interruption of the saccadic and pursuit pathways before they reach the eye-movement generators in the MRF and PPRF results in a loss of voluntary eye movements but relatively spares reflex movements, such as VOR, optokinetic response and Bell's phenomenon. This constellation of findings is referred to as a supranuclear gaze palsy and occurs classically in progressive supranuclear palsy (PSP) as well as a variety of disorders listed in Table 39.2. Technically, skew deviation and the ocular tilt reaction (OTR), which spare the final common efferent pathway
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Tabic 39.2:
Causes of ophthalmoplegias and gaze palsies (see also Tables 16.8 and 16.3)
Site Muscle
Neuromuscular junction
Ocular motor nerves Gaze palsies
Disorder Ocular myopathics Congenital myopathy Central core Centronudear (myotubular) Fiber-type disproportion Multicorc (ptosis, spares EOM) Noma line Neurocristopathy (EOM fibrosis) Ocu lop ha ryngo distal myopathy (Satoyoshi myopathy) (Mastaglia and Laing 1999) Autosomal dominant Autosomal recessive Reducing body myopathy (ptosis, spares EOM) Dystrophy Myotonic dystrophy (ptosis, usually spares EOM) Oculopharyngeal dystrophy Inflammatory Derma torn yositis Giant cell arteritis Orbital pseudotumor Metabolic and toxic (act at multiple sites, e.g., anticonvulsants) Mitochondrial cytopathy Kearn-Sayre syndrome Chronic progressive external ophthalmoplegia (CPEO) Pearson's syndrome POLIP syndrome (polyneuropathy, ophthalmoplegia, fcukoencephalopathy, intcstinal pseudo-obstruction) High myopia (large globes cause mechanical restriction) Infiltrative disorders (thyroid, amyloid, metastases, congenital familial fibrosis, cystinosis) Trauma (orbital entrapment) Vitamin E deficiency (associated with malabsotption) Myasthenia gravis Toxins (e.g., botulism, organophosphates) Lambert-Eaton syndrome (rarely affects the EOM, mainly causes ptosis) See Chapter 76 Nuclear and paranuclear Brainstem injury (vascular, multiple sclerosis, encephalitis, paraneoplastic, toxins, tumor) Familial congenital gaze palsy Glycine encephalopathy (nonketotic hypetglycinemia: hiccups, seizures, apneic spells) Machado-Joseph disease (SCA3) Leigh's disease Maple syrup urine disease Mobius' and Duane's syndromes (agenesis of cranial nerve nuclei) Spinocerebellar degeneration Tangier disease Vitamin E deficiency [nternuclear ophthalmoplegia One-and-a-half syndrome Prenuclear Monocular "supranuclear" elevator palsy Ocular tilt reaction Skew deviation Vertical one-and-a-half syndrome Supranuclear (predominantly horizontal) Congenital ocular motor apraxia Acutely, after hemispheric stroke Ipsiversive Contravcrsive (wrong-way eyes) Gaucher's disease (types 2 and 3) Ictal (ttansient, adversive) Con tinned
NEURO-OPHTHAI.MOI.OCY: OCULAR MOTOR SYSTEM Table 39.2,
713
Causes of ophthalmoplegias and gaze palsies (see also Tables 16.8 and 16.9]—conr'd
Site
Disorder
Gaze palsies—cont'd
Juvenile-onset GM2 gangliosidosis (mimics juvenile spinal muscular atrophy) Postictal (transient, ipsivcrsive) Paraneoplastic (prostatic adenocarcinoma) Supranuclear (predominantly vertical) Adult-onset C M ; gangliosidosis (mimics multiple-system atrophy or spinocerebellar degeneration) (V>H) Congenita] vertical ocular motor apraxia (rare) Amyotrophic lateral sclerosis (rare, V>H) Autosomal dominant parkinsonian-dementia complex with pallido-pontonigral degeneration (dementia, dystonia, frontal and pyramidal signs, urinary incontinence] Vitamin B12 deficiency (U>D) Cerebral amyloid angiopathy with leukoencephalopathy Dentatoruhral-pallidoluysian atrophy (autosomal dominant, dementia, ataxia, myoclonus, choreo athetosis) Diffuse Lewy body disease (ophthalmoplegia may be global) Dorsal midbrain syndrome (see Chapter 22 and Disorders of Vertical Gaze, later in this chapter) Familial Creurzfeldt-Jakob disease (U>D) Familial paralysis of vertical gaze Fisher's syndrome Gcrstmann-Srraussler-Scheinker disease (U>D, dysmetria, nystagmus) Guamanian Parkinson's disease-dementia complex (Lyrico-Bodig disease) HARP syndrome (^ypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration) Hydrocephalus (untreated, decompensated shunt) Joseph's disease Kernicterus (U>D) Late-onset cere be 11 o- pontomesencephalic degeneration (D>U) Neurovisceral lipidosis; synonyms: DAF syndrome (downgaze palsy-ataxia-foamy macrophages); dystonic lipidosis; Niemann-Pick disease type C (initially loss of downgaze, may become global) Pallidoluysian atrophy (dysarthria, dystonia, bradykinesia) Paraneoplastic disorders Progressive supranuclear palsy (D>U) Subcortical gliosis (U>D) Variant Creutzfeld-Jakob Disease (U>D) Wilson's disease (also slow horizontal saccades) (U>D) Supranuclear (global) Abetalipoproteinemia AIDS encephalopathy Alzheimer's disease (pursuit) Cerebral adrenoleukodystrophy Corticobasal ganglionic degeneration Fahr's disease (idiopathic striatopallidodentate calcification) Gaucher's disease Hexosaminidase A deficiency Huntington's disease Joubert's syndrome Leigh disease [infantile striatonigral degeneration) Methylmalonohomocystinuria Malignant neuroleptic syndrome (personal observation) Neurosyphilis Opportunistic infections Paraneoplastic disorders Parkinson's disease (transient gaze palsy with intercurrent infection) Pelizaeus-Merzbacher disease (H>V) Pick's disease (impaired saccades) Progressive multifocal leukoencephalopathy Tay-Sachs disease (infantile G M 2 gangliosidosis) (V>H) Wernicke's encephalopathy Whipple's disease (V>H)
AIDS = acquired immunodeficiency syndrome; D = loss of downgaze; FLOM = extraocular muscles; g1oba1 = loss of horizontal and vertical gaze; H = loss of horizontal gaze; MNCIE = mitochondrial neurogastrointestinal encephalomyopathy syndrome; OPCA = olivopontocerebellar atrophy; U = loss of upgaze; V = loss of vertical gaze.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
for eye movements, are also supranuclear, but because they are dy scon jugate, they are referred to here as prenuclear. Bilateral lesions of the fronto-mesencephalic pathways cause loss of horizontal saccades in both directions and impair vertical saccades (particularly upward) but spare pursuit, VORs, and the slow phases of OKN. Focal lesions in the PPRF can also cause selective saccadic defects (see Horizontal Eye Movements, earlier in this chapter). To evaluate disorders of gaze, first determine the range of versions (conjugate eye movements) to a slowly moving target, and then test saccades, as described in Chapter 16. If a dysconjugate defect is observed, check ductions, ocular alignment, and comitance. If a conjugate defect (i.e., a gaze palsy) is present, determine if the eyes move reflexively by testing for the oculoccphalic reflex (doll's eye maneuver) or VOR (calorics), and Bell's phenomenon (ocular deviation, usually upward, on forced eyelid closure); their presence indicates supranuclear dysfunction. With suptanuclcar gaze disorders, saccades may be impaired firsr, then pursuit, followed by loss of VORs. Causes of gaze palsies and ophthalmoplegias are outlined in Table 39.2.
Ocular Motor Apraxia Ocular motor apraxia is the inability to perform voluntary saccades; spontaneous saccades and reflex eye movements (vestibular and OKN slow phases) are preserved. The term is sometimes used loosely and incorrectly (see below), Congenital ocular motor apraxia (COMA) is more common in boys than in girls and is characterized by impaired voluntary horizontal pursuit and saccadic movements but preservation of vertical eye movements (Leigh and Zee 1999); teflex saccades may be partly retained. Because random eye movements are also absent in many of these children, the term apraxia is strictly incorrect; congenital saccadic palsy or congenital gaze palsy is more accurate (Leigh et al. 1997), but the term COMA is now established in the literatute. By 4-8 months of age, the child develops a thrusting head-movement strategy, often with ptominent blinking, to ovetcome the eye-movement deficit (see Figure 24.3). Because the VOR prevents a change in direction of gaze on head turning, the child closes the eyes to reduce the degree of reflex eye movement (the gain of the VOR falls with the eyes closed) while thrusting the head beyond the range of the VOR arc to bring the eyes in line with the target. Then, with the eyes open, the child slowly straightens the head while the contralateral VOR maintains fixation. Some patients may use the dynamic head thrust to facilitate saccadic eye movements or reflexively to induce fast phases of vestibular nystagmus. Because children with COMA cannot easily refixate or pursue new targets, particularly in the first 6 months of life, before they develop the head-thrusting strategy, they arc sometimes initially misdiagnosed as being blind.
After 6 months of age, children with COMA present because of the head thrusts. The diagnosis of COMA can be confirmed by demonstrating the inability to make saccades; this is most easily done by spinning the infant, as described in Development of the Ocular Motor System, earlier in this chapter. In normal infants, the eyes tonically deviate in the same direction as head movement; absence of reflex saccades (fast phases in the opposite direction) after 2 - 3 weeks of age is abnormal and indicates saccadic palsy. As children with COMA reach school age, pursuit and voluntary saccades variably improve. However, the condition does not completely resolve and can be detected in adulthood. COMA may be associated with hypoplasia of the cotpus callosum, hypoplasia of the cerebellar vermis in as many as 5 3 % of patients (Sargent et al. 1997), occipital porencephalic cysts, and bilateral cortical lesions. It may occasionally be familial. Strabismus, psychomotor developmental delay (particularly reading and expressive language ability), clumsiness, and gait disturbances are often associated. A similat ocular motor disordet occurs in children with Aicardi's syndrome, ataxia telangiectasia (80%), Cockayne's syndrome, Joubert's syndrome, PelizaeusMerzbacher disease, succinic semi-aldehyde dehydrogenase deficiency (Eustace et al. 1994), Wieacker's syndtome, carbohydrate deficient glycoprotein syndrome type la (Stark et al. 2000), and ataxia-oculomotor apraxia syndrome (which mimics ataxia telangiectasia, without the extraneurological features, and is probably autosomal recessive) (Gascon et al. 1995). Congenital vertical ocular motor apraxia is rare and must be differentiated from metabolic and degenerative disotdets that cause ptogtessive neurological dysfunction, such as neurovisceral lipidosis, and from stable disorders, such as birth injury, perinatal hypoxia, and Leber's congenital amaurosis. Acquired ocular motor aptaxia occuts in patients with bilateral parietal damage and with diffuse bilateral cerebral disease (see Table 39.2); the head thrusts are not as conspicuous as in the congenital vatiety.
Spasm of Fixation Spasm of fixation, a term introduced by Gordon Holmes in 1930, describes patients who have difficulty shifting visual attention because of impaired initiation of voluntary saccades when looking at a fixation target but normal initiation of saccades in the absence of such a target. Their saccades have a prolonged latency and may be hypometric in the presence of u a/urr.il visual rarurt; however, Minks or combined eye and head movements may sometimes facilitate normal saccades. Holmes stressed that fixation was an active process and attributed spasm of fixation to "exaggerated" fixation; evidence from other studies
supports this concept.
NEUKO-OPHTHALMOI,OCY: OCULAR MOTOR SYSTEM
The lesions that cause spasm of fixation may be bi hemispheric and interrupt indirect FEF projections via the caudate nucleus and SNr (see Horizontal Eye Movements, earlier in this chapter) to the SC. Normally, during saccades to auditory, visual, and remembered targets, neurons in the FEFs discharge via these pathways and disinhibit the SC to allow the saccades and disengage fixation. Interruption of these, and perhaps oilier path ways, might contribute to spasm of fixation by maintaining tonic inhibitory suppression of saccades by the SC (Leigh and Zee 1999).
Familial Horizontal Gaze Palsy Familial horizontal gaze palsy with scoliosis (HGPS) is an autosomal recessive disorder characterized by paralysis of horizontal gaze from birth, impaired OKN and VORs but intact convergence, vertical eye movements, and progressive scoliosis (Leigh and Zee 1999). HGPS maps to chromosome l l q 2 3 - 2 5 in some kindreds (Jen et al. 2002). Types of nystagmus described in HGPS include a fine pendular horizontal nystagmus, upbeat nystagmus, and see-saw nystagmus (Pieh et al. 2002). Individuals in some families may also have facial myokymia, facial twitching, hemifacial atrophy, and situs invetsus of the optic discs. Neutoimaging may demonstrate brainstem dysplasia, particularly pontine hypoplasia (Pieh et al. 2002). HGPS is one of a spectrum of disorders of maldevelopment of cranial nerve nuclei that include Duane's syndrome (see Chaprer 16), Mobius syndrome, the congenital fibrosis of the extraocular muscles syndromes, and congenital ptosis (Engle and Leigh 2002),
Acquired Horizontal Gaze Palsy Transient gaze deviation, usually of the head and eyes, occurs in about 2 0 % of patients with acute hemisphere stroke and other insults. The eyes are usually deviated toward the side of the lesion (ipsiversive gaze deviation} because of gaze paresis to the hemiplegic side (i.e., paralysis of gaze and limbs is on the same side). In stroke patients, right-sided lesions are more common but smallet; consequently, patients with left-sided lesions (gaze deviation to the left) have a worse prognosis. Ipsiversive gaze deviation occurs more often when the inferior parietal lobule (IPL) or circuits between the FEFs and the IPL or their projections to the brainstem (SC or PPRF) are involved; the FEFs are usually spared. After about 5 days, the intact hemisphere, which contains neurons for bilareral gaze, takes over; thereafter, subtle abnormalities such as prolonged saccadic latencies and impaired saccadic suppression can be detected only by quantitative oculography. Because the premotor neural network for voluntary horizontal eye movements in the PPRF is composed of subclasses
715
of neurons with different functions, selective lesions may affect some types of eye movement while sparing others (see Horizontal Eye Movements, earlier in this chapter). A lesion affecting the ipsilateral abducens nucleus or PPRF causes ipsilateral gaze palsy; a rostral PPRF lesion spares the VOR, whereas a caudal lesion does not. Paraneoplastic brainstem encephalitis can cause supranuclear, internuclear, or nuclear damage, resulting in selective loss of voluntary horizontal and vertical saccades (Crino et al. 1996). Patients with prostatic adenocarcinoma may, after an interval of 3—4 years, develop paraneoplastic gaze palsies followed by severe facial and bulbar muscle spasms (probable sustained myoclonus), diplopia, and respiratory insufficiency (Baloh et al. 1993). Other neurological features that may be associated with such paraneoplastic disorders include ataxia, hypcracusis, muscle spasms, myoclonus, periodic alternating gaze deviation (PAGD), and vertigo. Magnetic resonance imaging is often unrevealing, particularly in the early stages, but auditory evoked potentials and cerebrospinal fluid analysis may be abnormal. Clonazepam, valproic acid, and botulinum may help the myoclonus and muscle spasms. Other causes of horizontal gaze palsies are listed in Table 39.2,
Wrong-Way Eyes Conjugate eye deviation to the "wrong" side (i.e., away from the lesion and toward the hemiplegia [contraversive gaze deviation]) may occur with supratentorial lesions, particularly thalamic hemorrhage, and, rarely, large perisylvian or lobar hemorrhage. The mechanism is unclear, but possibilities include the following: 1. An irritative or seizure focus causing "contraversive ocular deviation" is unlikely because neither clinical nor electrical seizure activity has been reported in these patients. 2. Because eye movements are represented bilaterally in each frontal lobe, it is conceivable that the center for ipsilateral gaze alone may be damaged, resulting in contraversive ocular deviation. 3. An irritative lesion of the intralaminar thalamic neurons, which discharge for contralateral saccades, could theoretically cause contraversive ocular deviation (Leigh and Zee 1999). 4. Damage to the contralateral inhibitory center could also be responsible. Postictal "paralytic" conjugate ocular deviation occurs after adversive seizures as part of Todd's paralysis. Spasticity ol conjugate gaze (lateral deviation ot both eyes away from the lesion) during forced eyelid closure, a variant of Bell's phenomenon, can occur in patients with large, deep parietotemporal lesions; eye
716
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
movements are otherwise normal except for ipsilateral saccadic pursuit. Psychogenic ocular deviation can occur in patients feigning unconsciousness; the eyes are directed toward the ground irrespective of which way the patient is turned.
Periodic Alternating Gaze Deviation Periodic Alternating Gaze Deviation (PAGD) is a rare cyclical ocular motor disorder in which the direction of gaze alternates every few minutes. Lateral deviation can he sustained for up to \5 minutes; gaze then returns to the midline for 10-20 seconds before changing to the other side. Occasionally, PAGD is associated with structural lesions, such as pontine vascular disorders; Chiari malformations; congenital absence or abnormalities of the inferior cerebellar vermis, the uvula, and nodulus; CreutzfeldtJakob disease involving the flocculonodular lobe; spinocerebellar degeneration; occipital cnccphaloceles; and paraneoplastic brainstem encephalitis (Baloh et al. 1993). A reversible form of PAGD occurs with hepatic encephalopathy and is attributed to derangement of GABA metabolism (Averhuch-Heller and Meiner 1995}. PAN (sec Chapter 16) has a similar time cycle to PAGD and also results from lesions of the uvular and nodular regions. Indeed, PAGD may be PAN with loss of corrective saccades because of concomitant saccadic palsy or immaturity of the saccadic system in infants. Other cyclical ocular motor phenomena, including cyclical esotropia, cyclical oculomotor palsy, springing pupil, alternating skew deviation, and PAN, are discussed in the appropriate sections.
toward the side of the lesion. Saccadic lateropulsion occurs with lesions of the lateral medulla (most commonly ischemic) involving cerebellar inflow (inferior cerebellar peduncle). Saccadic lateropulsion with a bias away from the side of the lesion (contrapulsion) may occur with lesions involving the region of the superior cerebellar peduncle (outflow tract) and adjacent cerebellum (superior cerebellar artery territory) (Halmagyi 1994), Pulsion of vertical saccades, with a parabolic trajectory, occurs in patients with lateral medullary injury. Both upward and downward saccades deviate toward the side of the lesion, with corrective oblique saccades, whereas in those with lesions involving cerebellar outflow, vertical saccades deviate away from the side of the injury (Halmagyi 1994).
Torsional Saccades Pathological rapid torsional eye deviation during voluntary saccades may occur with large lesions involving the midline cerebellum, deep cerebellar nuclei, and dorsolateral medulla. The amplitudes of these torsional saccades (blips) are larger for ipsilesional (hypermetric) than for contralesional (hypometric) horizontal saccades. Eye movement recordings using a scleral search coil (see Eye Movement Recording Techniques, later in this chapter) demonstrated that the "blips" are followed by an exponenrially slow (see Chapter 16) torsional drift toward the initial torsional eye position. These blips may be a form of torsional saccadic dysmetria (Helmchen et al. 1997).
Slow Saccades
Ping-pong gaze is a conjugate horizontal rhythmic oscillation that cycles every 4-8 seconds (short-cycle PAGD) and occurs in comatose patients as a result of bilateral cerebral or upper brainstem damage (e.g., disconnection) or metabolic dysfunction. Ping-pong gaze implies that the horizontal gaze centers in the pons are intact. The prognosis for recovery is poor except in patients with a toxic or metabolic cause (Johkura et al. 1998).
Saccades of low velocity result from pontine disease, presumably because of burst cell dysfunction. They occur in patients with olivopontocerebellar degeneration and other disorders listed in Table 39,3. Some patients with hypometric saccades (see Chapter 16, Figure 16.18C), composed of multiple small-amplitude steps (as in myasthenia, Huntington's disease, brainstem encephalitis, and srriatonigral degeneration) appear to have slow saccades clinically (pseudo-slow saccades), but each small saccadc has a normal velocity-amplitude relationship.
Saccadic Lateropulsion
Prolonged Saccadic Latency
Saccadic lateropulsion is characterized by hypermetric (overshoot) saccades (see Chapter 16, Figure 16.1 SB) to the side of the lesion (ipsipulsion) and hypometric (undershoot) saccades (see Chapter 16, Figure 16.18C) to the opposite side. In darkness or with the eyelids closed, the patient may have conjugate deviation
Disorders of saccadic initiation, resulting in prolonged latencies for voluntary saccades, occur in patients with inattention acquired immunodeficiency syndrome (AIDS)dementia complex and a variety of encephalopathies and degenerative disorders of the nervous system, such as Alzheimer's, Huntington's, and Parkinson's disease.
Ping-Pong Gaze
NEURO-OPHTHALMOLOCY: OCULAR MOTOR SYSTEM Table 39.3;
717
Slow saccades
AIDS-dementi a complex Amyotrophic lateral sclerosis Anticonvulsant toxicity (consciousness usually impaired) Ataxia-telangiectasia Hexosaminidase A deficiency Huntington's disease Internuclear ophthalmoplegia (slow abduction) Joseph's disease Lesions of the paramedian pontine reticular formation Lipid storage diseases Long-standing cholestasis (proba hie vitamin E deficiency) Lytico-Bodig disease (Guamanian ALS-PD-dementia complex) Myotonic dystrophy Nephropathy cystinosis Ocular motor apraxia Ocular motor nerve or muscle weakness Olivopontocerebellar degeneration (ADCA type I) Progressive supranuclear palsy Wernicke's encephalopathyWhipple's disease Wilson's disease ADCA = autosomal dominant cerebellar ataxia; AIDS = aequired immunodeficiency syndrome; ALS-PD = amyotrophic lateral sclerosis-Parkinson'sdisease.
Square W a v e Jerks Square w a v e jerks (SWJs) (Table 39.4) a r e s p o n t a n e o u s , small-amplitude paired saccades with an intersaccadic latency of 1 5 0 - 2 0 0 ms t b a t briefly interrupts fixation (Figure 3 9 . 1 0 ) . They m a y occur physiologically in n o r m a l Table 39.4:
Square wave jerks
Normal subjects (, J-Bir, JMD, J-47) found by isolation of deletion junctions with pERT K7 probes arc shown connected to the DXS164 locus. Probe pERT84 and the untelated probes GMGX11 and P20 are shown in their approximate positions. The size of the gene is about 2 Mb. the observed increasing clinical severity of the autosomal dominant myotonic dystrophy gene over subsequent generations (Harper 2001). Typically, a father might have early-onset cataracts, his daughter mild muscle weakness and myotonia, and the daughter's child severe weakness and myotonia associated with mental retardation. This repeatedly observed clinical observation of increasing disease severity across generations has now been given a biologic foundation. Myotonic dystrophy is caused by the expansion of a trinucleotide repeat in the dystrophia myotonia protein kinase {DMPK) gene on chromosome
Three of these repeat diseases, however, are caused by repeat expansions in noncoding regions of the gene. In fragile-X syndrome, there is an expanded CGG repeat in the 5' untranslated region of the FRX-1 gene. Methylation of this sequence is associated with suppressed expression of the FRX-1 gene. Because FRX-1 is on the X-chromosome, males have only one copy of the gene and inactivation results in the fragile-X syndrome of mental retardation. In Friedreich's ataxia, an expanded repeat is present in an intron of the frataxin gene and is thought to decrease gene expression, Friedreich's ataxia is a recessive disease and both alleles have an expansion or mutation in affected individuals. In the most common form of myotonic dystrophy the repeat expansion occurs in the 3' untranslated region of the DMPK gene on chromosome 19. Therefore the repeat is present in the mRNA after the stop codon and does not alter the ORF for the protein. It has been demonstrated that the repeat can decrease DMPK expression by interfering with RNA processing and nuclear transport. The expanded CUG repeat in the RNA appears to cause the disease. Indeed, a similar myotonic dystrophy (DM2) is caused by the expansion of a CCTG repeat in the intron of the ZNF9 gene on chromosome 3, resulting in a CCUG repeat in the RNA. Trinucleotide repeat expansions have formed the basis of rapid diagnostic tests for their associated diseases. Polymerase chain reaction (PCR) (see later) and Southern hybridization to genomic DNA obtained from blood samples can be used to determine the repeat size in individuals. The presence of an expansion indicates that the individual inherited the mutation that can cause the disease.
794
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES Disorder
Chromosome
Normal
17 p 11.2
Gene/mutation 1.5 Mb
//
Q
CLINICAL NEUROGENETICS
79S
7%
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Interpretation of the results, however, can be complex (BirdI 1999). For example, having the expansion is not the same as; having the symptoms of the disease. Nor does it accuratelyr predict the age of onset or severity of disease for anyr individual. In many cases there is significant somatic: heterogeneity of repeat length, meaning that the expansioni size might be different in blood cells compared with other tissues, such as brain or muscle. Therefore althoughi expansion length roughly correlates with disease onscr andI severity when analyzing a large population, the correlationi is not sufficient to accurately predict the course of the: disease in any single individual. Furthermore, an individualI can have an expansion that is in an intermediate range between the normal and the affected populations (e.g., 29 to> 35 repeats in the HD gene). This ambiguity is a difficult: issue for both patients and physicians because their association with the disease phenotype is not clear. Finally, in some of these syndromes a few patients have been described who have the clinical characteristics of the disease but do' not have an expanded repeat at the disease locus. In summary, the ability to directly test for repeat size has dramatically improved our ability to identify people at risk for these inherited syndromes, but we still have much to learn about the application of this knowledge to patient care.
TOOLS OF GENETIC RESEARCH
construct a restriction map, showing the cutting sites for the various enzymes in relation to one another, The technique used to detect specific sequences of DNA is Southern blotting, named after its originator. The DNA of interest is digested into short fragments by one or more restriction enzymes, and gel electrophoresis is used to separate the fragments by size. The DNA is then denatured to the single-strand form and transferred by blotting with paper towels to a more stable medium, nitrocellulose filter membrane. The pattern of DNA fragments on the gel is faithfully transferred to the filter membrane. The resulting blot can be baked to make it more permanent and can then be hybridized to a specific probe. Using autoradiography, the fragment(s) of interest can be visualized on the blot (Figure 44.17). Because the size of each DNA fragment is determined by position of the sequence recognized by the restriction enzyme used to cleave the DNA, polymorphisms that alter a restriction site will result in a change in the size of a DNA fragment (Figure 44.17B), These RFLPs have been used in linkage analysis (see later). By analogy to Southern blots, the transfer of RNA molecules is called Northern blotting, and the transfer of proteins is Western blotting. (Northern and Western do not derive from names of scientists,)
Vectors
Restriction Endonucleases Certain bacterial enzymes have the ability to cleave foreign DNA into fragments, their site of action being restricted to specific sites within the molecule. This function appears to be an evolutionary development that protects the organism's own DNA from incorporating foreign DNA. Each restriction cndonuclease can recognize a specific DNA sequence (restriction site) several bases in length and cut a strand of foreign DNA at a particular position within that sequence. The sequences on the paired strands at which a restriction enzyme cuts arc palindromic; that is, the sequences on the two strands read the same but in opposite directions. For example, the restriction enzyme Hindlll cuts a duplex strand of DNA as follows: 1. 5'A | A G C T T 3 ' 2. 3' TTCGA | A 5' If the same enzyme is used to cut both the DNA of the vector and the DNA to be incorporated into it, the cut ends of the foreign and host DNA may join by complementary base pairing, thereby incorporating the foreign DNA into that of the vector. After base pairing, the ends of the strands are sealed together by the enzyme DNA ligasc (which tequires ATP), The fragments of the DNA produced by restriction enzymes along a particular DNA segment can he used to
Vectors arc prokaryotic organisms, or DNA molecules, into which foreign DNA can be grafted for cloning. Four types are commonly used: plasmids, phages, cosmids, and yeast artificial chromosomes (YACs). Plasmids are small, circular duplex DNA molecules within bacteria and yeast that replicate independently of the host chromosome. The genes they carry may be of great importance for the survival of the host cell, such as genes for antibiotic resistance. The plasmids used for DNA cloning have been constructed with three essentia] features: (1) an origin of DNA replication allowing the recombinant DNA molecule to replicate in the host; (2) a marker such as a gene for antibiotic resistance that can be used to select for bacterial cells containing the plasmid; and (3) a region into which small fragments (sphof|-uctokmasir/glyLogenosis type Vll Charcot-Marie-Tooth (CMT-1 B) Glucocerebrosidase/Gaucher's disease Nemaline myopathy (a tropomyosin) Alzheimer's, familial early onset (presenilin 2) 11\ pokalemic periodic paralysis (calcium channel) Rippling muscle disease Usher syndrome type 2 (deafness/ret in o pa thy) Retinitis pigmentosa Myoshimyopathy Limb girdle muscular dystrophy (LGMD 2B) Congenital myasthenic syndromes/" slow-channel'" syndrome (SCS) Familial spastic paraplegia (1) Holoproscnccphaly type 1 Xeroderma pigmentosum Nemaline myopathy (nehulin) Cerebrotcndinous xanthomatosis (sterol 27 hydroxylase) Paroxysmal dystonic choreoathetosis Amyotrophic lateral sclerosis (recessive) SCA 15 Dominant ataxia with retinal dystrophy (ADCA type II; SCA7) Xeroderma pigmentosa Limb girdle muscular dystrophy (LGMDIC) Rcra-galactosidasc ]/GM| gangliosidosis von Hippel-Lindau disease Retinitis pigmentosa (rhodopsin) Retinitis pigmentosa (ROM) Usher syndrome type 3 (deafness/retinoparhy) Essential tremor Myotonic dystrophy 2 (DM2) Blcpharophimosis/ovarian failure Retinitis pigmentosa (PDE) Huntington's disease Hurler and Hurler-Scheie syndrome Muscular dystrophy (limb-girdle, LGMD2K; fl sarcoglycan) Mucolipidosis types II and III Abetalipoprotcinemia (Rassen-Kornzweig) FSH muscular dystrophy D i h yd r o fo 1 a te red u eta sc/d cfic i e n cy Infantile/juvenile spinal muscular atrophy i levosiiiiiinidase !'. Sandhoffs disease Dominant limb girdle muscular dystrophy Type 1A SCA 12 CMT4C Muscular dystrophy (Limb-girdle, LGMD2F; f> sarcoglycan) Hfyperekplexia (startle disease; glycine receptor) Branch chain kctoacid dehydrogenase F.i/maplc syrup urine disease SCA 1 (spinocerebellar ataxia) Juvenile myoclonic epilepsy
Chromosome lp22-qter lp31 Ip34-p36.1 lp34 Ip.M lp35-36 \pM IP lp32-12 lcen-q32 lq22-23 Iq2l lq21-23 lq31-42 lq.il Iq41 iq iq 2pl2-14 2 p l 3 If, 2q 2p21-24 2p21 2q21 2q21.2-q22 2q33-qter 2q34 2q33-35 3p 3pl2-p2l.l 3p25 3p25 3pter-3p21 3p26-25 3q 3q 3q ?ql3 3q21 3q22-23 4pl6.3 4pl6.3 4pl6.3 4ql2 4q21-q23 4q24 4q35-ter .Sqll.2-ql3.2 5q 11.2-13.3 5ql3 5q22-34 5u3 1 5q23-33 5q33-q34 5q 6p22-p21 6p24 6p24
Inheritance pattern AR AR AR AR AD AD AR AD AR AR AD AR Al) AD AD AD AR AR AR AR AR Alt AD AR AR AR AD AR AD AD AR AD AR AD AD AR AD AD \D AD AR AD AR AR AR AR AD AD AR AR AD AD AR AR AD AR AD AD Continued
S04
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Tabic 44.4:
Chromosomal assignments of selected autosomal neurological disorders—cont'd
Disorder
Chromosome
Retinitis pigmentosa (periphenn) Congenital muscular dystrophy (mcrosin/laminin deficient) Lafora body myoclonic epilepsy SCA 17 Myopathy due to phosphoglyccrare mutasc deficiency Argininosuccinatc lyase/argininosuccinicaciduria Retinitis pigmentosa Retinitis pigmentosa type 10 Cavernous malformations of the brain Zellweger's syndrome type 1 (cerebro-hepato-renal) Myotonia congenital Holoprosencephaly type 3 Familial spastic paraplegia (recessive) Progressive epilepsy with mental retardation Retinitis pigmentosa typi .: Hereditary motor and sensory neuropathy-Lorn (with deafness) Ataxia, vitamin H deficiency; alpha tocopherol transport protein defect Benign neonatal seizures (EBN2; K1 channel) Charcot-Marie-Tooth (CMT-4A) SCA 16 Hereditary inclusion body myopathy, recessive Ga lactose-1-phosphate uridylrransferase/galacroscmia Friedreich's ataxia Hereditary sensory neuropath)' type 1 Walker-Warburg syndrome (WWS) Fukuynma congenital dystrophy Familial dysautonomia Sequin/amylin neuropathy, Finnish type (gelsolin) Torsion dystonia (some families) Ataxia oculomotor apraxia Coproporphyrinoxidase/coproporhyria Xeroderma pigmentosa Tuberous sclerosis (TSC1) Usher Syndrome ID (deafness/retinopathy) Epilepsy, simple partial with auditory features Ataxia, infantile onset G1 yco p rote i n n eu ra m i n i da se/si a 1 i dos is SCA 5 (spinocerebellar ataxia) Usher syndrome type [C (deafness/retinopathy) Niemann-Pick types A and B (sphingomyelinase) Usher syndrome type IB (deafness/retinopathy; myosin VII A) Retinitis pigmentosa (ROM) Tuberous sclerosis (some families) Usher syndrome ID (deafness/retinopathy) CY1T4B Ataxia telangiectasia Acute intermittent porphyria Apolipoprotein Al/amyloid neuropathy, Iowa type McArdlc's disease (myophosphorylase) Dentato-rubro-pallido-luysian atrophy; (DRPLA) F.pisodic ataxia/myokymia (K ' channel) Congenital fibrosis of the extraocular muscles Lipofuscinosis, late infantile Phenylalanine hydroxylase/phenylketonuria SCA 2 (spinocerebellar ataxia) Distal hereditary motot neuropathy type 11 British dementia SCA8
6p2 1 6q2 6q24 6q27 7pl3-pl2.3 7ptet-q22 7pl5.1-pl3 7q ?q • 7q 11.23 7q35 7p36 8q 8p 8pll-q21 8q24 .So 1 5
8q 8ql3-21 8q22-24 9q1 9ql3 9ql3-21.l 9q22.1-q22.3 9q3l-33 9q31-33 9q31-33 9q33 9q34 9q34 9 9q34 9q34.1-34.2 lOq I0q22 10q23-24 10 11 Up Upl5 Ilql3.5 1 lql 3 1 lq 14-23 lOq llq23 Uq23 1 lq23.2 11q23-q24 llql3 I2p 12-ter I2pl3 12cen 12q21-32 12q22-q24.2 I2q23-24.1 12q24 13 I3q
Inheritance pan em AD AR AR AD AR AR AD AD AD AR AD AR AR AR AD AR AR AD AR AD AR AR AR AD AR AR AR AD AD AR AD AR AD AR AD AR AR AD AR AR AR AD AD AR AR AR AD AD AR AD AD AD AR AD AD AD AD 'AD Continued
CLINICAL NEUROGENETICS Table 44.4:
805
Chromosomal assignments of selected autosomal neurological disorders—cont'd
Disorder
Chromosome
Inheritance pattern
Spastic ataxia (ARSACS) Muscular dystrophy LGMD 2C Wilson's disease Retinoblastoma Spastic paraplegia (SPG 3A, atlastin) Distal myopathy himilial Alzheimer's (early onset; presenilin 1) Krabbe's leukodystrophy SCA 3 (Machado-Joseph disease) Usher syndrome type 1A (deafness/retinopathy) Familial spastic paraplegia (2) Dopa-responsive dystonia Protoporphyrin oxidase/variegate porphyria Oculopharyngeal muscular dystrophy Angelman's and Prader-Willi syndromes SCA 1 1 Recessive limb girdle muscular dystrophy type 2A Hexosaminidase A/ray-Sachs disease Peripheral neuropathy and agenesis of the corpus callosum Familial spastic paraplegia (3) Infantile convulsions/paroxysmal chorcoathetosis Tuberous sclerosis (TSC2) Juvenile lipofuscinosis {Batten's disease) Bardct-Bicdl (mental retardation, retinitis pigmentosa, Polydactyly) SCA 4 (spinocerebellar ataxia) Spastic paraplegia (SPG7, paraplcgin) Giant axonal neuropathy Charcot-Marie-Tooth (CMT-1A; duplication) Neuropathy, recurrent, with pressure palsies (HNI'P; deletion) Retinitis pigmentosa Congenital myasthenic slow channel syndrome Canavan leukodystrophy Miller-Dicker syndrome, lissencephaly Limb-girdle muscular dystrophy (LGMD2D; a sarcoglycan) Frontotemporal dementia/parkinsonism (FTDP-17) (Pompe disease) acid alpha-glucosidase/acid maltase deficiency Sjogren-Larsson syndrome (ichthyosis, spasticity, MR) Neurofibromatosis NF1 Muscle sodium channel disorders (hyperkalemic periodic paralysis, atypical myotonia congenita, paramyotonia congenita) Niemann-Pick type C Familial amyloid neuropathy (transthyretin) Episodic ataxia with nystagmus Hereditary hcmiplcgic migraine Spinocerebellar ataxia (SCA6) Mannosidosis Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADS1L) SCA 13 and SCA 14 Malignant hyperthermia (ryanodine receptor) Central core myopathy (ryanodine) Myotonic muscular dystrophy Epilepsy with febrile seizures plus Familial Alzheimer's (late onset; APOF.4 related) Retinitis pigmentosa Cystatin C/Icelandic amyloid angiopathy PKAN (Hallervorden-Spatz) Familial prion dementias (Creutzfeldt-Jakob, Gerstmann-Straussler diseases)
13qll 13ql2 13ql4.2 13ql4.2 14q 14qll 14q24.3 14q24.3-32 14q24.3-32 14q32 14q 14q 14q 14qll.2-ql3 15q 11-12 15q 14-21 15ql5-?22 15q23-24 15q I5q 16p 16pl3.3 16pl2 I6q 16q24 16q24 16q24 17pll.2 17p-ll.2 I7pI3.3 I7p 17pl3 17p-13.3 17ql2-q21.33 I7q21-q22 17q23 l-i 17qll,2 17q22-24
AR AR AR AD AD AD AD AR AD AR AD AD AD AD Sporadic AD AR AR AR AD AD AD AR AR AD AR AR AD AD AD AR AR Sporadic AR AD AR AR AD AD
I8p I8qll.2-I2.1 19pl3 19pl3 19pl3 19p I9ql2
AR AD AD AD AD AR AD
9ql3 I9ql3.1 19ql3.1 19ql3.2 19ql3 19q I9q 20pl 1.22-11.21 20pl3 20ptcr-pl2
AD AD AD AD AD AD AD AD AR AD ( '.unturned
806
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NFUROSCIENCES
Table 44.4:
Chromosomal assignments of selected autosomal neurological disorders—cont'd
Disorder
Chromosome
inheritance pattern
Familial benign neonatal convulsions (EBN1; K + channel) Epilepsy, nocturnal frontal lobe Familial Alzheimer's (APP gene, early onset) Familial amyotrophic lateral sclerosis (some families) Bethlem myopathy (Collagen type VI) Cystathionine bcta-synthasc/homocystinuria Dutch hereditary cerebral hemorrhage; APP gene (codon 693) Myoclonic epilepsy (Unverricht-Lundborg) SCA 10 Neuroaxonal dystrophy Cytochrome P450 HD/debrisoquine sensitivity Metachromatic leukodystrophy (arylsulfatasc A) Bilateral acoustic neurofibromatosis (NF2)
20q, 13 20ql3.2-ql3.3 21qll-22 21q22.1-22.2 21q22.3 21q22.3 21q21.2 21q22.3 22qI3 22q 13-qter 22ql3.1-ql3.2 22q13.3-qter 22qll-13.1
AD AD AD AD AD AR AD AR AD AD AD AR AD
AD = autosomal dominant; AR = autosoma! recessive; MR = mental retardation; SCA = spinocerebellar ataxia.
for inheriting the pertinent gene. Risks a l w a y s need to be put into c o n t e x t and perspective. For e x a m p l e , with each pregnancy all n o r m a l couples take a 2-A% risk of having a child with birth defects. It is often unpredictable h o w any given person will react to a risk probability for inheriting a disease. Some people will find a 5 0 % risk of no great concern, whereas others m a y find a 1% risk to be very disturbing. Obviously, the perceived severity or b u r d e n of the disease is of major i m p o r t a n c e . Physicians, patients, a n d other family m e m b e r s m a y not agree as to w h a t constitutes a " s e v e r e " disease. In addition to risk estimates, t h e
Table 44.S:
counselor m u s t give a description of expected s y m p t o m s and signs, n a t u r a l history of t h e disease, variability of expression, a n d long-term p r o g n o s i s . Potential treatment o p t i o n s m u s t also be discussed. Physicians are a c c u s t o m e d to c o n s i d e r a b l e variability in s y m p t o m s a n d prognosis of various diseases, but these ambiguities can be difficult concepts for m a n y patients. T h e p r e s y m p t o m a t i c diagnosis of n e u r o g e n e t i c disorders is b e c o m i n g m o r e c o m m o n . H u n t i n g t o n ' s disease has been a m o d e l in this regard. By D N A testing for t h e trinucleotide r e p e a t e x p a n s i o n o n c h r o m o s o m e 4 , carriers o f the H D
Regional assignments of selected X-linked neurological disorders
Kallman anosmia-hypogonadism Aicardi's syndrome (MR, seizures, agenesis corpus callosum) CMTX2 Mental retardation, nonspecific (1) 1 Hichcnne's/Becker's muscular dystrophy (dystrophin) Retinitis pigementosa type 3 Ornithine transcarbamylasc deficiency Retinitis pigmentosa type 2 Norrie's disease (retinal malformation, deafness, MR) Menkes' kinky hair Cha rcot- M a r i e -Too th (CMTX; connexin 32) Ataxia/sideroblastic anemia Mental retardation, nonspecific (2) X-linked spastic paraplegia (1) Lubag dystonia parkinsonism Choroidcremia Spinal-bulbar muscular atrophy (Kennedy's disease) Fabry's disease (tnhexoside storage) MR = mental retardation.
Xp22.3 Xp22 Xp22.2 Xp22 Xp21.2 Xp21.1-pll.4 Xp21.1 Xpl 1.4-11.2 Xpll.4-11.3 Xpll-qll Xql3-q21 Xql3 Xqll-ql2 Xq13-22 Xq21 Xq21.2 Xq2l.3-ql2 Xq22
Pelizaeus-Merzbacher disease Coffin-Lowry (MR, seizures, dysmorphic) l.isseriu-phaly subcortical hand hererorypia Lowe's oculocercbral renal syndrome CMTX3 Lesch-Nyhan HGPRT deficiency Iduronate 2-sulfatase/Hunter's syndrome Fragile X/mental retardation Deutan and protan colot blindness Adrenoleukodystropby X-linked spastic paraplegia (2) Fmery-Dteifuss muscular dysttopby X-linked myotubular central nuclear myopathy X-linked hydrocephalus (aqueductal stenosis) Bilateral periventricular nodular heterotypia Rett's syndrome
Xq22 Xq22 Xq22.3 Xq25-q26.1 Xq26 Xq26 Xq27.3-q28 Xq27.3 Xq28 Xq28 Xq28 Xq28 Xq28 Xq28 X28 Xq28
CLINICAL NEUROGENETICS Table 44,6:
807
Neurological disease genes classified by function
Gene class
Disease
Protein
Chratnosome
Structural gents
Duchenne's muscular dystrophy (DMD) Becker's muscular dystrophy Paramyotonia congenita Hypcrkalemic periodic paralysis 1 lypokaleinic periodic paralysis Myotonia congenita Episodic ataxia/myokymia Epilepsy, benign neonatal (2 rypes] Charcot-Marie-Tooth disease (CMT-1A) Hereditary neuropathy with liahiliry to pressure palsies (HNPP) CMT-1B X-linkcd C M T Alzheimer's disease Retinitis pigmentosa Startle disease (hyperekplexia) Neurofibromatosis 2 (NF2) Neurofibromatosis 1 (NF1) Retinoblastoma von Hippcl-Lindau disease Tuberous sclerosis TSC1 I uberous sclerosis TSt 1 X-linked adrenoleukodystrophy Menkes' syndrome Wilson's disease Eragilc-X mental retardation Huntington's disease [HD} Myotonic dystrophy Spinocerebellar ataxia {SCA 1) Spinocerebellar ataxia (SCA 2) Macha do-Joseph disease (SCA 3) Spinocerebellar ataxia (SCA 6} Spinocerebellar ataxia (SCA 7) Kennedy's spi na 1 -b u 1 b a r muscular atrophy De ntato - ru b ra 1- pa 11 id o-l u ys i a n atrophy Familial amyotrophic lateral sclerosis (AI.S) CMT-1B Miller-Dieker syndrome Retinitis pigmentosa Leigh's disease MERRF MELAS Leber's optic atrophy Kcarns-Sayrc disease Crcutzfekk-Jakob disease Ccrstmann-Straussler-Sheinker syndrome Familial fatal insomnia Retinoblastoma von 1 lippcl 1 ind.ni JisiMsi' Myotonic dystrophy 2 (DM2] Rett's syndrome Myotonic dystrophy 1
Dystrophin
Xp21.2
Dystrophin Sodium channel Sodium channel Calcium channel Chloride channel Potassium channel Porassium channels
Xp21.2 17q23.1-25.3 17q23.1-25.3 lq31 7q35 12pl3 8q;20q
PMP-22
17p11.2
PMP-22
17pll.2
P0 myelin Cunnexin32 Amyloid precursor protein (APP) Rhodopsin Glycine receptor Merlin Neurofibromin Kb Unknown Hammertin Tuberin ALDP Copper transport protein Copper transport protein IMRI Huntingtin Myosin kinase Ataxin Unknown Unknown Unknown Unknown Androgen receptor
tq21,2-23 Xq13 21q21.3-22.05 3q 5q 2 2 q l 1.21-13.1 17qll,2 13ql4.1-14.2 3p25 9q34 16pl3.3 Xq28 Xql3.3 13ql4.3 Xq27,3 4q!6.3 19ql3.3 6p23-24 12q23 14q 19pl3 3pl2 Xq21.3-22
Unknown
12
Superoxide disinutase (SODI)
21q22.1-22.2
I'O myelin protein G-proteins Rhodopsin O X P H O S pathway O X P H O S pathway O X P H O S pathway O X P H O S parhway O X P H O S pathway Prion protein (PrP} PrP
lq21.2-23 17pl3.3 3q
PrP Rb Unknown ZNF9 MeCP2 DMPK
20prcr-pl2 13q 14.1-14.2 3p25 3q21 Xq28 I9ql3
Myotonic dystrophy 2 (DM2)
7.NF9
3q21
Tumor suppressor genes
Transport protein genes
Trinucleotide expansion genes
Cell protection genes Signaling molecules
Mitochondrial genes
Prion proteins
Cell cycle genes Nuclear regulatory factors Potential diffuse RMA toxic effect
20prer-pl2 2()prer-pl2
Source: Adapted, updated, and reprinted with permission from Greenstein P & Bird T.D. 1994, "Neurogenetics: triumphs and challenges," West) Med, vol. 161, pp. 242-245. MELAS — mitochondrial, encephalopathy, lactic acidosis, and strokelike episodes; MERRF myoclonic epilepsy, ragged red fibers.
SOS
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
gene can now be fairly reliably detected, as described previously (the exception being the equivocal range of 33 to 35 repeats). This means we have the ability to discover who has inherited the gene for a severe, progressive, incurable, fatal degenerative brain disease. At the same time, we are unable to predict age of onset or severity of the disease with much accuracy. These issues raise serious problems for both the physician and the patient, including the patient's motivation for having the test, the patient's emotional reaction to the result, and potential long-term implications for employment and insurance. Detailed discussions of these medical and ethical issues are available (Bird 1999; Guidelines 1994; Hersch et al. 1994). Finally, genetic counseling should include opportunities fot follow-up and long-term contact with the patient. The patient must be given an opportunity to ask questions. Additional testing of the patient and other family members may be necessary. Detailed genetic counseling often involves a long-term process involving months or years, and it becomes a basic thread in the fabric of good medical care.
REFERENCES Alberts, R., Bray, D., Lewis, J., et al, (eds) 2002, Molecular Biology of the Ceil, 4th ed, Garland Publishing, New York and London Bird, T. D. 1999, "Risks and benefits of DNA testing for neurogenetic disorders," Semin Neurol, vol. 19, pp. 253-259 Darnell, R. R. 1993, "The polymerase chain reaction: Application to nervous system disease," Ann Neurol, vol. 34, pp. 513-523 Dc Jonghe, P., Timmerman, V., Nelis, E., et al. 1997, "CharcotMarie-Tooth disease and related peripheral neuropathies," / Peripb hlerv Syst, vol. 2, no. 4, pp. 370-387 "Guidelines for the molecular genetics predictive test in Huntington's disease," 1994, Neurology, vol. 44, pp, 1533-1536 Harper, P. S. 2001, Myotonic Dystropy, 3rd ed, W. B. Saunders, London Hersch, S., Jones, R., Koroshetz, W., et al. 1994, "The neurogenetics genie: Testing for the Huntington's disease mutation," Neurology, vol. 44, pp, 1369-1373 On, J. 1990, Analysis of Human Genetic Linkage, 2nd ed, Johns Hopkins University Press, Baltimore Zoghbi, H. & Orr, H. 2000, "Glutamine repeats and neurodegenerarion," Ann Rev Nenrosci, vol. 23, pp. 217-247.
Chapter 45 Neuroimmunology Tanuja Chitnis and Samia J. Khoury
Adaptive and Innate Immunity Principal Components of the Immune System Monocytes and Macrophages Natural Killer Cells T Lymphocytes T-Cell Receptors B Lymphocytes Immunoglobulins Genetics of the Immune System Antigen Receptor Gene Rearrangements Major Histocompatibility and Human Leukocyte Antigens Organization of the Immune Response Initiation of the Immune Response Regulation of the Immune Response Termination of an Immune Response Self-Tolerance
809 810 810 81 81 81 81 81 812 812 813 814 814 817 817 8 19
The past decade has provided a rich interaction between the fields of neurology and immunology. This has given rise to new therapies for multiple sclerosis (MS) and has improved existing treatments of many other neuroimmunological diseases. A solid grasp of immunology is required to use the emerging therapies in the field of neuroimmunology. Here we provide a brief overview of the major components of the immune system and highlight important advances in the field of neuroimmunology. The immune system function is to protect the organism against infectious agents and prevent reinfection by maintaining immunologic memory, to perform tumor surveillance, and to help healing and prevent damage from dying cells. The immune system normally does not react to selfantigens, a state known as tolerance, except in the setting of autoimmune disease. Conversely, an active immune system is important in tumor surveillance. A critical factor in tumor survival is its ability to mask itself from immune surveillance. The normal functions of the immune system and the disorders resulting from its dysfunction arc listed in Table 45.1.
ADAPTIVE AND INNATE IMMUNITY The immune system has two functional divisions: the innate immune system and the adaptive immune system. The
Central Tolerance Peripheral Tolerance The Immune System and the Central Nervous System Putative Mechanisms of Human Autoimmune Disease Genetic Factors Environmental Factors Diseases in Neuroimmunology Multiple Sclerosis Acute Disseminated Encephalomyelitis Immune-Mediated Neuropathies Autoimmune Myasthenia Gravis Inflammatory Muscle Diseases The Immune Response to Infectious Diseases Tumot Immunology Pataneoplastic Syndromes The Immunology of CNS Transplant Conclusion
819 819 821 821 822 822 823 823 825 825 826 827 827 827 X2.8 828 828
innate immune system acts nonspecifically as the body's first line of defense against pathogens. However, this type of response, if perpetuated, would result in unwanted nonspecific damage to the host. Therefore a secondary, antigen-specific response develops and leads the attack. This is mediated by T cells and B cells, which are equipped with antigen specific receptors. The effector cells release mediators and trigger other components of the immune system to eliminate the target. Subpopulations of T and B cells develop and maintain immunological memory, which facilitates a more rapid response in the case of recurrenr infection. The innate immune system consists of the following components: 1. Skin—The exterior surface of the body, primarily the skin, is the body's primary defense against foreign pathogens. In addition many inflammatory cells and antigen-presenting cells (APCs) line the epidermis and serve as the first line of defense. 2. Phagocytes—Phagocytes are cells capable of phagocytosing foreign pathogens. They include polymorphonuclear cells, monocytes, and macrophages. These cells are present in the blood, as well as in organs. They recognize cell surface receptors on a variety of microorganisms that allow them to attach nonspecifically and phagocytose pathogens, which are then killed via intracellular lysosomes. 809
S10
Ni:UROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Tabic 45.1:
Normal functions and disorders of the immune
system
Normal functions Immunity against microorganisms and pathogens Wound healing Tumor surveillance Disorders resulting from immune system dysfunction Autoimmunity Immune-mediated disorders Bystander damage Graft rejection
3. Natural killer (NK) cells—NK cells recognize cell surface molecules on virally infected or tumor cells. They subsequently bind to the infected cells and kill them via cell-media ted cytotoxicity. 4. Acute-phase proteins—C-reactive protein is a model acute-phase protein whose concentration increases in response to infection. C-re active protein binds to cell surface molecules on a variery of bacteria and fungi and acts as an opsonin, essentially increasing recognition of pathogens by phagocytic cells. 5. Complement system—The complement system is a cascade of scrum proteins whose overall function is to enhance and mediate inflammation. The complement system has the intrinsic ability to lyse the cell membranes of many cells including bacteria. It functions in concert with components of both the innate and adaptive immune systems and can also act as an opsonin, facilitating phagocytosis. The complement cascade can be directly activated by certain microorganisms through the alternative pathway, or it can be activated by particular antibody subtypes through the classical parhway. The adaptive immune response consists of the following components: 1. Antibodies—Antibodies, otherwise known as immunoglobulins (Igs) are able to specifically recognize a variety of free antigens. Igs are produced by B cells and arc present on their cell surface. In addition, Igs arc secrered in large amounts in the serum. Antibodies recognize specific microbial and other antigens through their antigen-binding sires and bind phagocytes via their Fc receptors, thereby facilitating antigen removal. Some subclasses of Ig are capable of activating complement via their Fc portion, thereby lysing their targets. 2. B cells—The primary function of B cells is to produce antibody. Antigen binding to B cells stimulates proliferation and maturation of that particular B cell, with subsequent enhancement of antigen-specific antibody production. Most B cells express class II major
histocompatibility complex (MHC) antigens and have the ability to function as APCs. i. T cells—T cells or thymus-derived cells have the ability to recognize specific antigens via their T-cell receptors (TCRs). T cells may be classified into two main groups, T-helper (Th) cells expressing CD4 antigen on their cell surface and T cytotoxic (Tc) cells expressing CDS on rheir surface. CD4 T cells recognize antigen presented in association with M H C class II on the surface of APCs. CD4 T cells provide help to promote B-cell maturation and antibody production and produce factors called cytokines to enhance the innate or nonspecific immune response. CDS T cells recognize antigen in association with M H C class I antigen on the surface of most cells and play an important role in the elimination of virus-infected cells. Cytotoxic T cells are capable of damaging rarger cells via the release of degrading enzymes and cytokines. Responses in which the T cell plays a major role are termed cell-mediated immunity (CMI), T celi-macrophage interactions often lead to delayed reactions, termed delayed-type hypersensirivity (DTH). 4. Antigen-presenting cells (APCs)—APCs are required to present antigen to T cells. They are found primarily in the skin, lymph nodes, spleen, and thymus. Unlike B cells that can recognize free antigen, T cells are only capable of recognizing antigen in the context of self M H C molecules. APCs process antigen intracellularly and present antigen peptide in the groove of their M H C class II molecules. The primary APCs are macrophages, monocytes, dendritic cells, and Langerhans' cells.
PRINCIPAL COMPONENTS OF T H E IMMUNE SYSTEM Cells of the immune system arise from the pluripotent stem cells in the bone marrow and diverge into the lymphoid or myeloid lineages. The myeloid lineage primarily contains cells with phagocytic functions such as neutrophils, basophils, eosinophils, and macrophages. The lymphoid lineage consists of T cells, B cells, and NK cells.
Monocytes and Macrophages Bone marrow-derived myeloid progenitor cells give rise to monocytes (mononuclear phagocytes of the reticuloendothelial system) that serve important immune functions. They constitute about 4% of the peripheral blood leukocytes and are morphologically identified by an abundant cytoplasm and a kidney-shaped nucleus. Their cyroplasm conrains many enzymes, which are important for killing microorganisms and processing antigens. Monocytes
NEUROIMMUNOLOGY differentiate into tissue-specific macrophages, Kupffer cells of the liver, and brain microglia.
including
Natural Killer Cells NK cells make up about 2 . 5 % of peripheral blood lymphocytes and are synonymous with large granular lymphocytes because of their large intracytoplasmic azurophilic granules and high cytoplasm-to-nucleus ratio. Unlike cytotoxic CD8+ T cells, NK cells lack immunological memory and have the ability to kill a wide variety of tumor and virus-infected cells without M H C restriction (see the discussion of the function of MHC genes) or activation. NK cells lack the cell surface markers present on B cells and T cells. The biological function of the NK cell is uncertain. In view of its in vitro function of lysing tumor cells, it may play a role in tumor immunity (Trichincri 1989). NK1+ T cells are a subset of cells sharing characteristics of both NK cells and T cells. They express the «/jf> TCR and the N K l . l receptor. These cells are significant because of their ability to secrete large amounts of interleukin-4 (IL-4) in response to TCR stimulation and may play a role in maturation of Th2 cells (see later).
T Lymphocytes T cells originate from the thymus. Differentiation of T cells occurs in the thymus, and every T cell that leaves the thymus is conferred with a unique specificity for recognizing antigens. T cells that recognize self-antigens are generally either deleted or rendered tolerant within the thymus, a process called central tolerance. T cells may be divided into two groups on the basis of expression of either the CD4+ or CD8+ marker, Functionally, CD4+ T cells are involved in DTH responses and also provide help for B-cell differentiation (and hence are termed helper T cells). In contrast, C D 8 + T cells are involved in class I restricted lysis of antigen-specific targets (and hence are termed cytotoxic T cells). T cells with suppressor activity can express either CD4 or CD8.
T-Cell Receptors The TCR consists of two glycosylated polypeptide chains, alpha (a) and beta (/3), of 45,000 and 40,000 dalton molecular weight, respectively. This heterodimer of an alpha and beta chain is linked by disulfide bonds. Amino acid sequences show that each chain consists of variable (V), joining (J), and constant (C) regions closely resembling Igs (Figure 45.1). There are about 10 2 TCR-variable genes, grouped by homology into a small number of families, compared with 10 3 or greater for Igs (see later). The principles governing generation of diversity in the TCR are
811
very similar to those for Ig genes. T cells can only recognize short peptides that are associated with M H C molecules. In contrast, the Ig receptor can recognize peptides, whole proteins, nucleic acids, lipids, and small chemicals. T cells also express a variety of nonpolymorphic antigens on their surfaces. The most abundantly expressed is CD45, comprising 10% of lymphocyte membrane proteins. CD45 exists as a number of isoforms that differ in the molecular weight of their extracellular domains as a result of RNA splicing. These isoforms can be distinguished serologically. The low molecular weight (CD45RO) isoforms define activated, or memory, T-cell populations.
B Lymphocytes B cells are the precursors of antibody-secreting cells. The cells develop in the bone marrow and during their ontogeny acquire Ig receptors that commit them to recognizing specific antigens for the rest of their lives. B cells normally express IgM on their cell surfaces but switch to other isotypes as a consequence of T cell help, while maintaining antigen specificity (see later). Following antigenic challenge, T lymphocytes assist (help) B cells directly (cognate interaction) or indirectly by secreting helper factors (noncognate interaction), to differentiate and form mature anti body-sec ret ing plasma cells.
Immunoglobulins Igs are glycoproteins that are the secretory product of plasma cells. Their biochemical structure and genomic organization is shown in Figure 4 5 . 1 . All Ig molecules share a number of common features. Each molecule consists of two identical polypeptide light chains (kappa or lambda) linked to two identical heavy chains. The light and heavy chains arc stabilized by intrachain and interchain disulfide bonds. According to the biochemical nature of the heavy chain, Igs are divided into five main classes: IgM, IgD, IgG, IgA, and IgE. These may be further divided into subclasses depending on differences in the heavy chain. Each heavy and light chain consists of variable and constant regions. The amino terminus is characterized by sequence variability in both the light and the heavy chain, and each variable heavy- and light-chain unit acts as the antigen-binding site (the Fab portion). The carboxy terminal of the heavy chain (also known as the Fc portion) is involved in binding to host tissue and in fixing complement. This part of the molecule is important for antibody-dependent, cell-mediated cytotoxicity by cells of the reticuloendothelial system and for complementmediated cell lysis. Classes of Igs differ in their ability to fix complement. In humans, IgM, IgGl, and IgG3 antibodies are capable of activating the complement cascade.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSC1ENCES FIGURE 45.1
Molecular and
gl'llCtic
antibody rarely persists for more than a few months. Detection of intrathecal virus-specific antibody production is a useful diagnostic test for many CNS viral infections. However, increases in virus-specific antibody in the CSF may result from breakdown of the blood-brain barrier or from polyclonal immune activation as occurs in certain diseases including systemic lupus erythematosus and MS. Correcting for leakage of protein across the blood-brain barrier using the CSF to serum albumin ratio may enhance the specificity of intrathecal antibody tests. Showing that intrathecal antibody responses arc limited to a particular virus, rather than part of a more general phenomenon, also enhances the specificity of antibody testing. When antibody production resulrs from activation of a few discrete B-cell clones within the CNS compartment, oligoclonal bands may be detected in CSF. Oligoclonal bands are not specific for viral infection and occur in a wide variety of immunological neurological diseases. Virusspecific antibody responses are rarely detectable until 2 or 3 weeks after onset of illness, and hence an increase in such a titer between acute and convalescent sera is required for diagnosis. As a result, serological tests arc rarely useful in acute diagnosis and management of viral infections. Diagnosis of specific viral infections can be made also by identification of viral antigens in tissues or body fluids including CSF. The most commonly employed techniques use radiolabeled or enzyme-linked antibodies in immunosorbent assays. Viral antigens in tissues or cells can be identified using enzyme-linked or fluorescent-labeled virusspecific antibodies. In general, detection of viral antigens provides rapid, sensitive, and specific diagnosis, but the techniques are suitable for only a limited number of viral infections. The major limitation of the technique is the requirement that virus-infected tissue be available for study. In the case of viral CNS infections, this often requires brain biopsy, because antigen is only rarely detectable in CSF. The application of molecular biological techniques to the diagnosis of viral CNS infections has revolutionized diagnosis. The most useful techniques are designed to identify viral nucleic acid in body fluids or tissue specimens. For analysis of intact tissues, ISH with radiolabeled or enzyme-labeled (especially horseradish peroxidase and digoxigenin) viral nucleic acid probes allows for reasonably rapid viral identification. This technique also has been adapted for use with small populations of cells, as might be available from body fluids such as saliva or urine. The major advantages of this technique are its great specificity and its capacity to detect even a few copies of the viral nucleic acid. ISH is useful also in identifying individual infected cells in tissue specimens. After extracting cellular and genomic DNA or RNA from a tissue, two basic techniques, immunoblotring and PCR, can be used to determine whether viral nucleic acid is present in the sample. The older techniques, Southern hybridization for DNA and Northern hybridization for RNA, involve the same hybridization techniques described
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NF.UROSCIENCES
previously for ISH, except the target nucleic acid has been extracted from the infected tissue, digested with restriction end on ue leases, run on a gel, and transferred and fixed to a membrane. The advantages of these techniques are the same as for ISH, and they are technically simpler. Their only disadvantage is the inability to identify which cells in a population are infected, but this has little effect on the clinical management of the patient. The major revolution in diagnostic virology has been the rapid development of PCR {DcBiasi and Tyler 1999). By using known nucleotide sequences 20 bases or longer as primers, PCR allows for amplification of tiny quantities of whole genes or just fragments of genes of interest. In its simplest form, this is performed as liquid PCR, with a single set of primers, using exttacted DNA or RNA samples. Aliquots of the amplified nucleic acid arc run on a gel containing ethidium bromide and visualized under ultraviolet light. This is a highly specific and sensitive technique, which is able to identify a small number of copies of viral nucleic acid among thousands ot cells. Technical and methodological advances have allowed for even greater sensitivity and specificity, so that single copies of genes can often be identified in samples of nucleic acid derived from large numbers of cells. These advances include the addition of a hybridization step after running the sample on a gel; the use of nested PCR, in which a PCR reaction is first done with an outer set of primers, and then a small aliquot of this fitst teaction is subjected to a second round of PCR using an inner set of primers that are contained within the first amplified gene prod net; and in situ PCR, in which PCR is done on intact tissues and followed by ISH. In clinical laboratory practice nearly all PCR tests involve liquid PCR of target nucleic acid extracted from body fluids or tissues. For viral meningoencephalitis, PCR of CSF or other body fluids is the study of choice. Reptoduciblc protocols exist for HSV-1 and -2, CMV, EBV, VZV, HHV-6, HIV-1, and enteroviruses.
reliable laboratory according to generally accepted techniques designed to minimize the risk of inadvertent contamination. The value of a negative CSF PCR test result in excluding a specific viral infection varies with the specific virus and the clinical setting. PCR has been used also to amplify viral nucleic acid directly from brain tissue. The sensitivity and specificity of brain tissue PCR have not yet been established. Initial studies suggest that PCR may amplify viral nucleic acid from the brain tissue of asymptomatic individuals without known or neuropathologically evident neurological disease. The frequency of positive brain tissue PCR results depends on the specific virus, the PCR techniques, and the region of the brain being examined. The high incidence of positive brain tissue PCR results in apparently normal individuals means that extreme caution should be exercised in interpreting positive brain tissue PCR results as evidence for acute viral infection. Positive brain tissue PCR results have been used also to suggest a viral cause for a diverse group of neurological disorders including Rasmussen's syndrome, MS, epilepsy, and Alzheimer's disease. These associations should be considered suspect until more information about brain tissue PCR becomes available.
THERAPY
Sensitivity of PCR varies according to the tissue or body fluid from which the nucleic acid is derived and the viral genes assayed. For example, from patients with AIDS with biopsy-proven PML, JC virus can be amplified from 100% of brain samples, 89% of peripheral blood lymphocytes, and 7 9 % of CSF samples. By contrast, sensitivity of HSV PCR from CSF of patients with biopsy-proven HSV-1 encephalitis is extremely high and exceeds 9 5 % . There have been reports of false-negative HSV PCRs obtained during the first 72 hours of infection (Weil et al. 2002). The incidence of positive PCRs also declines with time following infection and associated therapy. Only "~20% of CSF PCRs remain positive after day 14 of illness.
Therapy for viral infections of the nervous system can be categorized as preventive, supportive, or antiviral (Rcdington and Tyler 2002). The simplest preventive therapies are designed to eliminate or greatly reduce the likelihood of inoculation with potential infectious agents. This can include public health measures such as mosquito or tick eradication programs and improvement of sewage systems and aggressive eradication of insects and mammals infected with tabics or arboviruses; blood transfusion screening programs to avoid transmission of HIV-1, hepatitis B and C, HTLV-I, and other infections via blood products; and education programs, such as the promotion of safe sex programs to limit the risk of transmission of sexually transmitted diseases, or efforts to increase the number of homes with screened windows and doors in areas with arbovirus epidemics. Changes in personal behavior, such as elimination of unsafe sexual practices (to avoid contact with, e.g., HIV-1) or changing of work schedules (to avoid exposure at high-risk times to arboviruses) also may be extremely important. Postexposure practices such as removal of ticks or proper wound care (e.g., in rabies permitting bleeding and washing with inactivating soap and water) also may reduce the risk of viral transmission in some cases.
In asymptomatic immunocompetent individuals the CSF does not contain amplifiablc viral nucleic acid. The finding in the appropriate clinical setting of viral nucleic acid in CSF by PCR is virtually diagnostic of viral CNS infection. Extensive experience suggests that false-positive CSF PCR results arc extremely rare when the test is performed by a
The other significant approach to prevention is immunoprophylaxis with vaccines. Traditionally, vaccines have been divided into live attenuated vaccines, producing infection with and immune response to nonvirulcnt strains of virus, and immunization with inactivated, nonreplicating virus vaccines. Recombinant DNA technology
NEUROVJROLOGY
has produced vaccines that stimulate immune responses directed against single viral antigens or subunits of antigens. The antiviral vaccines routinely administered in the United States during early childhood, including those to mumps, measles, varicella, polio, and rubella viruses, all are live, attenuated vaccines, which may retain a certain amount of pathogenicity or may revert to a more neurovirulcnt form. This may pose a relatively higher risk of the use of these vaccines in immunocompromised patients, who may not cleat the infection properly. In the United States, the relative risk of paralytic complications of oral polio vaccine is increased markedly in the immunocompromised patient population. The vaccine to Japanese encephalitis virus, used extensively in Japan, China, and other areas of the Far East, is inactivated. The inactivated rabies vaccine is used both for preexposure prophylaxis in individuals at relatively high risk of bites from rabid animals and in combination with human rabies immune glohulin for postexposure prophylaxis.
Supportive and Symptomatic Therapy After onset of viral infections of rhe nervous system, supportive care can be very helpful. For the common viral meningitides and encephalitides, this may include bed rest, analgesics, anticonvulsants, and antipyretics. Aggressive management of pneumonia and other bacterial infections, hypotension, dysautonomia, and elevated intracranial pressure may be crucial in more severe infections such as rabies or EEEV. Judicious use of high-dose glucocorticoids in the first several (.lays ot HSV-1 encephalitis therapy, when there is a great deal of cerebral edema and the risk of herniation is high, may be useful, although this has not been properly studied. After resolution of the acute neurological illness, rehabilitative services may be a necessary and important part of the patient's return to his or her usual activities. For postinfectious neurological illnesses, modulation or alteration of the immune system may have positive results. In Guillain-Barrc syndrome, both plasmapheresis and administration of intravenous immunoglobulin have been shown to significantly reduce morbidity. In acute disseminated encephalomyelitis and related postinfectious demyelinating disorders, high doses of intravenous glucocorticoids typically arc used, although their efficacy has never been established. The era of antiviral drug use in nervous system infections was ushered in with the landmark studies of Whitley and colleagues, who looked first at adenosine arabiuoside and subsequently acyclovir in the treatment of HSV-1 encephalitis. Their studies showed a clear, significant effect of acyclovir in reducing mortality, especially if given early in the course of the illness, and morbidity. Subsequently,
847
acyclovir has been shown effective against VZV, also a member of the alpha-herpesvirus subfamily. All of the antiviral therapies developed to date interrupt one or more crucial steps in the life cycle of the replicating virus. Acyclovir inhibits the HSV-encoded DNA polymerase. The active metabolite is acyclovir triphosphate. The initial phosphorylation of acyclovir occurs much more efficiently in virus-infected cells, because it requires a virus-encoded enzyme (thymidine kinase). This selective phosphorylation, and the fact that acyclovir triphosphate is a much more potent inhibitor of HSV DNA polymerase than human DNA polymerase, accounts for acyclovir's specificity of action. Acyclovir is not effective as an antiviral agent against viruses that lack a DNA polymerase (e.g., RNA viruses) or against DNA viruses without a virusencoded thymidine kinase (e.g., CMV). The newer antiviral drugs famciclovir and valacyclovir have similar mechanisms of action and specificity as acyclovir. The primary advantage of these agents is their enhanced bioavailability after oral administration and their longer half-life that permits less frequent dosing intervals. Ganciclovir has a similar mechanism of action to acyclovir. Its major advantage is its efficacy against CMV infection. CMV lacks a virus-encoded thymidine kinase, but ganciclovir, unlike acyclovir, is phosphorylated in CMV-infected cells by another virally encoded kinase. Cidofovir is a newer antiviral nucleoside analogue that like ganciclovir does not depend for its activity on the presence of a virus-encoded thymidine kinase. It is efficacious against CMV and has been used with success in treating CMV retinopathy and CNS infections. The drug has a prolonged iiitiML-ellular half-lite that permits once-daily dosing. Complications of intravenous therapy include nephrotoxicity and bone marrow suppression. Another antiviral drug, foscarnet, is also effective against CMV. Foscarnet is an inorganic pyrophosphate analogue that differs in its mechanism of action from the nucleoside analogues (e.g., acyclovir, ganciclovir). Unlike the nucleoside analogues, foscarnet is not metabolized inside infected cells, but like the nucleosides it also acts to inhibit viral DNA polymerase. The utility of foscarnet is limited by its toxicity, nonetheless it remains useful in the treatment of infections caused by CMV and acyclovir-resistant strains of HSV. A number of antiviral drugs have been developed to combat HIV-1 infection (Bcrgcr and Eevy 1997; Gendelman et al. 1998). The first generation of antirctrovirai drugs were inhibitors of reverse transcriptase, the viral enzyme necessary for production of the DNA form of the virus. Zidovudine, and subsequently dideoxyinosinc and didcoxycytidine, have been shown to delay the progression of AIDS-demcntia complex. Newer antiretroviral drugs include a number of protease inhibitors. These drugs work by inhibiting an enzyme required for the processing of viral proteins. Therapeutic regimens using complex combinations of several different protease inhibitors have
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NEUROLOGICAL INVESTIGATIONS AND KLLATED CLINICAL NEUROSCIENCES
had a d r a m a t i c effect on the progression of H I V infection, a n d in the incidence of m a n y HIV-related o p p o r t u n i s t i c infections. It remains to be seen w h e t h e r these effects will be sustained. Studies of the efficacy of p r o t e a s e inhibitors on the neurological complications of H I V infection arc limited, but one study has s h o w n t h a t m u l t i d r u g t h e r a p y including protease inhibitors can reduce HIV-1 viral load in the CSF. Although a z i d o t h y m i d i n e a p p e a r s to h a v e efficacy in vitro against H T L V - I , it has not been clinically successful in the treatment of H A M . This m a y reflect the fact t h a t n e u r o n a l injury in H A M m a y result from i m m u n o l o g i c a l attack by virus-specific cytotoxic T cells, rather t h a n as a result of direct viral infection. Consistent with this model of pathogenesis is the suggestion t h a t t r e a t m e n t with i m m u n o m o d u l a t o r y agents including corticosteroids a n d interferon-a m a y be beneficial in H A M .
REFERENCES Berger, J. R. & Levy, R. M. 1997, AIDS and the Nervous System, 2nd ed, Lippincort-Raven, Philadelphia Davis, L. E. 2000, "Diagnosis and treatment of acute encephalitis," Neurologist, vol. 6, pp. 145-159 DeBiasi, R. L. & Tyler, K. L. 1999, "Polymerase chain reaction in the diagnosis and management of central nervous system infections," Arch Neurol, vol. 56, pp. 1215-1219 Gendclman, H. E., Lipton, S. A., Epstein, L. G., & Swindells, S. 1998, The Neurology of AIDS, Chapman and Hall, New York
Gilden, D. H., Kleinschmidt-DeMasters, B. K., et al. 2000, "Neurologic complications of the reactivation of varicellazoster virus," N Engl J Med, vol. 342, pp. 635-645 M M W R 2002a, "Acute flaccid paralysis syndrome associated with West Nile virus Infection-Mississippi and Louisiana, JulyAugust 2002," MMWR, vol. 5 1 , pp. 825-828 M M W R 2002b, "Investigations of West Nile virus infections in recipients of blood transfusions," MMWR, vol. 5 1 , pp. 973-974 Nash, D., Mostashari, F., Fine, A., er al. 2001, "The outhrcak of West Nile virus infection in the New York City area in 1999," N Engl J Med, vol. 344, pp. 1807-1814 Raschilas, R, Wolff, M., Delatour, F., ct al. 2002, "Outcome and prognostic factors for herpes simplex virus encephalitis in adult patients: results of a multiecntcr study," Clin infect Dis, vol. ^5, pp. 254-260 Rcdington, J. [. Sc Tyler, K. L. 2002, "Viral infections of the nervous system, 2002. Update on diagnosis and treatment," Arch Neurol, vol. 59, pp. 712-718 Rotbart, H. A. 2000, "Viral meningitis," Scmin Neurol, vol. 20, pp. 277-292 Tyler, K. L. & Nathanson, N. 2 0 0 1 , "Pathogenesis of viral infections," in Fields Virology, 4th ed, eds D. M. Knipe & P. M. Howley, I.ippineott William & Wilkins, Philadelphia Weil, A. A., Glaser, C. A., Amad, Z., & Forghani, B. 2002, "Patients with suspected herpes simplex encephalitis: Rethinking an initial negative polymerase chain reaction result," Clin Infect Dis, vol. 34, pp. 1154-1157 Whitley, R. J. 1997, "Herpes simplex virus," in Infections of the Central Nervous System, 2nd ed., eds. W. M. Scheld, R. J. Whitley, & D. T. Durack, Lippincott-Ravcn, Philadelphia Whitley, R. J. & Gnann, J, W. 2002, "Viral encephalitis: Familiar infections and emerging pathogens," Lancet, vol. 359, pp. 507-514
Chapter 47 Neuroendocrinology Paul E. Cooper
Nonendocrine Hypothalamus Neuropeptides, Neurotransmitters, and Neurohormones Neuropeptides and the Immune System Temperature Regulation Fever Appetite Emotion and Libido Biological Rhythms Hypothalamic-Pituitary Unit Functional Anatomy Blood Supply Anterior Pituitary Hypothalamic Control of Anterior Pituitary Secretion Abnormalities of Anterior Pituitary Function Pituitary Tumors and Pituitary Hyperplasia Other Tumors
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Homeostasis—the maintenance of the constancy of the internal milieu—requires, in all but the simplest of organisms, communication among cells and organs that are widely separated. This communication is achieved through the coordinated interaction of the nervous, endocrine, and immune systems. It is the study of this coordinated interaction that is the field of neuroendocrinology,
NONENDOCRINE HYPOTHALAMUS Neuropeptides, Neurotransmitters, and Neurohormones The term neurotransmitter is applied traditionally to a substance released by one neuron to act on an adjacent neuron in a stimulatory or inhibitory fashion. The effect is usually rapid, brief, and confined to a small area of the neuron surface. In contrast, a hormone is a substance that is released into the bloodstream and travels to a distant site to act over seconds, minutes, or hours to produce its effect over a large area of the cell. Neuropeptides can act in cither fashion. For example, the neuropeptide vasopressin, produced by the neurons of the supraoptic and paraventricular nuclei, is released into the bloodstream and has a hormonal action on the collecting ducts in the kidney. In the central nervous system, vasopressin acts as a neurotransmitter. Similarly, the neuropeptide substance P acts as a neurotransmitter in primary sensory neurons that
Hypophysitis Posterior Pituitary Physiology Diabetes Insipidus Syndrome of Inappropriate Antidiuretic Hormone Secretion Cerebral Salt Wasting Approach to the Patient with Hypothalamic-Pituitary Dysfunction History and Physical Examination Assessment by Imaging Studies Endocrinological Investigation Treatment of Pituitary Tumors Treatment of Hypopituitarism Neurosecretion Syndromes Apudomas
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convey pain signals and as a neurohormone in the hypothalamus. The influence of neuropeptides on the brain can be divided into two broad categories: organizational and activational. Organizational effects occur during neuronal differentiation, growth, and development and bring about permanent, structural changes in the organization oi the brain that affect its function. An example is the structural and organizational changes brought about in the brain by prenatal exposure to testosterone. Activational effects are those that change pre-established patterns of neuronal activity, such as an increased rate of neuronal firing caused by exposure of a neuron to substance P. Numerous neuropeptides are found in the brain, and research has shown these compounds to have a variety of effects on neuronal function (Table 47.1).
Neuropeptides and the Immune System Stress, acting through the hypothalamic-pituitary-adrenal axis, modulates the function of the immune system. Certain peptides and their receptors, once thought to be unique to either the immune or neuroendocrine system, are actually found in both. Cytokines (interleukin [IL]-I, -2, -4, and -6, and tumor necrosis factor [TNF]) arc synthesized by glial cells in the central nervous system in response to cell 849
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NFUUH.OCICAI [ W I S LIGATIONS AM) RLI AMI) CLINICAL NLUKOSCIKNCKS
Table 47.1:
Neuropeptides found in the brain and their effects on brain function*
Neuropeptide Hypothalamic peptides modulating pituitary function Corticotropin (ACTH )-relea sing hormone Vasopressin Oxytocin Growth hormone-releasing hormone Growth hormone release inhibiting hormone (somatostatin) Ghrelin Thyrotropin-releasing hormone
Gonadotropin-reIcasing hormone (luteinizing hormone-releasing hormone) Prolactin-releasing peptide Neurotensin
Neuropeptide V
Pituitary peptides Prolactin Growth hormone Thyroid-stimulating hormone Follicle-stimulating hormone Luteinizing hormone Proopiomelanocortin ACTH ACTH-like intermediate lobe peptides ^-Endorphin
Central nervous system function Regulation of ACTH secretion Integration of behavioral and biochemical responses to stress Learning and memory facilitation Memory processes Induction of maternal and M-viial behaviors Regulation of growth-hormone secretion Regulation of growth-hormone secretion Regulation of growth-hormone secretion Regulation of feeding Regulation of thyroid-stimulating hormone secretion May he involved in depression Enhances neuromuscular function Regulates gonadotropin secretion Sexual receptivity Stimulates prolactin secretion Endogenous neuroleptic Regulates mesolimbie, mesocortical, and nigrostriatal dopamine neurons Thermoregulation Analgesia Satiety and drinking Sexual behavior Locomotion Memory
Analgesic mechanisms Feeding Thermoregulation Learning and memory
/i-Lipotropic hormone Melanocyte-stimulating hormone (a and y) Oxytocin Vasopressin Neurophysins Brain-gastrointestinal tract peptides Vasoactive intestinal polypeptide Somatostatin Insulin Glucagon Pancreatic polypeptide Gastrin Cholecystokinin
Tachykinins (e.g., substance P)
Cerebral blood flow Feeding behavior Hunger
Feeding behavior Satiety
Modulates dopamine neuron activity Substance P colocalizcs with serotonin and is involved in nociception Continued
NEJJROENDOCRINOLOGY Tabic 47.1,
851
cont'd. Neuropeptides found in die brain and their effects on brain function*
Neuropeptide Secretin Thyrotropin-releasing hormone Bombesin Orcxins (hypocretin)
Central nervous system function
Thermoregulation Appetite Gastric and GI motility and secretion Pancreatic hormone release Regulation of energy homeostasis
G r o w t h factors
Insulin-like growth factors I and II Nerve growth factors Opioid family Endorphins Enkephalins (Met-, Leu-)
Axonal plasticity
Analgesic mechanisms Feeding Temperature control Learning and memory Cardiovascular control
Dynorphins Kytorphin Neuropeptides modulating immune function ACTH Endorphins Interferons Neuro leu kins Thymosin Thymopeptin Other neuropeptides Atrial natriuretic factors Bradykinins Angiotensin
Cerebral blood flow Migraine Hypertension Thirst
Synapsins
Calcitonin gene-re I a ted peptide Calcitonin Sleep peptides Orexins (hypocretin)
Regulation of sleep cycles SleepAvake regulation Narcolepsy cniTgv homeostasis
Carnosine Precursor peptides P ro -op iomela n ocort i n Proenkephalins (A and B) Calcitonin gene product
Vasoactive intestinal polypeptide gene product Pro-glucagon Pro insulin
"This is only a partial list of all of the neuropeptides that have been found in the brain and not all of the putative functions have been listed. Gl = gastrointestinal. Snurci-. Modified with permission from Doraiswamy, P. M., Krishnan, K. R., Nemeroff, C. B. 1992, "Hormonal effects on brain function" in Neuroendocrinology. Concepts in Neurosurgery, vol. 5, eds D. L. Barrow & W. Selman, Williams & Wilkins, Haiti more. injury, 1L-1, t h r o u g h its ability to stimulate t h e synthesis of nerve g r o w t h factor, m a y he an i m p o r t a n t p r o m o t e r of t h e repair of n e u r o n d a m a g e . Cytokines also a p p e a r to play a role in t h e h y p o t h a l a m u s to activate t h e h y p o t h a l a m k - p i t u i t a r y - a d r e n a l axis in response to infla-
m m a t i o n elsewhere in the b o d y a n d to inhibit the pituitary-thyroid a n d p i t u i t a r y - g o n a d a l axes in response to systemic disease. Several o t h e r h o r m o n e s a n d n e u r o p e p t i d e s have m o d u l a t o r y effects on i m m u n e function (Table 4 7 . 2 ) .
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Tabic 47.2:
Immunoregu latory effects
of several hormones and peptides
Hormone or peptide
Immune function
affected
Inhibitory Glucocorticoids Corticotropin (ACTH) Chorionic gonadotropin a-Endorphin Somatostatin Vasoactive intestinal peptide or-Mel a n oeyte-sri m u I ati ng hormone
Lymphokine synthesis, inflammation Macrophage activation, synthesis of immunoglobulin G (IgG) and y-intcrfcron Activity of T cells and natural killer cells IgG synthesis, T-cell proliferation T-cell proliferation, inflammatory cascade T-cell proliferation and migration in Peyer's patches Fever, prostaglandin synthesis, secretion of intcrleukin-2
Stimulatory Estrogens Growth hormone Prolactin Thyrotropin ^-Endorphin Substance P ACTH-releasing hormone
Lymphocyte proliferation and secretion Thymic growth, lymphocyte reactivity Thymic growth, lymphocyte proliferation IgG synthesis Activity of T, R, and natural killer cells Proliferation of T cells and macrophages, inflammatory cascade Lymphocyte and monocyte proliferation and activation
Source: Reprinted with permission from Rcichlin, S. 1993, "Neuroendocrine-immune interactions," N Engl j Med, vol. 329, pp. 1246-1253.
Similarly, i m m u n o c o m p e t e n t cells c o n t a i n h o r m o n e s a n d neuropeptides t h a t m a y affect n e u r o e n d o c r i n e a n d brain cells (Table 4 7 . 3 ) . Despite speculation a b o u t the ability of the psyche to influence immunological function a n d therefore disease o u t c o m e , there is no conclusive evidence to date to suggest t h a t this is clinically significant (Reichlin 1993).
T e m p e r a t u r e Regulation T h e h y p o t h a l a m u s plays a key role in ensuring t h a t b o d y t e m p e r a t u r e is m a i n t a i n e d within n a r r o w limits by balancing the heat gained from metabolic activity a n d t h e e n v i r o n m e n t with the heat lost to the e n v i r o n m e n t . A theoretical schema of the m e c h a n i s m s of h y p o t h a l a m i c
Table 47.3:
t e m p e r a t u r e regulation is depicted in Figure 4 7 . 1 . Although n u m e r o u s n e u r o t r a n s m i t t e r s a n d peptides alter b o d y t e m p e r a t u r e , their physiological roles r e m a i n unclear. H y p o t h a l a m i c injury can cause disordered t e m p e r a t u r e regulation. O n e potentially serious consequence is the h y p e r t h e r m i a t h a t m a y occur w h e n t h e p r e o p t i c anterior h y p o t h a l a m i c area is d a m a g e d or irritated by ischemia, s u b a r a c h n o i d h e m o r r h a g e , t r a u m a , or surgery. In s o m e p a t i e n t s , t h e m a r k e d i m p a i r m e n t of heat loss m e c h a n i s m s and the resulting hyperthermia may be fatal. In those individuals w h o survive, t e m p e r a t u r e c o n t r o l returns t o n o r m a l over a p e r i o d of days to w e e k s ; chronic hypert h e r m i a of h y p o t h a l a m i c origin is u n c o m m o n . It m a y occur w h e n there is o n g o i n g inability to dissipate heat a d e quately or w h e n there is difficulty sensing t e m p e r a t u r e elevations. C h r o n i c h y p o t h a l a m i c h y p e r t h e r m i a does n o t
Hormones and neuropeptides found in immunocompetent cells
HaniHitie
Source
Comments
Corticotropin
B lymphocytes
Growth hormone Thyrotropin
T lymphocytes
Stimulated by corticotropin-re I easing hormone; inhibited by Cortisol Stimulated by growth hormone Stimulated by thyrotropin-relcasiiig hormone; inhibited by somatostatin
Prolactin Chorionic gonadotropin Enkephalins Vasoactive intestinal peptide Somatostatin
Mononuclear cells T cells B lymphocytes Mononuclear leukocytes, mast cells Mononuclear leukocytes, mast cells, polymorphonuclear leukocytes Thymus Thymus Thymus
Vasopressin Oxytocin
Neurophysin
T cells
Source: Reprinted with permission from Reichlin, S. 1993, "Neuroendocrine-immune interactions," N Engl j Med, vol. 329, pp. 1246-1253.
M ; I K O I ; M N K : K I \ O I cx.Y
s.v!
FIGURE 47.1 Schematic representation of hypothalamic temperature-regulation mechanisms. The preoptic anterior hypothalamus functions as a thermostat and contains mechanisms for regulation of heat loss. The posterior hypothalamus integrates heat-production mechanisms. Lesions of the preoptic anterior hypothalamus result in hyperthermia; lesions of the posterior hypothalamus cause hypothermia or poikilothermia. (Reprinted with permission from Cooper, P. E. & Martin, J. B. 1983, "Neuroendocrine disease," in The Clinical Netimsciences, ed R. N. Rosciiherg, Churchill Livingstone, New York) respond to salicylates and other antipyretics because it is increases the body temperature set point. The body then not prostaglandin-mediated. Both acute and chronic uses its normal physiological mechanisms of vasoconstrichypothermia can be caused by hypothalamic injury, the tion, vasodilation, sweating, and shivering to maintain most common causes being head trauma, infarction, and this new set point. TNF, another cytokine, acts directly on demyelination. Also in the differential diagnosis one should the hypothalamus to raise the set point and stimulates the consider severe hypothyroidism, Wernicke's disease, and production of IL-1. Bacterial endotoxin is a potent drug effect. Some patients with no apparent hypothalamic stimulator of macrophages, the major source of production structural abnormalities may have episodes of recurrent and release of TNF. IL-6 and ^-interferon are two other hypothermia. The cause of this syndrome is unclear cytokines that act directly on the hypothalamus to raise the although the response of some patients to anticonvulsant set point. It is probably through interfering with prostaagents, and of others to clonidine or cyproheptadine, glandins that drugs such as acetylsalicylic acid and suggests a possible neurotransmitter abnormality. Agenesis acetaminophen are useful in treating fever. of the corpus callosum, in association with episodic A complex interaction occurs among the cytokines. IL-1 hyperhidrosis and hypothermia (Shapiro's syndrome), is stimulates its own production, as do elevated levels caused in some individuals by an abnormally low of y-interferon. IL-4 suppresses the production of IL-1, hypothalamic set point. These symptoms may respond to TNF, and IL-6. IL-1 production is inhibited also by clonidine (an « 2 -adrenergic agonist). A similar condition glucocorticoids and prostaglandin E. associated with hyperthermia (so-called reverse Shapiro's In otherwise healthy individuals, extreme elevations of syndrome) has been found to respond with normalization body temperature (as high as 41.1 U C [106°F]) sometimes of temperature to low-dose L-dopa and hypothermia with can be toletated without serious effects. However, higher doses (Hirayama et al. 1994). Large lesions in the hyperthermia associated with prolonged exertion, heatposterior hypothalamus may impair both heat production stroke, malignant hyperthermia, neuroleptic malignant by altering the set point and heat loss by damaging the syndrome, hyperthyroidism, phcochromocytoma crisis, outflow from the preoptic anterior hypothalamic area. This and some drugs may have serious and even fatal results in poikilothermia, a condition in which body consequences (Simon 1993). Exertional hyperthermia temperature varies with the environmental temperature. occurs with prolonged physical activity, particularly in hot, humid weather. It may decrease athletic performance and cause muscle cramps or heat exhaustion. When severe, Fever it may result in heatstroke, a syndrome characterized by hyperthermia, hypotension, tachycardia, hyperventilation, The body's inflammatory cells (primarily monocytes) and decreased consciousness. Malignant hyperthermia, a release cytokines in response to infection and inflammation. syndrome associated most often with the use of various These cytokines act on the hypothalamus to cause fever. general anesthetic agents, is caused by a disorder of muscle IL-1 circulates from areas of inflammation to the hypo- that involves an excessive release of calcium from sarcothalamus, where it acts to induce phospholipases that plasmic reticulum that stimulates severe muscle contraction release arachidonic acids from plasma membranes. This (see Chapters 70 and 85). The neuroleptic malignant results in an increase in prostaglandin E, which in turn syndrome is characterized by diffuse muscular rigidity,
854
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
akinesia, and fever accompanied by a decreased consciousness level and evidence of autonomic dysfunction: labile blood pressure, tachyarrhythmias, excessive sweating, and incontinence. The neuroleptic malignant syndrome is associated with taking major tranquilizers, with rapid withdrawing from dopaminergic agents, and less commonly with administration of tricyclic antidepressants. It appears to result from an alteration of temperature control mechanisms in the hypothalamus. As part of treatment, withdrawal of the patient from all neuroleptics is mandatory. In addition to general supportive measures, the use of bromocriptine (5 mg orally or nasogastrically four times daily) or dantrolene (2-3 mg/kg daily intravenously to a maximum of 10 mg/kg per day) may hasten recovery.
Appetite Given free access to food and water, most animals maintain their body weight within narrow limits. If there is a change in the intake of energy (a change in the size or number of individual meals that is not balanced by an equal and opposite change in energy LLSC), then the animal experiences a change in weight. One possible model of nutrient balance is depicted in Figure 47.2. There are four components to energy balance: (1) the afferent system, (2) the central nervous system processing unit, (3) the efferent system, and (4) the absorption of food from the gut and its metabolism in the liver. Disorders at any point in these systems may lead to weight loss or weight gain. In response to a meal or to starving, hormonal and neural signals are generated in the periphery. Some are short-term, and others are long-term. Some relate to satiety, others relate to feeding behavior, and still others relate to "thinness and fatness." Ghrelin, a stimulator of growth hormone (GH) release, is released from the stomach in the fasting state. Ghrelin activates neuropeptide Y and agoutirelatcd protein in the hypothalamus that leads to increased feeding and deposition of energy into body fat. Peripheral insulin seems to mediate a satiety signal in the ventromedial! hypothalamus. Leptin is the other component of the afferent system (see later), Destruction of the ventromedian hypothalamus, both in animals and in humans, leads to obesity. Lesions in the paraventricular nucleus have a similar effect. Overeating (hyperphagia) is only one of the mechanisms producing hypothalamic obesity. Hypothalamic lesions also can cause weight loss. Lesions in the dorsomedial nucleus lead to a reduction in body weight and fat stores, as do lesions in the lateral hypothalamus. Studies in the decerebrate rat suggest that oral motor and meal-size responses are dependent on centers in the caudal brainstem on which the hypothalamus has only a modulatory effect (Grill and Kaplan 2002). Meal size and food intake are influenced by many different stimuli. Sensory cues such as the sight, aroma, and taste of food arc major factors in dietary obesity. A
E1GURE 47.2 Sympathetic Nervous System. In the regulation of energy balance, the brain is the central processing unit. It receives afferent neuronal signals from the vagus nerve, via the brainstem and hormonal signals—ghrelin (from the stomach), insulin (from the pancreas), and leptin (from adipocytes). The brainstem also has input to the hypothalamus via norepinephrine (from the locus ccrulcus) and serotonin (5-OH-tryptamine) (from the raphe nuclei). These afferent signals are interpreted both in the brainstem (in the nucleus of the tractus solitarius) and in the hypothalamus (in the ventral medial nucleus). The ventral medial nucleus of the hypothalamus communicates with the lateral hypothalamic area (I.HA) and the paraventricular nucleus (PVN) by means of pro-opiomelanoeortin-cocaine/ampheta mine-regulated transcript (POMC-CART) an anorexigenic peptide (the release of which is stimulated by insulin and leptin) and by neuropeptide Y/agoutirelated protein (NPY/AGRP) an orexigenic peptide (the release of which is stimulated by ghrelin and inhibited by leptin and insulin). Output from the LHA and PVN is either via the sympathetic nervous system—which leads to energy expenditure through physical activity, activation of ^-adrenergic receptors and uncoupling proteins in the adipocyte to cause energy release through lipolysis. Output via the vagus nerve leads to increased insulin secretion, which causes adipogenesis and energy storage. For a more complete explanation of this control of energy balance the interested reader is directed to I.ustig 2001.
decrease in blood glucose or a decrease in the oxidation of fatty acids in the liver stimulates the act of eating. Stomach distention gives rise to neural and hormonal signals that reduce food intake. Gastrointestinal (GI) peptides such as cholecystokinin, bombesin, and glucagon inhibit feeding by their actions on the autonomic nervous system, particularly the vagal nucleus. Increased fatty acid oxidation leads to higher levels of 3-h yd roxy bury rate that act on the hypothalamus to reduce food intake. Interference with any of these sensing systems in the central nervous system can lead to obesity. Neuropeptide Y infused into the ventral
M:UKOL;NIKX;KINOI.<X;Y
medial nucleus of the hypothalamus induces obesity, perhaps by inhibiting sympathetic drive and stimulating insulin release. Although this may explain obesity with hypothalamic lesions, obesity related to eating highly palatable food is probably not related to central changes in neuropeptide Y, In animals, the ob, db, and fa genes play a role in the ability of adipose tissue to regulate feeding through a circulating factor. The product of the ob gene, leptin, is a peptide that when administered peripherally to the genetically obese (ob/ob) mouse—an animal that is deficient in leptin—reduces its intake of food, with a resulting decrease in body weight The role ot leptin in appetite regulation is complex. Leptin does not reverse the obesity seen in db/db mice and in obese humans. In these situations, serum leptin concentrations are higher than in subjects of normal weight, suggesting an insensitivity to endogenous leptin production. When melanocyte-stimulating hormone (alpha-MSH) binds to its receptor in the hypothalamus it causes satiety. Up to 5% of obese children have been found to have an abnormality of the alpha-MSH receptor—MC 4 R as a cause of their obesity (Lustig 2001). The orexins (hypocretins) are neuropeptides that play a role in energy balance and arousal. Narcolepsy is caused by failure of orexin-mediated signaling. They are found in the hypothalamus where they regulate sleep-wake cycles and in the GI tract where they excite secretomotor neurons and modulate gastric and intestinal motility and secretion. Anorexia nervosa and bulimia nervosa are clinical eating disorders seen primarily in young women and girls. Anorexia nervosa is characterized by reduced caloric intake and increased physical activity associated with weight loss, a distorted body image, and a fear of gaining weight. Bulimia nervosa is characterised by episodic gorging, followed by self-induced vomiting, laxative and diuretic abuse, dieting, and exercise to reduce weight. For many years, these syndromes were considered to be purely psychiatric. However, the finding of reduced serotonin levels in the cerebrospinal fluid (CSF) of patients with bulimia nervosa, the low CSF levels of norepinephrine in patients with anorexia nervosa, and the enhanced secretion of cholecystokinin in patients with anorexia nervosa suggest that neurotransmitter or neuropeptide abnormalities could be responsible for at least part of the clinical picture in these patients. Furthermore, patients with anorexia nervosa seem to have an increased total daily energy expenditure because of their increased physical activity. Whether these are causes or effects of the condition remains to be determined.
Emotion and Libido Fxperimental and clinical data support the hypothesis that interaction of the frontal and temporal lobes and the limbic
s>>
system is necessary for normal emotional function. Lesion and stimulation experiments in the cat have shown that rage reactions can be provoked from the hypothalamus. In the human, electrical stimulation of the septal region produces feelings of pleasure or sexual gratification, whereas lesions of the caudal hypothalamus or manipulation of this area during surgery may cause attacks of rage. The amygdala, with its rich input from polyscnsory areas and limbic-associated areas and its output to the hypothalamus, and other subcortical areas are important structures through which the external environment can influence and cause emotional responses. Libido, like other feelings, requires the participation of both hypothalamic and extrahypothalamic sites. In most instances of hypothalamic disease, loss of libido is caused by impaired release of gonadotropin-releasing hormone (GnRH) and a subsequent decrease in testicular testosterone in men. In women, libido is related more to adrenal androgens. These levels may be low in women with cotticottopin (ACTH) deficiency and secondary adrenal insufficiency. Hypersexuality associated with hypothalamic disease is rare and may occur with or without a subjective increase in libido. There is a gradually expanding understanding of the human hypothalamus in relation to normal development, sexual differentiation, aging, and some degenerative neurological disorders (Swaab et al. 1993). The sexually dimorphic nucleus, or intermediate nucleus, of the preoptic area is twice the volume in male subjects as it is in female subjects. The size does not differ between homosexual and heterosexual men. Although the shape of the suprachiasmatic nucleus differs in male and female subjects, the vasopressin cell number and volume are similar in men and women. Homosexual men seem to have a larger suprachiasmatic nucleus, containing twice as many cells as heterosexual men (Swaab et al. 1993). The significance of this observation is, at present, uncettain.
Biological Rhythms Most endocrine rhythms are circadian—that is, a complete cycle takes approximately 24 hours. Although longer and shorter cycles do occur, the circadian rhythms have been studied most extensively. In many animals, light plays an important role in regulating circadian rhythms. Nerve fibers project from the optic chiasm to the suprachiasmatic and arcuate nuclei of the hypothalamus. The hypothalamus is responsible for the hormonal rhythms, such as Cortisol and GH secretion and the behavioral rhythms such as sleep-wake cycles and estrous activity. Although patients with hypothalamic disease often have disturbances in their biological rhythms, these are usually of less clinical importance than the other problems caused by such lesions.
SS6
NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Hyporhalamic-Pituitary Unit Functional Anatomy In humans, discernible hypothalamic-pituitary tissue begins to develop during week 5 of embryonic life. Rathke's pouch, a diverticulum of the buccal cavity, forms and expands dorsally to contact and invest the diverticulum, which develops from the floor of the third ventricle. By week 11, the buccal tissue has lost its connection with the foregut and has flattened to form the primitive anterior pituitary, whereas the neural tissue from the floor of the third ventricle is forming the posterior pituitary. Residual Rathke's pouch tissue is postulated to give rise to the craniopharyngiomas, which can occur in this region. Rarely, ectopic functional pituitary tissue in the oropharynx can cause signs and symptoms of hyperpituitarism. The hypothalamus, despite its small size, is the region of brain with the highest concentrations of neurotransmitters and neuropeptides. Beginning with the pioneering work of Ernst and Berta Scharrer and Geoffrey Harris in the 1940s, the hypothalamus lias been assigned a central role in the regulation of anterior pituitary function. In addition to the identified hypophysiotropic hormones (Table 47.4), other peptides with putative regulatory functions are found in high concentration in the hypothalamus, including neurotensin, substance P, cholccystokinin, neuropeptide Y, vasoactive intestinal polypeptide, and the opioid peptides. The hypothalamus is also rich in acetylcholine, norepinephrine, dopamine, serotonin, histamine, and y-aminobutyric acid. In many neurons, these neurotransmitters colocalize with peptides, although this colocalization and presumptive corelease have uncertain physiological significance. A common presentation of patients with nonfunctioning pituitary or parapituitary tumors is symptoms produced by compression of neural structures adjacent to the pituitary gland. Understanding these symptoms requires knowledge of the anatomy of the region (Figure 47.3). Tumor erosion of the floor of the sella turcica may lead to CSF rhinorrhea. Conversely, sinusitis or sphenoid sinus mucocele can invade the sella and cause anterior pituitary dysfunction. Expansion of pituitary tumors into the cavernous sinus can produce a variety of upper cranial nerve palsies. This is especially common with the sudden
Tahlc 47.4:
expansion of pituitary tumors that occurs in pituitary apoplexy. Carotid aneurysms or ectatic carotid arteries in the cavernous sinus may expand medially and mimic pituitary adenomas by enlarging the sella and causing anterior pituitary hypofunction. The dura overlying the sella is sensitive to pain and, when stretched by expanding pituitary tumors, gives rise to headache referred to rhe vertex and retro-orbital ly. In certain individuals, especially if intracranial pressure is elevated, the dura may herniate in the reverse direction into the sella, where with time continued pulsation of the CSF leads to remodeling and expansion of the sella. This produces the radiological finding of the empty sella syndrome, another cause of which is lymphocytic hypophysitis. The pituitary gland becomes a thin ribbon of tissue along the walls of the expanded sella, and the sella consists mostly of CSF. Rarely is there evidence of pituitary function impairment in such patients. Expansion of pituitary tumors out of the sella tends to lead to compression of the anterior and inferior crossing fibers of the optic chiasm (see Chapters 14 and 40). These fibers subserve vision in the superior temporal quadrants. Therefore pituitary adenomas typically cause bitemporal superior quadrantanopias. Lesions such as craniopharyngiomas that impinge on the posterior and superior optic chiasm tend to present with bitemporal inferior quadrantanopias. Despite these rules, the variability of the positioning of the optic chiasm and the tendency for tumors to be asymmetrical in their growth result in a wide variety of field defects being caused by parasellar lesions.
Blood Supply The pituitary's major source of blood is via the superior and inferior hypophyseal arteries (Figure 47.4). The posterior pituitary gland is supplied principally by the inferior hypophyseal arteries and is drained by the inferior hypophyseal veins. The superior hypophyseal artery forms a primary capillary plexus in the median eminence of the hypothalamus. From here, the blood flows into the long hypophyseal portal veins, which carry it to the anterior
Hypothalamic peptides controlling anterior pituitary hormone release
Pituitary hormone
Hypothalamic factor
Growth hormone
Growth hormone-releasing hormone Growth hormone release inhibiting hormone (somatostatin) ProJactin-rcleasing factor Pnihctiii rvli':iv: inhibiting faemr: dopamine and JKHMIIIV (Inprecursor of gonadotropin-releasing hormone Thyrotropin-releasing hormone Thyrotropin release inhibiting factor: somatostatin can do this, but it is uncertain if it docs so physiologically Corticotropin-releasing hormone Gonadotropin-releasing hormone
Prolactin Thyrotropin
Proopiomelanocortin is cleaved to form corticotropin Luteinizing hormone and follicle-stimulating hormone
NEUROENDOCRINOLOCY
857
FIGURE 47.3 Diagrammatic representation of the anatomical relations of the pituitary fossa and cavernous sinus. The lateral wall of the sella turcica is formed by the cavernous sinus. The sinus contains the carotid artery, two branches of the fifth cranial nerve (ophthalmic and maxillary), third nerve (oculomotor), fourth nerve (trochlear), and sixth nerve (abducens). The optic chiasm and optic tract are located superior and lateral, respectively, to the pituitary. (Reprinted with permission from Martin, J. B., Reichlin, S., &c Brown, G. M. 1977, Clinical Neuroendocrinotogy, Davis, Philadelphia. Drawing by B. Newberg.)
pituitary. Although some of the blood from the anterior pituitary drains into the cavernous sinus, some drains into the posterior pituitary, and some returns to the median eminence via the long portal veins, which are capable of bidirectional blood flow. This vascular anatomy provides a potential mechanism for the important feedback loops that ate necessary for regulation of hypothalamicpimitary function.
ANTERIOR PITUITARY Hypothalamic Control of Anterior Pituitary Secretion The hypothalamus produces hypophysiotrophic substances that control the secretion of anterior pituitary hormones. Five neuropeptides and one neurotransmitter (dopamine) are known to be important physiological regulators of FIGURE 47.4 The blood supply of the median eminence and pituitary gland. {Reprinted with permission from Marrin, Primary pi ex us J. B. &C Cooper, P. E. 1983, "Neuroendocrine disease,'1 in The Clinical h!enrosciences, ed R. N. Rosenberg, Churchill Superior hypophysial Livingstone, New York) artery Long hypophysial portal veins Artery of trabecula
Efferent aural vein Short portal veins
858
NEUROLOGICAL INVESTIGATIONS AND RFLATF.D CLINICAL NEUROSCIENCES
pituitary function {see Table 47.4). In addition, several neurotransmitters affect pituitary hormone release, although their physiological role remains uncertain. The pri-cursor moliviili' for (riiKI i, in addition to containing the sequence for GnRH, contains a peptide that is a potent inhibitor of prolactin release, suggesting that hypothalamic control of pituitary secretion may be even more complicated than previously thought.
Abnormalities of Anterior Pituitary Function Hypofunction The causes of pituitary insufficiency are summarized in Table 47.5. In general, the symptoms of hypopituitarism (Table 47,6) are those of the secondary failure of endorgan function. Because the symptoms usually develop slowly and some autonomous end-organ function remains, the symptoms are often less severe than those that occur with primary end-organ disease. The term Simtnonds' disease is applied to panhypopituitarism. When this develops postpartum following an episode of pituitary infarction, it is called Sheeban's syndrome. Intrauterine growth is independent of GH. Therefore although GH-dcficient children are of normal size at birth, they fail to grow. Somatic growth in the human is mediated by at least two factors: insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II). IGF-I production in the liver is GH-dependent, whereas IGF-II is relatively insensitive to GH. True GH deficiency is rare. It may present in an isolated fashion or as part of general pituitary failure. Apparent GH deficiency may result from an isolated deficiency of GH-releasing hormone or a lack of GH receptors in the liver leading to failure of IGF-I production (Laron dwarf). GH is a contra-insulin hormone,
Table 47.6:
Tabic 47.S:
Causes of pituitary insufficiency
Pituitary aplasia Complete Mono hormonal Trauma Head injury Surgery Radiotherapy Compression by cysts or tumors Pituitary apoplexy Pituitary infarction Hypophysitis Infection Granulomatous disease Autoimmune disease Hypothalamic failure
and, in children especially, its deficiency may be associated with episodes of fasting hypoglycemia. A detailed discussion of growth is beyond the scope of this chapter. The interested reader is referred to the review by Rosenfield (19%). Pituitary insufficiency in the child may present as delayed or absent puberty. Onset of puberty depends, to some extent, on achievement of a critical body mass. Thus, anything that delays growth, such as GH deficiency or hypothyroidism, delays puberty. If breasts or sexual hair have not started to develop in girls by age 14, or if testicular enlargement and sexual hair have not occurred in boys by age 15, then puberty should be considered delayed. Luteinizing hormone (LH) or follicle-stimulating hormone (FSH) deficiency may occur as part of generalized pituitary failure or as a result of high prolactin levels or of GnRH deficiency. One cause of hypopituitarism is pituitary apoplexy, a term that should be reserved for infarction of, or
Clinical syndromes of anterior pituitary dysfunction
Hormone
Excess secretion
Deficient secretion
Growth hormone
In children: gigantism
In children: growth failure and tendency to hypoglycemia
Prolactin
Luteinizing hormone and follicle-stimulating hormone
Thyrotropin Pro-opiomelanocortin
In adults: acromegaly In children: delayed puberty In adults: Women: amenorrhea, galactorrhea, and infertility Men: impotence, infertility, and (rarely) galactorrhea In children: precocious puberty In adults: infertility, hypogonadism, polycystic ovary syndrome Hyperthyroidism Hyperprolactinemia Cushmg's disease, Nelson's syndrome
In adult women: inability to breast-feed and possible infertility In children: delayed puberty In adults: amenorrhea, infertility, impotence Hypothyroidism Hypoadrenalism—glucocorticoids affected more severely than mineralocorticoids
NEUROENDOCRINOl.OGY hemorrhage into, the pituitary gland or a pituitary adenoma that is of sufficient severity to produce signs of compression of parasellar structures or evidence of meningeal irritation. The sudden expansion of the pituitary gland may lead to chiasmal compression or cranial nerve palsies. Rupture of the necrotic gland into the CSF may lead to a picture that is indistinguishable clinically from subarachnoid hemorrhage caused by rupture of a berry aneurysm or arteriovenous malformation. Hypotension, aggravated by pre-existing ACTH deficiency, may further complicate the picture. The diagnosis can usually be made readily by computed tomographic (CT) scanning or magnetic resonance imaging (MRI). Treatment includes general supportive measures, corticosteroid replacement, and, if necessary, surgical decompression. Hyperfunction Precocious Puberty. Development nf secondary sexual characteristics before age $ in girls and age 9 in boys is considered abnormal. Approximately one fifth of girls and one half of boys develop precocious puberty because of neurological lesions. A variety of tumors have been associated with the development of precocious puberty including hamartoma; teratoma; ependymoma; optic nerve glioma; glioma; and neurofibroma, either alone or as part of von Recklinghausen's syndrome. Tumors are most commonly located in the posterior hypothalamus, pineal gland, or median eminence, or they put pressure on the floor of the third ventricle. The cause of precocious puberty under these circumstances has not been clearly delineated. However, some of these tumors may be an ectopic source of GnRH or of human chorionic gonadotropin, a placental peptide with LH- and FSH-like activity. In the investigation of precocious puberty, LH and FSH levels should be measured as well as human chorionic gonadotropin. A CT scan or MRI of the head is mandatory. If LH and FSH levels are in the adult range and the head scan result is negative, it is most likely that the precocious puberty is idiopathic. High human chorionic gonadotropin levels suggest ectopic production. If LH and FSH levels are low, then adrenal, ovarian or testicular, or exogenous causes must be sought. Chronic administration of long-acting analogues of GnRH is followed by an initial stimulation of LH and FSH secretion and then complete inhibition. This effect on LH and FSH release can be used to prevent progression of hypothalamic precocious puberty. Hyperprolactinemia. Probably the most common abnormality of pituitary function encountered by the neuroendocrinologist is hyperprolactinemia. The causes of hyperprolactinemia are summarized in Table 47.7. Prolactin levels in excess of 200 ng/mL (normal, A
AED = antiepileptic drug; BDZ = benzodiazepine; GABA = K-aminobutyric acid; GAD = glutamic acid dehydrogenase; Rx = treatment.
882
NEUROr.OGlCAI. INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Table 49.2:
Examples of clinical disorders (human unless noted) puratively associated with mutations of ligand-gated receptors Gene, channel component affected
Disorder(s)
Comments
Childhood absence epilepsy plus (GEFS+) 1. Hyperekplexia 2. Nonketotic hyperglycinemia (glycine encephalopathy)
Linkage disequilibrium detected in French, but not Chinese, families 1. Uncouples ligand binding from opening of chloride channel 2, Inadequate mitochondrial metabolism of glycine 1. Product of Huntington's disease gene interacted « itll NMDA receptors to enhance vulnerability 2. HD gene modulates NMDA receptor expression 3. Accounts for variable age of onset of Huntington's disease in patients 4. Metabotropic glutamate receptors play a role in learning 5. AMPA receptors play a role in learning 6. AMPA receptor changes contribute to phenorype First epilepsy mutation discovered
GABA
GABRG2 affect ins- iiaiimia-2 Milium!
Glycine
1. GLRA1 affecting alpha-1 subunit 2, Glycine cleavage enzyme genes P (85%), T (15%), H (rare)
Glutamate
1. Mutant huntingtin expressed in cell line 2. Expression of exon 1 of human Huntington's disease gene in transgenic mice 3. Polymorphism linked to kainate receptor 4. mGluRS knockout mice 5. GluRl AMPA receptor subunit knockout mice 6. Receptor subtype mRNA for GluR3 low, GiuR4 high
1. Enhanced NMDA-mediated excitotoxicity 2. Increased NMDAR1 and decreased NMDAR2 currents and proteins 3. Huntington's disease 4. Reduced nonvisual learning 5. Impaired spatial learning 6. mnd mouse model of motor neuron disorders and ceroid lipofuscinosis
Acetylcholine
CHRA4 gene for nicotinic cholinergic receptor muscarinic receptor decreases cyclic adenosine monophosphate (cAMP) production presynaptically and indirectly decreases neurotransmitter release, presumably by decreasing activation by phosphorylation of calcium-dependent calmodulin. Released ACh diffuses across the synaptic cleft and activates both nicotinic and muscarinic receptors in the CNS. Nicotinic receptors are ionotropic, and activation results in admission of sodium and exit of potassium through the channel. Muscarinic receptors are metahotropic. Muscarinic M h M 5 , and M 5 receptors are linked by Gq to phospholipase C. Activation of these receptors results in increased intracellular calcium due to the production of inositol Triphosphate (IP.i) as the intracellular second messenger. Muscarinic M z and M 4 are linked to adenylyl cyclase hy the inhibitory G protein Gj. The result is decreased intracellular cAMP, Some postsynaptic M; and M^ receptors arc linked by G proteins directly to ion channels, which allow entry of calcium and exit of potassium. The action of ACh at its postsynaptic receptors is terminated principally by degradation. Acetylcholinesterase (AChE) in the postsynaptic membrane results in the release of choline, which is rescqucstcrcd by a specific transporter (T) in the presynaptic membrane and is then resynthesized into ACh for subsequent release. Agonists (+) and antagonists ( - ) have been identified for many of these specific receptors and processes,
nicotinic-cholinergic receptors suggesting that they enter the channel. Other toxins bind at different sites. Neosurugatoxin selectively blocks ganglionic nicotinic receptors, and lophotoxin blocks ganglionic and neuromuscular nicotinic receptors. The marine cr-conotoxins, G1A and M l , potently block neuromuscular transmission but not ganglionic nicotinic activity. This differential binding suggesrs that the ganglionic nicotinic receptors differ in subunit composition from the neuromuscular receptor.
with mRNAs for a- and ,6-receptor subunits in combination or when cell lines are transfected with cDNAs for both u- and /I receptor subunits. Central nicotinic neuronal receptors have been mapped using in situ hybridization methods. The «2-subunit is widely distributed. Different brain regions contain variable electrophysiological and pharmacological properties of receptors containing a2-subunits in combination with several other subunits.
Neuronal
Neuronal
Nicotinic
Receptors
Neuronal nicotinic receptors are inotropic receptors. Ten or more receptor subunit genes have been cloned. Functional ACh-gated channels arc expressed in frog oocytes injected
Muscarinic
Receptors
Muscarinic receptors are metahotropic receptors. Five receptors belonging to the family of G protein-associated receptors have been isolated. Agonists bind in a deep
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
pocket formed by the seven transmembrane regions. Variations in the long third intracellular loop result not only in differences in the binding to G proteins, but also in the effects of antagonists, as shown by site-directed mutagenesis. This technique introduces mutations of one or a few amino acids that alter receptor function. Selectivity of antagonists for cloned receptors parallels pharmacologically defined receptor activity in naturally occurring, intact systems. For example, pirenzepine selectively blocks both cloned and naturally occurring Ml receptors and AFDX-116 preferentially blocks M2 receptors. Muscarinic receptor types M l , M 3 , and M5 couple to members of the Gq family of G proteins. In turn, the G protein activated by ligand binding to the receptor activates phospholipase C. This results in phospholipid hydrolysis that liberates two intracellular second messengers, IP3 and diacylglyccrol (DAG). Each of these intracellular second messengers has unique effects, as described previously. The IP3 releases intracellular calcium stores and can be involved in cascades of cellular injury. DAG activates protein kinase C, which phosphorylates several receptors and alters their conductance states. Receptors of the M2 and M4 type couple to the a-subunit of the inhibitory Gi protein that inhibits adenylyl cyclase and reduces intracellular cAMP levels. Alternatively, these two receptors can couple to certain ion channels directly by either of the GTP-binding proteins, Gi or Go. Muscarinic receptor subtypes are differentially distributed in the brain. The hippocampus is virtually devoid of the M2-type receptor, but the other four types are expressed to varying degrees, with Ml having the densest expression. ACh induces a pirenzepine-insensitive hyperpolarization in the thalamus where the M2 receptor is significantly expressed. The hyperpolarization appears to result directly from increased potassium conductance secondary to receptor activation coupled to Gi. Thus physiologically and pharmacologically defined regional effects of ACh parallel expression of genes for various subtypes of muscarinic receptors. A consideration of long-term regulation of receptor numbers is an important property of muscarinic receptors for designing drugs to treat neurological disorders. Prolonged exposure to ACh or other agonists causes downregulation of muscarinic receptors. The Alzheimer's disease treatment agent, tetrahydroaminoacridine, raises brain ACh levels by weakly inhibiting AChE. Reports of mixed efficacy could in part be due to downregulation of receptors, which opposes the effect of chronically increased ACh levels. Protein kinase activation can mimic the effects of prolonged exposure to agonists. Presumably, phosphorylation reduces affinity of the receptor for agonists, and dephosphorylation, by unknown phosphorylases, results in resensitization or availability of the receptors. Phosphorylation-dcpendent desensitization may be a common mode of regulation of G protein-coupled receptors. Control of this process could provide therapeutic agents designed to modulate receptor numbers in specific brain regions.
Acetylcholine Receptors in Disease States The treatment of several clinical disorders uses cholinergic agents (Table 49.4). A number of important clinical disorders involve muscarinic cholinergic neurotransmission. Reduction of cholinergic neurons and capacity to synthesize ACh occurs with normal aging. However, premature degeneration of cholinergic neurons occurs in Alzheimer's disease. Excitotoxic injury to cholinergic neurons plays a role in Parkinson's and Huntington's diseases. Experimental models also implicate ACh in the pathophysiology of human epilepsy. Reduced ACh synthesis occurs in some inherited disorders of mitochondrial enzymes and thiamine-dependent pyruvate dehydrogenase (the enzyme that catalyzes the oxidation of pyruvate to acetyl Co-A). Affected patients have mental retardation, spasticity, ataxia, and dystonia. The symptom diversity emphasizes the multiple functions subserved by cholinergic neurotransmission. Medications that block muscarinic receptors are used to treat vertigo, motion sickness, and diarrhea. ACh triggers the pontogeniculooccipital (PGO) spikes at the onset of rapid eye movement (REM) sleep and anticholinergic medications have sleepinducing properties. Smoking is an example of addiction resulting from habitual use of nicotine. Myasthenia gravis is an important clinical problem involving nicotinic receptors. Intoxications with pesticides, nerve agents, and bacterial toxins (e.g., botulinum toxin) affect cholinergic receptors centrally and peripherally. No discussion of cholinergic mechanisms would be complete without mentioning the mydriatic effect of belladonna (Atropa belladonna), once used as a cosmetic and later as a poison. A mutation in the gene encoding the c4 nicotinic cholinergic receptor has been associated with autosomal dominant nocturnal frontal lobe epilepsy {see Table 49.2). Ongoing genetic research is examining the role of polymorphisms in AChR-associated genes in susceptibility to Alzheimer's disease
DOPAMINE The role of dopamine in neurological disease initially received attention in 1957 with the demonstration that reserpine depletes the brain and heart of NE and dopamine. Dihydroxyphcnylalaninc (DOPA), a precursor of catecholamine synthesis, restores dopamine levels and reverses the sedative action of reserpine. During the 1960s, the formaldehyde fluorescence technique allowed the visualization of monoamines, including dopamine. Reports of low dopamine concentrations in the basal ganglia of patients with Parkinson's disease led to the discovery that increasing doses of L-dopa relieved the symptoms of parkinsonism. Optimizing dopaminergic neurotransmission remains central to the treatment of Parkinson's disease (see Chapter 78).
PRINCIPLES OF NEUROPHARMACOLOGY AND THERAPEUTICS Table 49.4:
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Acetylcholine in disease states
Disorder Nicotinic receptors 1. Smoking 2. Myasthenia gravis 3. Myasthenic syndrome 4. Botulism i. Snake bite (krait) 6". Pain
Trail men t
Pathophysiology Habituation, associated behaviors Antibodies against postsynaptic receptors at neuromuscular junction Antibodies against presynaptic calcium channels reduce A eh release Ingested toxin decreases Ach release c-Bungarotoxin decreases Ach release; /f-Rungarotoxin blocks NAChR ACh released by acupuncture in adrenergic locus ceruleus and serotonergic dorsal raphe
Slow taper and discontinuation AChE inhibitors + muscarinic antagonists Guanidine; amino pyridines sensitize netve terminals to Ca 2 + ; AChE' inhibitors Guanidine or aminopyridiues; pyridostigmine; antitoxin Antivenin; good luck Nicotine (old war movies); nicotinic agonists(dimethylphenylpiperazine)
Muscarinic receptors 1. Aging 2. Alzheimer's disease .5. Parkinson's disease 4. Huntington's disease 5. Epilepsy
6. AChE inhibitor intoxication 7. Pain
8, Sleep 9. Mitochondropathies
10. Vertigo/motion and space sickness
Decreased CAT and AChE accompany cognitive decline Excessive and premature loss of cholinergic neurons (n. basalts of Meynert) Excessive cholinergic activity in basal ganglia with loss of dopaminergic innervation Decreased (. .AT in striatum Seizures produced in animals by pilocarpine Seizures in man/anitnals by nerve agents (AChE inhibitors) Nerve agents and pesticides producedeadly seizures Spinal cord (posterior horn) and midbrain circuits involved in pain neu retransmission; Acupuncture releases ACh and opioids ACh triggers PGO spike at onset of REM Insomnia and narcolepsy increase REM Decreased ACh synthesis (decreased acetyl Co-A synthesis due to low activity of thiamine-dependent pyruvate dehydrogenase and other enzymes) Vestibular ± vestibulocerebellar dysfunction
No known preventative treatment Tacrine and doncpezil slow course Muscarinic antagonists (trihexyphenidyl); tricyclic antidepressants Muscarinic antagonist for some abnormal movements Anticonvulsants; benzodiazepines; memantine
Muscarinic anticholinergics; anticonvulsants Tricyclic antidepressants; acupuncture
Antimuscarinic tricyclic aillidcpres^inK No effective treatment
Antihistamines (meclizine}, tricyclic antidepressants, and phenorhiazines with anticholinergic action Antimuscarimcs (scopolamine + dcxedrine)
ACh = acetylcholine; AChE = acetylcholinesterase; CAT = choline acetyl transferase; REM = rapid eye movement.
Chemistry, Pharmacology, and Distribution The catecholamines' (dopamine, NE, and epinephrine) synthesis from L-tyrosine is by a cascade of enzymes. Immiinoeytochemical and in situ hybridization techniques have allowed these enzymes to be purified to homogeneity, cloned, and localized in the CNS. Phenylalanine forms tyrosine, which is actively transported across the blood-brain barrier. The enzyme phenylalanine hydroxylase catalyzes the conversion. Deficiency of this enzyme is responsible for the classic form of phenylketonuria (see Chapter 71). Tyrosine hydroxylase catalyzes an alternate pathway in the synthesis of tyrosine from phenylalanine. Tyrosine hydroxylase is a cytoplasmic mixed-function oxidase that requires retrahydrobiopterin and oxygen as cofactots. Tyrosine hydroxylase catalyzes the conversion of Ltyrosine to L-dopa, and dopa decarboxylase, a pyridoxal
phosphate-dependent enzyme (also known as aromatic acid decarboxylase), converts [,-dopa to dopamine. This lattet reaction is the target of oral precursor treatment with Ldopa in the treatment of Parkinson's disease. Dopa decarboxylase is present in the cytoplasm of catecholaminergic and serotonergic nerve terminals; this enzymatic step is intermediate in the synthesis of the other monoamines. Dopamine is transported into storage vesicles for later release as a neurotransmitter. Amine transporters similar to drug resistance transporters of bacteria have been cloned; they characteristically have twelve transmembrane domains. The uptake of monoamines into storage vesicles is ATP-depcndent and linked to a proton pump. In the vesicles, the catechols form complexes with ATP and acidic proteins called chromogranins. Monoamine oxidase (MAO) deaminates free dopamine inside nerve terminals, Drugs that interfere with vesicular storage, such as
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINIC:Al. NEUROSCIENCES
amphetamines or reserpinc, displace dopamine into the cytoplasm, where it is inactivated. Catechol-o-methyl transferase (COMT) breaks down dopamine that has diffused into the extracellular space. The basal ganglia contain about 8 0 % of total brain dopamine. Dopaminergic neurons in the ventral tegmental tract send fiber bundles to the nucleus acumbens (the mesolimbic tract) and to the cerebral cortex (the mcsocort:;,)l h.iiui\' . I I:HT-, also I'MLTIII from [IK- arcuate nucleus ro the median eminence. The mesolimbic projection ascends in the medial forebrain bundle. The further distribution of these fibers is to telencephalic structures including the olfactory bulb, olfactory nucleus and tubercle, lateral septal nucleus, stria terminalis, and parts of the hippocampus and amygdala. This branch also innervates the mesial frontal, anterior cingulatc, pyriform, and entorhinal cortices. The mesocortical projections terminate predominantly in the frontal (especially prefrontal) neocortex. Scattered groups of dopaminergic neurons are also present in the retina and spinal cord,
Dopamine Receptors Dl and D2 arc the two families of dopamine receptors. Their different effects on adenylate cyclase originally separated these two families. DJ receptor activation augmented enzyme activity and D2 receptor activation decreases activity. Both families are linked to G proteins and have the predicted structure of seven transmembrane domains. The major difference between the two families of dopamine receptors is the sequence of the third intracytoplasmic loop, which governs G protein binding. The Dl family consists of two receptors, Dl and D5, which couple to the 3, and MCBFV increments >50 cm per second within a 24-hour period) (Suarez et al. 2002); verification of cerebral hyperemia after traumatic brain injury (elevated MCBFV with Lindegaard's ratio 4 as potential thrombolytic candidates. Patients with NIHSS scotes >18 have the worst clinical outcomes. In addition to the use of the NIHSS, imaging techniques such as CT, MR1, angiography, and TCD can assist in the evaluation of acute stroke patients. With the advent of rapid MRI technology, imaging can even help with the triage of acute stroke patients for treatment (Sunshine et al. 1999}.
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However, before there can be any discussion of treating a patient, the stroke victim must be clinically stabilized. This brings us back to the "ABCs" of basic life support. For patients whose airway is at risk, who arc in respiratory distress, or whose GCS score is less than eight, immediate intubation and mechanical ventilation arc necessary. Acute stroke patients with evidence of Cushing's triad {systemic hypertension, bradycardia, and respiratory disturbances) raise the suspicion of elevated ICP and therefore require immediate intubation. Controlled hyperventilation for management of elevated ICP can then be performed {see later discussion). Rapid sequence intubation, the generally preferred method, is described previously (Peterson et al. 1998). Following intubation, optimization of patient comfort and the need to avoid elevations in intracranial pressure (caused by vasodilation as a result of abnormal cerebrovascular compliance that occurs in cerebral tissue damage) warrant sedation with short-acting agents such as propofol or midazolam. If the patient is acutely hypotensive at presentation, aggressive fluid replacement must be initiated. Because of the need to avoid dextrose or hypotonic solutions that can worsen cerebral edema, 0.9% saline fluid is routinely used. Should vasopressors be necessary, phenylephrine is used because it is an a\ agonist, and cerebral vessels tend to have a very small population of al agonists. Dopamine is often used when bradycardia is present. Animal studies and clinical evidence suggest the benefit of increasing CPP through the ischemic penumbra that surrounds the core ischemic brain tissue. As a result it is recommended to aggressively hydrate all ischemic stroke patients (with due consideration for other factors such as heart failure). This is thought to increase the CPP by increasing total intravascular volume or truly increasing cerebrovascular ABP. Some clinicians try to achieve a systolic blood pressure between 140 and 180 mm Hg in acute ischemic stroke patients. Although it may not be necessary to induce hypertension in clinically stable patients, for patients with known stenoses of the cerebral arteries (both intracranial and extracranial vessels, such as the carotid and vertebral arteries), it has been shown to be safe and effective to do so. Note also needs to be made about control of elevated ABP. Auto regulation following ischemic sttoke usually produces elevated ABP. This is in fact the inherent compensatory mechanism of the brain to maintain adequate CBF. It also forms part of the basis for the theory behind the efficacy of induced hypertension to improve clinical outcome in stroke by increasing CBF to the ischemic penumbra. But m the setting of the need to administer thrombolytic therapy, systemic hypertension can be dangerous. This is due to the increase in incidence of postthrombolysis ICH seen with elevated ABP. Likewise, even in the absence of the use of thrombolytics, extremely elevated ABP can alone be a risk factor for hemorrhagic conversion of an infarct. Guidelines for the management of
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
elevated ABP in the setting of acute ischemic stroke have been established (Adams et al. 1996): 1. For diastolic blood pressure >140 mm Hg on two readings 5 minutes apart, administer IV infusion of sodium nitroprusside (0.5-10 jjg/kg/min) and titrate until diastolic blood pressure goes down by 2 0 % . 2. For systolic blood pressure >230 mm Hg and/or diastolic blood pressure of 121-140 mm Hg, administer IV infusion of labetalol (10 mg delivered over 1-2 minutes; repeat this bolus or double the dose of labetalol successively every 10 minutes up to a total dose of 150 mg). If labetalol is still not effective, administer sodium nitroprusside. 3. For systolic blood pressure of 180-230 mm Hg and/or diastolic blood pressure of 105-120 mm Hg, administer IV infusion of labetalol as in (2), up to 150 mg total dosage. 4. After initial control of the elevated ABP, labetalol can be administered every 4-8 hours. For patients with asthma, bronchial hyper-re activity, heart failure, or severe cardiac conduction defects, labetalol is not the drug of choice, and other agents are indicated. In addition to close monitoring of ABP, blood glucose must also be monitored closely. At a minimum blood glucose should be checked every six hours for all acute ischemic stroke patients, even nondiabetic ones. For serum concentration above 150 mg/dL serum glucose should be lowered, since hyperglycemia is known to exacerbate focal neurological deficits (Weir ct al. 1997}. T needs to be taken frequently and maintained at less than 37.5 C. F.levated T has also been associated with poor outcomes in acute stroke patients. If a patient who has received thrombolytic therapy for an acute stroke is suspected to have bled, the hematocrit, hemoglobin, PTT, PT/INR, platelet count, and fibrinogen must be determined. Transfusion of blood products may be necessary. Because patients receiving thrombolytic therapy should be admitted to an NSU in the immediate postthrombolysis phase, recommendations by the American Heart Association for management of bleeding are reviewed here: 1. Thrombolytic therapy should not be used unless there are readily available facilities to handle bleeding complications. 2. Until head CT scanning is available for a patient who experiences new or worsened neurological deficits, ICH must be suspected as the likely cause of deterioration of clinical status. In this case—as in all cases of suspected thrombolysis-associated bleeding— the infusion of the thrombolytic agent or any anticoagulant therapy must be stopped, I lead CT scanning is obviously emergently necessary. 3. Surgical consultation should be considered.
For large ICH, any coagulopathy will have to be corrected. Cerebellar hematomas and large (>60 cc) lobar hemorrhages that have mass effect require emergent drainage. Either in the case of ICH or simply because of large ischemic strokes (for example, complete MCA occlusion with poor collateral flow [has causing infarction of the complete MCA territory) or for other reasons, there can be so much cerebral edema that significant mass effect and elevation of ICP can occur. In these cases an intensive care environment, if the patient is not already in one, is critically important. Management of this condition is reviewed in the following section.
Cerebral Edema and Elevated Intracranial Pressure Through a complex mechanism relating to multiple membrane proteins and transporters involved in the formation of the blood-brain barrier (BBB) and to several autacoids and proinflammatory proteins, under certain pathological conditions this barrier can break down. Once BBB is permeable there can be a net influx of water and solutes to the interstitium and intracellular spaces, thereby causing cerebral edema. Some of the conditions that can cause this are primary cerebral injuries such as ischemic infarcts, ICH, and traumatic brain injury. Cerebral edema can be worsened by such secondary factors in brain injuries as hypotension, hypoxemia, and seizures. Once an affected area of the brain is edematous, the potential for mass effect arises, because the intracranial volume is essentially fixed by the rigidity of the skull. In the setting of mass effect, ICP can rise and raise the grim prospect for the development of herniation syndromes. This is the profound danger of cerebral edema and explains the need for close monitoring of patients with the potential for cerebral edema who show neurological worsening or of parients with significant cerebral edema even without evidence of neurological worsening. An example of the latter is large lobar ischemic strokes that can develop cerebral edema up to 96 hours after the initial infarct. The normal mean ICP is in the range of 5-10 mm Hg, Levels above 15 mm Hg are considered absolutely abnormal (see the previous discussion). Once ICP is elevated, it is considered an emergency and may require emergent treatment to lower it. Management of elevated ICP involves both medical and surgical maneuvers (Suarez 1999). The first step (assuming the cervical spine is stable for flexion) is to place the patient's head and upper trunk at 30"; in many cases this is effective in reducing ICP (Frank 1993). Medical treatment then begins with evaluating the need for intubation. If the airway is unstable, if there is respiratory distress, or if the GCS is less than 8, the patient needs emergent intubation. However, elevated ICP alone can necessitate intubation to perform one of the primary means of treatment, which is controlled hyperventilation (HV). This means increasing
PRINCIPLES OF NEUROINTENSIVE CARE
the respiratory rate of the intubated patient to blow off more C 0 2 . The goal Pa«>2 is between 28 and 33 mm Hg. Lowering the Paco 2 beyond this range carries a risk of inducing cerebral ischemia and therefore must be avoided. Hyperventilation is the fastest method of medical management for elevated ICP, and its effect lasts for several hours. Once the target Pact); has been achieved, recommended practice is to slowly decrease the ventilatory rate to allow the Paco2 to rise at about a rate of 2 mm Hg per hour up to the normal range. This will allow the treating physician to use hyperventilation later on, should it be necessary in a given patient. The next step is to administer hyperosmolar solutions, most commonly mannitol. Generally mannitol is given as a bolus over 10-15 minutes at a dose of 0.5-2.0 g/kg. A phenomenon known as "rebound" cerebral edema has been described in the setting of continuous mannitol infusions, and thus continuous infusion is not advised. Serum osmolarity must be measured, usually every six hours, to adjust the requisite dose of mannitol to keep osmolarity above normal (usually 300-320 mOsm/L). If an intraventricular catheter is already in place, this can be used to draw off CSF to directly lower ICP. When these methods fail to lower ICP, barbiturate coma is the next step. The commonly recommended technique is to induce coma with high-dose pentobarbital as a 40 mg/kg IV bolus followed by a continuous infusion at a dose of 1-2 mg/kg per hour. The coma should be maintained for 24-48 hours after achieving control of the elevated ICP. Several factors, especially the adverse effects of the treatment, must be kept in mind while using this therapy. These are summarized in Table 51.8. As with stroke patients, part of the neurocritical care of patients with elevated ICP is
Table 51.8: Protocol of care of patients treated with pentobarbital coma Intubation/mechanical ventilation Peripheral arterial line Pulmonary artery catheter placement (Swan-Ganz catheter) to measure central venous, pulmonary capillary wedge pressure, and cardiac output Aggressive IV hydration for a goal wedge pressure of 12-18 mm Hg Use of vasopressors (phenylephrine, norepinephrine, or dopamine) to keep CPP >70 mm Hg Normothermia: 35.5-37.5"C Pulmonary toilet DVT/GI prophylaxis Adequate nutrition: ideally through enteral route; parenteral route if this is not possible Avoid hypotonic solutions Maintain normoglycemia: 100-150 mg/dl, Monitor leukocyte count on peripheral blood smear (CBC) closely; pan culture and possible empiric antibiotics to be started at first sign of significant elevation Bedside I'.I'C monitoring tor bursi suppression partem Jugular bulb catheter for monitoring (and treatment) of cerebral venous oxygen saturation
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maintaining normothermia and normoglycemia, avoiding increased intrathoracic pressures, and monitoring closely for, as well as taking prophylactic measures against, seizures (including giving phenytoin). One of the alternative or adjunctive experimental therapies to barbiturate coma that is showing promise is hypertonic saline administration (Qureshi and Suarez 2000; Suarez et al. 1998). Other experimental therapies, such as induced hypothermia and the use of neuroprotective agents, are on the horizon. Surgical management obviously involves treatment of surgically relevant lesions. Therefore tumors need to be resected or dcbulked, hematomas may need to be evacuated, and brain abscesses may need to be aspirated and drained. There are experimental surgical techniques of performing bifrontal craniectomy for head trauma to reduce ICP and performing hemicranicctomy for large cerebral infarcts (Schwab et al. 1998).
Subarachnoid Hemorrhage Virtually all patients with SAH will need to be initially managed in an NSU setting because of the complications associated with this potentially devastating condition (Van Gijn and Rinkel 2001). The goal of management in the acute phase of SAH is to prevent rebleeding and the sequelae from the initial hemorrhage, such as vasospasm and consequent cerebral ischemia. As a result of autoregulation, as well as other systemic factors, hypertension in the immediate post-hemorrhage phase can be profound. Extreme hypertension must be treated in this phase to reduce the risk of rebleeding. While some argument exists as to what constitutes the level at which to treat elevated ABP, the recommendation is to keep systolic blood pressure below 160 mm Hg. Even mundane measures such as maintaining a quiet environment with few distractions can keep ABP low. Artificially lowering ABP should not cause problems with respect to vasospasm-induced ischemia because available evidence indicates this process does not take place until at least postbleed day 3. Patients will need continuous ABP monitoring, usually with an arterial blood pressure transducer. Once cerebral aneurysms are secured, aggressive fluid hydration with normal saline solution (often at twice maintenance rates) can help to prevent vasospasm and cerebral salt wasting. Symptomatic cerebral vasospasm usually occurs between 4 and 14 days after SAH and manifests itself acutely as focal or diffuse neurological symptoms. Should vasospasm occur, hydration with intravenous normal saline is part of recommended hyperdynamic therapy or, as it is colloquially called, "triple H" therapy, for hypervolemia, hypertension, and Aemodilution (Egge et al. 2001). While demonstrated efficacy in controlled trials is currently lacking, the American Heart Association docs recommend use of aggressive hydration with crystalloid such as normal saline or 5% albumin to elevate central venous pressure
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(Mayberg et al. 1994). The technique of induced hypertension is essentially the same as noted above for acute ischemic stroke, with the use of phenylephrine and possibly dopamine or other pressor agents. Some of the other complications, which may complicate management of SAH in the neurocritical care setting, are hydrocephalus, hyponatremia, and seizures. Hyponatremia can be caused by increased levels of atrial natriuretic factor (ANF) or by SIADH. Distinguishing between the two causes can be difficult but is important because restricting fluid for SIADH mitigates the therapeutic effect of hypervolemia and precludes aggressive fluid hydration. While a full discussion of this issue is not possible here, it should be noted that measuring the patient's volume status (i.e., weight, fluid balance, central venous pressure, and pulmonary capillary wedge pressure) can be critical to distinguishing between these two causes. These measurements are low in cerebral salt wasting (due to diminished intravascular volume), but normal or elevated in SIADH. Thus placement of a central venous catheter may be necessary. Communicating hydrocephalus (HCP) can present acutely (within 1 week) or subacutely (a few weeks) after SAH. Clinical presentation of these patients is usually diffuse brain dysfunction secondary to elevated ICP. HCP is usually treated with intraventricular catheters; some patients may require permanent ventticuloperitoneal shunts. Clinical seizures are seen in about 2 6 % of SAH patients. Such patients should be managed as described in the following section.
Spontaneous Intracranial Hemorrhage Our purpose here, as in the other sections, is to simply note issues in neurocritical care of patients with ICH. Most important is the fact that the risk of neurological deterioration and cardiovascular instability in patients with ICH achieves its highest level during the first 24 hours after the bleed {Qureshi et al. 2001). For this reason many experts recommend admitting such patients to an NSU setting for at least 24 hours after the onset of ICH (Broderick et al. 1999). However, such a decision is often based on the fact that around 3 0 % of patients with supratentorial ICH and nearly all patients with brainstem or cerebellar ICH have impaired consciousness, require intubation, and thus require admission to an NSU. Once m the NSU, monitoring of various clinical parameters just as for acute ischemic stroke will apply to patients with ICH except for the issue of aggressive hydration and induced hypertension. Much controversy surrounds the question of whether elevated ABP causes expansion of the hematoma. Current guidelines from the American Heart Association recommend that patients with a mean ABP >130 mm Hg be treated with IV antihypertensive agents (but keeping CPP above 70 mm Hg) for 3 days. After this, oral hypotensive agents can be given as long as the patient is clinically
stable. Other issues of neurocritical care that may come up for a patient with ICH are mass effect from the hematoma and surrounding cerebral edema resulting in elevated ICP. The principles of management are the same as described previously. In addition, some cases ol K I 1 involve intraventricular blood, which can predispose the patient to hydrocephalus.
Myasthenia Gravis Crisis A myasthenia gravis crisis (MGC) is defined as myasthenia gravis (MG) weakness severe enough to require mechanical ventilation (Mayer 1997). In 7 4 % of patients in whom MGC occurred, it did so within the first two years after disease onset, and M G C can occur in up to 2 0 % of all patients with MG (Thomas et al. 1997). A number of factors have been identified as precipitants of MGC (Table 51.9), although up to 3 0 - 4 0 % of patients with MGC do not have clearly identifiable predisposing factors. It is important to do as much as possible to identify these precipitants, because a fundamental principle of managing the M G C is to remove them. Because of the involvement of the oropharyngeal and respiratory muscles, as the weakness of these muscles progresses, the FVC declines, which allows atelectasis to develop and then lead to respiratory failure. As described in Chapter 84, serial monitoring of hospitalized MG pun cuts must he performed with close attention to physical examination evidence of respiratory distress, as well as ABG and bedside rests of respiratory function (namely, NIF and VC). It must be remembered that the ABG, NIF, and VC can become abnormal only very late in the progression towards MGC. Also, while a maximal NIF or VC may be apparently adequate in a one-time test, fatigue may reduce respiratory function to below a critical level shortly thereafter, Rapid-sequence orotracheal intubation, as described previously, is preferred. Recommended ventilator settings are small tidal volumes at 7-8 cc/kg with more rapid respiratory rates at 12-16 breaths per minute. In addition, atelectasis can be avoided with intermittent sighs of 1.5 x tidal volume at a frequency of 3-4 times per hour. Tahlc 51.9:
Precipitants of myasthenia gravis crisis
Infections: Most commonly upper and lower respiratory tract Medications: Corticosteroids Antibiotics: aminoglycosides, ciprofloxacin, clindamycin Antiarrhythmics: procainamide, propranolol, timolol Neuropsychiatric drugs: phenytoin, trimethadione, lithium Stress:
Recent surgery Trauma Botulinum toxin administration Thymoma
PRINCIPLES OF NEUROINTENSIVE CARE
Several conditions should be met to make a decision about readiness for extubation. The ability of the patient to withstand procedures producing respiratory or bulbar muscular fatigue is crucial. Proper care of the MGC in the NSU setting also involves attention to adequate nutritional support, maintenance of adequate hydration, careful attention to electrolytes, aggressive pulmonary toilet, and DVT and GI prophylaxis. Acute treatment of neuromuscular failure from MG includes plasma exchange or intravenous immunoglobulin and corticosteroid therapy {Qureshi et al. 1999),
Guillain-Barre Syndrome As with patients with MG, those with GBS will need neurocritical care most commonly for difficulty with respiration, although other critical conditions such as cardiac arrhythmias, sepsis, and pulmonary embolus can complicate their hospital course and require admission to an NSU {Ropper 1992). For this reason, when patients with GBS are admitted to nonintensive care settings within the hospital, special attention must be given to pulmonary toilet (e.g., incentive spirometry and chest percussion), GI and DVT prophylaxis, hydration, adequate nutrition, and frequent neurological examinations to avoid complications and rapidly identify patients who are clinically decompensating. Inspiratory and expiratory weakness together with bulbar weakness, if present, forms the basis of the significant risk that patients with GBS have for respiratory failure, either directly because of the weakness or because of aspiration and pneumonia. It is precisely this risk that necessitates the frequent neurological monitoring, including measurement of NIF and FVC. Should FVC fall to 20 cc/kg or less, the patient needs to be transferred or admitted ditectly to the NSU. FVC less than or equal to 15 cc/kg necessitates intubation and mechanical ventilation. Corresponding levels exist for NIF, but because of effort dependence they are less reliable. Fatigue is as much of a factor in GBS as it is in MG. A study on vital capacity in GBS showed that a decrease of 5 0 % in the vital capacity over 48 hours predicted the need for mechanical ventilation (Chevrolet and Deleamont 1991). Other clinical clues predicting a need for mechanical ventilation include severe bulbar weakness, tachycardia, tachypnea, staccato speech, inability to count from 1 to 20 in a single breath, use of accessory muscles for breathing, and paradoxical breathing. Hypoxemia and respiratory acidosis seen on ABG tend to be late findings. Should intubation be necessary, as with other neurological conditions, rapid-sequence intubation and avoidance of depolarizing agents are recommended. In addition, the risk of aspiration is significant in patients with GBS. Therefore extreme vigilance must be maintained for the earliest evidence of pneumonia to promptly initiate antibiotic therapy. It has been well documented that patients with GBS may have autonomic dysfunction and even failure, in addition to
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muscle weakness. Thus in addition to respiratory reasons for neurocritical care, there can sometimes be cardiac reasons. Some of the reported cardiovascular abnormalities include ECG changes, bradycardia, labile ABP (both extreme hypotension and hypertension, brady-rachycardias, and even fatal arrhythmias). Therefore careful attention must be paid to an admission ECG and any evidence of cardiac rhythm changes or other evidence of autonomic dysfunction (such as orthostatic hypotension, pupillary abnormalities, sweating abnormalities, and gastrointestinal dysfunction). Depending on the clinical scenario, cardiac monitoring may be appropriate. In such settings vasoactive medications must be used with caution.
Status Epilepticus With as many as an estimated 250,000 cases of status epilepticus (SE) in the United States annually and with a mortality as much as SO,000 annually, it is no wonder that it desetves aggressive neurocritical care (Fountain 2000). Currently SE is defined as either two consecutive seizures within five minutes without intervening recovery of consciousness or a prolonged seizure (with or without impaired consciousness) for 30 or more minutes (Lowenstein and Alldredge 1998). The patient in SE needs to be acutely stabilized. This involves attending to some of the same factors as in acute ischemic stroke: establishing airway patency, maintaining adequate breathing, and determining the need for intubation; delivering oxygen, providing intravenous hydration, and ensuring cardiovascular stability; and controlling the seizures. We provide the following recommended protocol: 1. Lorazepam should be administered at 0.1-0.2 mg/kg IV at a rate of 2 mg per minute. 2. If seizures continue, if the etiology is known but not corrected, or a cause for the seizure activity is not known, the patient should be loaded with phenytoin 20 mg/kg IV at a rate of 50 mg per minute or fosphenytoin 20 mg/kg IV at a rate of 150 mg per minute. If IV access cannot be obtained, fosphenytoin can be administered intramuscularly. For patients allergic to phenytoin, valproic acid can be loaded at 20-25 mg/kg IV at a rate of 50-100 mg per minute. 3. For repeated seizures, additional lorazepam may be given (at above dose) or additional phenytoin or fosphenytoin can be administered at 10 mg/kg IV at a rate of 50 mg per minute. 4. Should seizures continue after this, the next step is essentially some kind of induced coma using one of the following agents: • Midazolam IV 0.2-0.3 mg/kg loading dose, with maintenance dose of 0.1-2 mg/kg per hour • Propofol IV 50-250 gg/kg per minute
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Either of these agents requires t h a t the patient be intubated and have central v e n o u s access, c o n t i n u o u s cardiovascular m o n i t o r i n g , a n d c o n t i n u o u s E E C m o n i t o r ing for the p u r p o s e of titrating these m e d i c a t i o n s to achieve a burst-suppression p a t t e r n . T h e m e d i c a t i o n m u s t be continued for at least 12 h o u r s after initiation of t h e r a p y . O t h e r choices include p h e n o b a r b i t a l 20 mg/kg IV at a rate of 5 0 - 7 5 mg/min and valproic acid as described previously. As with the o t h e r c o n d i t i o n s discussed, the neurocritical care of SE patients involves attention to p r o p e r p u l m o n a r y toilet, cardiac m o n i t o r i n g , electrolyte balance, GI a n d D V T prophylaxis, and a d e q u a t e nutrition. Fxccpt in cases in which the specific cause of the seizures is u n q u e s t i o n a b l y k n o w n . n is ;iKn r-c-ciiMiMiended to give thiamine 1 0(1 mg IV upon presentation and daily to cover for seizures in c h r o n i c alcoholics, while various etiologies a r e being e x p l o r e d .
REFERENCES Adams, H. P. Jr., Brott, T. G., Furlan, A. J„ et al. 1996, "Guidelines for thrombolytic therapy for acute stroke: A supplement to the guidelines for the management of patients with acute ischemia: A statement for healthcare professionals from a special writing group for the Stroke Council, American Heart Association," Stroke, vol. 27, pp. 1711-1718 Alvarez del Castillo, M. 2001, "Monitoring neurologic patients in intensive care," Curr Opin Crit Care, vol. 7, pp. 49-60 American College of Critical Care Medicine of the Society of Critical Care Medicine. "Critical care services and personnel: Recommendations based on a system of categorization into two levels of care," Crit Care Med, vol. 27, pp. 422-426 Anderson, R. E. 1996, "Cerebral blood flow Xenon-133," Neurosurg Clin N Am, vol. 7, pp. 703-708 Andrews, R. J. 2000, "Monitoring for neuroprotection: New technologies for the new millennium," Ami NY Acad Set, vol. 939, pp. 101-113 Attia, J., Ray, J. G., Cook, D. J., et al. 2001, "Deep vein thrombosis and its prevention in critically ill patients," Arch Intern Med, vol. 161, pp. 1268-1279 Ay, H., Arsava, E. M., 8c Saribas, O. 2002, "Creatine kinase-MB elevation after stroke is not cardiac in origin: Comparison with troponin T levels," Stroke, vol. 33, pp. 286-289 Banner, M. J., Lampotang, S., Blanch, P. B., &c Kirby, R. R. 1997, "Mechanical ventilation," in Critical Care, eds J. M. Civctta, R. W. Taylor, & R. R. Kirby, Lippincott-Ravcn, Philadelphia Brochard, L., Rauss, A., Benito, S., et al. 1994, "Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation," Am J Respir Crit Care Med, vol. 150, pp. 896-903 Broderick, J. P., Adams, H. P., Barsan, W., et al. 1999, "Guidelines for the management of spontaneous intracerebral hemorrhage: A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association," Stroke, vol. 30, pp. 905-915 Busto, R. & Ginsberg, M. D. 1998 "The influence of altered brain ternpetatute in cerebral ischemia," in Cerebrovascular disease: Pathophysiology, diagnosis, and management, eds M. D. Ginsberg & J, Bogousslavsky, Blackwell Science, Maiden, Mass Carter, L. P. 1996, "Thermal diffusion flowmctry," Neurosurg Clin N Am, vol. 7, pp. 749-754
Cartmill, M., Dolan, C, Byrne, J. I.., & Byrne, P. O. 2000, "Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies," Br j Neurosurg, vol. 14,458-461 Chevrolet, J. C. & Dcleamont, P. I 991, "Repeated viral capacity measurements as predictive parameters for mechanical ventilation need and weaning success in the Guillain-Barre syndrome," Am Rev Respir Dis, vol. 144, pp. 814-818 Cook, D., Guyatt, G., Marshall, ]., et al. 1998, "A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation," N Engl] Med, vol. 338, pp. 791-797 Cook, D., Heyland, D., Griffith, L., ct al. 1999, "Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Cate Trials Group," Crit Care Med, vol. 27, pp. 2812-2817 Cruz, J., Miner, M. E., Allen, S. j . , et al. 1991, "Continuous monitoring of cerebral oxygenation in acute brain injury: Assessment of cerebral hemodynamic reserve," Neurosurg, vol. 29, pp. 743-749 Denehy, L. 1999, "The use of manual hyperinflation in airway clearance," Eur Respir J, vol. 14, pp. 958-965 Diringer, M. 2001, "Sodium disturbances frequently encountered in a neurologic intensive care unit," Neurol India, vol. 49, suppl 1, pp. S19-S30 Diringer, M, N. 1992, "Early prediction of outcome from coma," Curr Opin Neurol Neurosurg, vol. 5, p. 826 Egge, A., Waterloo, K., Sjoholm, H., et al. 2 0 0 1 , "Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: A clinical, prospective, randomized, controlled study," Neurosurgery, vol. 49, pp. 593606 Esteban, A., Erutos, F., Tobin, M. J., et al. 1995, "A comparison of four methods of weaning patients from mechanical ventilation," N Engl J Med, vol. 332, pp. 345-350 Fallis, W. M. 2000, "Oral measurement of temperature in orally intubated critical care patients: State-of-the-science review," Am J Crit Care, vol. 9, pp. 334-343 Feldman, Z. & Robertson, C S. 1997, "Monitoring of cerebral hemodynamics with jugular bulb catheters," Crit Care Clin, vol. 13, pp. 51-77 Fountain, N. B. 2000, "Status epilepticus: Risk factors and complications," I pilepsia, vol. 4 1 , pp. S2.'i S30 Frank, J. I. 1993, "Management of intracranial hypertension," Neurol Clin North Am, vol. 77, pp. 61-76 Giuliano, K, K„ Giuliano, A. J., Scott, S. S., et al. 2000, "Temperature measurement in critically ill adults: A comparison of tympanic and oral methods," Am J Crit Care, vol. 9, pp. 254-261 Gluck, E. H. 1996, "Predicting eventual success or failure to wean in patients receiving long-term mechanical ventilation," Chest, vol. 110, pp. 1018-1024 Gluecker, T., Capasso, P., Schnyder, P., et al. 1999, "Clinical and radiologic features of pulmonary edema," Radiographics, vol. 19, pp. 1507-1531 Crcenwald, D. A. 2001, "Ischemic bowel diseases in the elderly," Gastroenterol Clin North Am, vol. 30, pp, 445-473 Gujjar, A. R., Deibert, E., Manno, E. M., et al. 1998, "Mechanical ventilation for ischemic stroke and intracerebral hemorrhage: Indications, timing, and outcome," Neurology, vol, 5 1 , pp. 477-451 Haberl, P. 1.., Villringer, A., & Dirnagl, U. 1993, "Applicability of laser-Doppler flowmetry for cerebral blood flow monitoring in
PRINCIPLES OF NEUROINTF.NSIVE CARE neurological intensive care," Acta Neurochir (Suppl), vol. 59, pp. 64-68 Hassler, W., Steinmetz, H., & Gawlowski, J. 1988, "Transcranial Doppler ultrasonography in raised intracranial pressure and in intracranial circulatory arrest," J Neurosurg, vol. 68, pp. 745-751 Hebbar, A. K. 2002, "Management of common arrhythmias: Part I. Supraventricular arrhythmias," Am Earn Physician, vol. 65, pp. 2479-2486 Helfman, S. M., Gold, M. I„ DeLisser, E. A., et al. 1991, "Which drug prevents tachycardia and hypertension associated with tracheal intubation: lidocaine, fciitanyl or esmolol?" Anesth Analg, vol. 72, pp. 482-486 Hillbom, M., Erila, T., Sotaniemi, K., et al. 2002, "Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischemic stroke: A randomized, double-blind study," Acta Neurol Scand, vol. 106, pp. 84-92 Holland, K. D. 2001, "Efficacy, pharmacology, and adverse effects of antiepileptic drugs," Neurol Clin, vol. 19, pp. 313-345 Jobsis, E. E. 1977, "Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters," Science, vol. 198, pp. 1264-1267 Jordan, K. G. 1995, "Neurophysiology monitoring in the neuroscience intensive care unit," Neurol Clin, vol. 13, pp. 579-626 Kirkpatrick, P. J., Czosnyka, M., & Pickard, J. D. 1996, "Multimodal monitoring in ne uro in tensive care," ] Neurol Neurosurg Psychiatry, vol. 60, pp. 131-139 Knudsen, F., Jensen, H. P., £c Petersen, P. L. 1991, "Neurogenic pulmonary edema: Treatment with dobutamine," Neurosurgery, vol. 29, pp. 269-270 Koh, W. Y., Lew, T. W., Chin, N. M., et al. 1997, "Tracheostomy in a neuro-intensive care setting: Indications and timing," Anaesth intensive Care, vol. 25, pp. 365-368 Landolt, H., Langemann, H., & Alessandri, B. 1996, "A concept for the introduction of cerebral tnicrodia lysis in neuroin tensive care," Acta Neurochir Suppl, vol. 67, pp. 31-36 Lang, K., Borner, A., Figulla, H. R. 2000, "Comparison of biochemical markers for the detection of minimal myocardial injury: superior sensitivity of cardiac troponin T ELISA," / Intern Med, vol. 247, pp. 119-123 Lang, E. W. St Chestnut, R. M. 1994, "Intracranial pressure: Monitoring and management," Neurosurg Clin North Am, vol. 5, pp. 573-588 Langerderfer, B. 1998, "Alternatives to percussion and postural drainage, A review of mucus clearance therapies: Percussion and postural drainage, autogenic drainage, positive expiratory pressure, flutter valve, intra pulmonary percussive ventilation, and high-frequency chest compression with the ThAIRapy Vest," J Cardiopulm Rehabil, vol. 4, pp. 283-289 Latronico, N., Beindorf, A. E., Rasulo, F. A., et al. 2000, "Limits of intermittent jugular bulb saturation monitoring in the management of severe head trauma patients," Neurosurg, vol. 46, pp. 1131-1138 Lewis, S. B., Myburgh, J. A., Thornton, E. L., et al. 1996, "Cerebral oxygenation monitoring by near-infrared spectroscopy is not clinically useful in patients with severe closed-head injury: A comparison with jugular venous bulb oximetry," Crit Care Med, vol. 24, pp. 1334-1338 Liolios, A., Oropello, J, M., & Benjamin, E. 1999, "Gastrointestinal complications in the intensive care unit," Clin Chest Med, vol. 20, pp. 329-345 Lowenstein, D. H. 8c Alldredge, B. K. 1998, "Status epilcpticus," N Engl) Med, vol. 338, pp. 970-976
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Manno, E. M. 1997, "Transcranial Doppler ultrasonography in the neurocritical care unit," Crit Care Clin, vol. 13, pp. 79-104 Markowicz, P., Wolff, M., Djedaini, K., et al. 2000, "Multicentcr prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome. Incidence, prognosis, and risk factors. ARDS Study Group," AM j Respir Crit Care Med, vol. 161, pp. 1942-1948 Martin, N. A. 8c Doberstein, C. 1994, "Cerebral blood flow measurement in neurosurgical intensive care," Neurosurg Clin N Am, vol. 5, pp. 607-618 Mayberg, M. R., Batjer, J. J., Dacey, II., et al. 1994, "Guidelines for the management of aneurysmal subarachnoid hemorrhage. A statement for healthcare professions from a special writing group of the Stroke Council, American Heart Association," Stroke, vol. 25, pp. 2315-2328 Mayer, S. A, Sc Kossoff, S. B. 1999, "Withdrawal of life support in the neurological intensive care unit," Neurology, vol. 52, pp. 1602-1609 Mayer, S. A. 1997, "Intensive care of the myasthenic patient," Neurology, vol. 48 (Suppl .5), pp. S70-S75 McGuirc, G., Crossley, D., Richards, J., Wong, D. 1997, "Effects of varying levels of positive end-expiratory pressure on intracranial pressure and cerebral perfusion pressure," Crit Care Med, vol. 25, pp. 1059-1062 Moulton, R. J., Brown, J. 1. M., & Konasiewicz, S. J. 1998, "Monitoring severe head injury: a comparison of EEG and somatosensory evoked potentials," Can j Neurol Sci, vol. 25, pp. S7-S11 Moxham, J. 1984, "Respiratory muscle fatigue—Aspects of detection and treatment," Bull Eur Pbysiopathol Respir, vol. 20, pp. 437-444 Nilsson, O. G., Brandt, L., Ungerstedt, U., Sc Saveland, H. 1999, "Bedside detection of brain ischemia using intracerebral microdialysis: Subarachnoid hemorrhage and delayed ischemic deterioration," Neurosurg, vol. 45, pp. 1176-1185 Peterson, P. L., O'Neil, B. J., Alcantara, A. L., & Michael, D. B. 1998, "Initial evaluation and management of neuroemergencies," in Neurologic and Neurosurgical Emergencies, cd J. Cruz, WB Saunders, Philadelphia Pricto, A,. Eisenberg, J., & Thakur, R. K. 2 0 0 1 , "Non arrhythmic complications of acute myocardial infarction," Eincrg Med Clin North Am, vol. 19, pp. 397-415 Qureshi, A. D., Tufifim, S., Broderick, J. P., et al. 2001, "Spontaneous intracranial hemorrhage," N Engl } Med, vol. 344, pp. 1450-1460 Qureshi, A. I., Choudhry, M. A., Akbar, M. S., et al. 1999, "Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis," Neurology, vol. 52, pp. 629-632 Qureshi, A. I, ik Suarez, J. I. 2000, "Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension," Crit Care Med, vol. 28, pp. 3301-3313 "Recommendations for intracranial pressure monitoring technology," 2000, J Neurotrauma, vol. 17, pp. 497-505 Robertson, C. S., Narayan, R. K., Gokaslan, Z. L., ct al. 1989, "Cerebral arteriovenous oxygen difference as an estimate of cerebral blood flow in comatose patients,"/ Neurosurg, vol. 70, pp. 222-230 Rolak, L. A. & Rokey, R. 1999, "The patient with concomitant stroke and myocardial infarction: clinical features," in CorOMary and Cerebral Vascular Disease: A Practical Guide, eds L. A. Rolak & R. Rokey, Futura, New York Roppcr, A. H. 1992, "The Guillain-Barre syndrome," N Engl ] Med, vol. 326, pp. 1130-1136
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Rordorf, G., Koroshctz, W., Efird, J. T., & Cramer, S. C. 2000, "Predictors of mortality in stroke patients admitted to an intensive care unit," Crit Care Med, vol. 28, pp. 1301-1305 Rosner, M. J. 1993, "Pathophysiology and management of increased intracranial pressure," in Neurosurgical Intensive Clare, ed B. T. Andrews, McGraw-Hill, New York Rosner, M. J., Rosner, S. D., & Johnson, A. H. 1995, "Cerebral perfusion pressure; Management protocol and clinical results," / Neurosurg, vol. 83, pp. 949-962 Sahn, S. A. & Lkshminarayan, S. 1973, "Bedside criteria for discontinuation of mechanical ventilation," Chest, vol. 6 3 , pp. 1002-1005 Sakr, Y. L, Ghosn, I., 6c Vincent, J. L. 2002, "Cardiac mani testations after subarachnoid hemorrhage: A systematic review of the literature," Prog Cardiovasc Dis, vol. 45, pp. 67-80 Scheats, G. J. & Deutschman, C. S. 1997, "Common nutritional issues in pediattic and adult critical care medicine," Crit Care Clin, vol. 13, pp. 669-690 Schwab, S., Steiner, T., Aschoff, A., et al. 1998, "Early hemicraniectomy in patients with complete middle cerebral artery infarction," Stroke, vol. 29, pp. 1888-1893 Shelledy, D. C, Rau, J. L., & Thomas-Goodfellow, L. 1995, "A comparison of the effects of assist-control, SIMV, and S1MV with pressure support on ventilation, oxygen consumption, and ventilatory equivalent," Heart Lung, vol. 24, pp. 67-75 Sternberg, R. £c Sahebjami, H. 1994, "Hemodynamic and oxygen transport characteristics of common ventilatory modes," Chest, vol. 105, pp. 1798-1803 Suarcz, J. I., Qureshi, A. I., Bhardwaj, A., et al. 1998, "Treatment of refractory intracranial hypertension with 23.4% saline," Crit Care Med, vol. 26, pp. 1118-1122 Snare/., J. I., .Sunshine, J. L., Tatr, R, W., etal. 1999, "Predictors of clinical improvement, angiographic recanalization, and intracranial hemorrhage after intra-arterial thrombolysis for acute ischemic stroke," Stroke, vol. 30, pp. 2094-2100 Suarez, J. I, 1999, "Neurological intensive care in patients with raised intracranial pressure," Rev Neurol, vol. 29, pp. 1337-1340 Suarez, J. 1., Qureshi, A, I, Aabutaher, B. Y., et al. 2002, "Symptomatic vasospasm diagnosis after subarachnoid hemorrhage: Evaluation of transcranial Doppler ulttasound and cerebral angiography as related to compromised vascular distribution," Crit Care Med, vol. 30, pp. 1348-1355 Sunshine, J. L., Tarr, R. W., Lanzieri, C. F., et al. 1999, "Hyperacute stroke: Ultrafast MR imaging to triage patients prior to therapy," Radiology, vol. 212, pp. 325-332 Synek, V. M. 1988, "Prognostically important EEG coma patterns in diffuse anoxic and traumatic encephalopathies in adults," / Clin Neurophysiol, vol. 5, p. 161 Taiucci, R. C, Shaikh, K. A., & Schwab, C. W. 1998, "Rapid sequence induction with orotracheal intubation in the multiply injured patient," Am Surg, vol. 54, pp. 185-187 Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine. 1999, "Guidelines for intensive care unit admission, discharge, and triage," Crit Care Med, vol. 27, pp. 633-638
Task Force on Guidelines Society of Critical Care Medicine. 1988, "Recommendations for critical care unit design," Crit Care Med, vol. 16, pp. 796-806 Taylor, S. J., Fettes, S. B., Jewkes, C, Nelson, R. J. 1999, "Prospective, randomized, controlled trial to determine the effect of early enhanced nutrition on clinical outcome in mechanically ventilated patients suffering head injury," Crir Care Med, vol. 27, pp. 2525-2531 The American Association of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care. 2000, "Indications for intracranial pressure monitoring," J Neurotrauma, vol. 17, pp. 479-491 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. 1995, "Tissue plasminogen activator for acute ischemic stroke," N Engl } Med, vol. 333, pp. 1581-1587 Thomas, C. E., Mayer, S. A., Gungor, Y., et al. 1997, "Myasthenic crisis: Clinical features, mortality, complications, and risk factors for prolonged intubation," Neurology, vol. 48, pp. 1253-1260 van den Brink, W. A., van Santbrink, H., Steyerberg, E. W,, et al. 2000, "Brain oxygen tension in severe head injury," Neurosurgery, vol. 46, pp. 868-878 Van Gijn, J. &C Rinkel, G. J. 2001, "Subarachnoid haemorrhage: Diagnosis, causes, and management," Brain, vol. 124, pp. 249-278 Vespa, P. M., Bleck, T. P., Brock, D. G., et al. 1994, "Impaired oxygenation after acute subarachnoid hemorrhage," Neurology, vol. 4 3 , p. A344 Vespa, P., Prins, M., Ronne-Engsttom, E., et al. 1998, "Increase in extracellular glutamate caused by reduced cerebral perfusion and seizures after human traumatic brain injury: A microdialysis study," j Neurosurg, vol. 89, pp. 971-982 Warbel, A., Lewicki, L., &c Lupica, K. 1999, "Venous thromboembolism: Risk factots in the craniotomy patient population," / Neurosci Nurs, vol. 3 1 , pp. 180-186 Weir, C. J., Murray, G, D., Dyker, A. G., & Lees, K. R. 1997, "Is hyperglycemia an independent predictor of poor outcome after acute stroke? Results of a long term follow up study," BMj, vol. 314, pp. 1303-1306 Whitelaw, W. A. &c Derenne, J. P. 1993, "Airway occlusion pressure," / Appl Physiol, vol. 74, pp. 1475-1483 Wijdicks, E. F. M. 1995, "Determining brain death in adults," Neurol, vol. 4 5 , pp. 1003-1011 Wijdicks, E. F. M., Fulgham, J. R., & Batts, K. P. 1994, "Gastrointestinal bleeding in stroke," vol. 25, pp. 2146-2148 Yang, K. L. & Tobin, M. J. 1991, "A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation," N Engl) Med, vol. 324, pp. 1445-1450 Young, G. B., Jordan, K. G., & Doig, G. S. 1996, "An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: An investigation of variables associated with mortality," Neurol, vol. 47, pp. 83-89 Zimmerman, J. L. Be Dellinger, R. P. 1996, "Blood gas monitoring," Crit Care Clin, vol. 12, pp. 865-874
Chapter 52 Principles of Neurosurgery Roberto C. Heros, Deborah O. Heros, and James M. Schumacher Neurosurgical Emergencies in the Neurology Patient Acute Hydrocephalus Cerebellar Hemorrhage and Infarction Intracerebral Hemorrhage Intracranial Tumors Brain Abscess Pituitary Abscess Pituitary Apoplexy Spinal Cord Compression Neurosurgical Considerations in Common Neurological Disorders Subarachnoid Hemorrhage Vascular -Malformations Brain Tumors Ischemic Cerebrovascular Disease Dementia Pseudotumor Cerebri Pain Trigeminal Neuralgia
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The practice of neurosurgery is founded in neurology, and a solid understanding of neurological diseases is fundamental to good clinical neurosurgical practice. Likewise, neurology cannot be practiced well without a basic knowledge of the surgical implications of neurological diseases. Most of the specific pathological entities that constitute the bulk of neurosurgical practice (e.g., head and spinal cord injury, brain tumors, aneurysms and arteriovenous malformations [AVMs], degenerative and neoplastic spinal disorders, central nervous system infections, peripheral nerve problems, and pain) are covered in detail in specific chapters elsewhere in this book. Therefore in this chapter, we concentrate on three particular aspects of current neurosurgical practice. The first section deals with some neurosurgical emergencies that can occur in patients who are generally cared for by neurologists. The second section deals with some specific neurosurgical considerations that arise frequently in patients cared for by neurologists. Finally, in the third section, we discuss briefly some recent technological developments that have had a significant impact on neurosurgical practice and that are of interest to neurologists.
Hemifacial Spasm . Spinal Arteriovenous Malformations Spasticity Cervical Spondylosis Brain Biopsy Seizures and Epilepsy Movement Disorders and Parkinson's Disease Recent Neurosurgical Developments Microsurgery Skull Base Techniques Endoscopy Intraoperative Angiography Neurophysiologies] Monitoring t rameless Stereotaxis Real-Time [mage-Guided Surgery Radiosurgery En do vascular Neurosurgery Neurotranspl a oration
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NEUROSURGICAL EMERGENCIES IN THE NEUROLOGY PATIENT Acute Hydrocephalus Hydrocephalus is usually a relatively chronic problem, but it can result in very dramatic acute symptomatology in a number of clinical settings. An awake patient can rapidly become drowsy, sometimes preceded by agitation, and progress rapidly to stupor and coma with small, poorlyreactive pupils. The importance of considering acute hydrocephalus in this setting is that the condition can often be reversed by one of the simplest neurosurgical maneuvers, an emergency ventriculostomy. Any neurosurgeon can perform a ventriculostomy in a matter of minutes with simple equipment kept available in a sterile tray specifically designed for this purpose in almost all hospitals in which neurosurgery is practiced. Most frequently, a frontal "twist drill" trephination is performed through a small incision in the frontal region (11 cm behind the nasion and 3 cm lateral to the midline), and the anterior horn of the lateral ventricle is cannulated with a small ventricular catheter connected to external drainage. There 963
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arc a number of specific instances in which this maneuver can be life saving, Herniation after a lumbar puncture is indeed a rare event. Before computed tomographic (CT) scanners were available, this was seen more often when patients with large supra ten to rial or posterior fossa masses underwent lumbar puncture. However, there are still occasional instances of patients with conditions that are not diagnosed by an initial CT scan, which can result in herniation after a lumbar puncture, such as in patients with acute bacterial meningitis and in patients with basal meningitis due to either tuberculosis or sarcoidosis. A simple ventriculostomy can immediately reverse this situation. Patients who have had a subarachnoid hemorrhage (SAH), usually from a ruptured aneurysm, can deteriorate abruptly and rapidly lapse into coma, usually as a result of rerupture of the aneurysm cither into the parenchyma of the brain or into the ventricles causing acute hydrocephalus. In these patients, we recommend an emergency ventriculostomy even before a CT scan is performed. We have seen several patients wake up within a few minutes of a ventriculostomy when the problem was intraventricular hemorrhage and acute hydrocephalus. Obviously, the patient with a massive intracerebral hemorrhage would not be helped by this maneuver, but even then nothing is lost except the time taken to do the ventriculostomy. Acute hydrocephalus from intraventricular hemorrhage can also be suspected as the cause of abrupt coma in patients known to have an AVM or a cavernous angioma in the periventricular region.
FIGURE 52.1 Colloid cyst of the third ventricle. Note the severe hydrocephalus caused by this small colloid cyst, which is blocking hoth foramina of Monro. The lesion was removed by a microsurgical transcallosal approach without neurological complications,
Cerebellar Hemorrhage and Infarction
invariably be made on clinical grounds alone and can be confirmed by a CT scan or magnetic resonance imaging (AlRIj. rhc neurologist must recognize when neurosurgical intervention, which is frequently life saving and function restoring for these patients, is indicated. For this reason, it is convenient ro classify the clinical stages seen in both of these conditions as follows: an initial "cerebellar" stage in which the only clinical deficits detected are referable to the cerebellum; an intermediate stage in which in addition to cerebellar signs, there are signs and symptoms referable to hydrocephalus; and the final stage of brainstem compression. We firmly believe that neurosurgical intervention is indicated when the earliest signs and symptoms of hydrocephalus develop. At this stage, the patient may be treated with a ventriculostomy alone; however, this carries the danger of upward herniation, which is seen frequently after the lateral ventricles are decompressed if the large posterior fossa mass is not dealt with. We prefer to use ventriculostomy cither to gain time to perform a definitive surgical decompression of the posterior fossa or to go directly to the operating room for surgical decompression without a preliminary ventriculostomy. Once definite signs of brainstem compression develop, emergency surgical decompression is mandatory if the patient's life and function are to be saved.
Most patients with cerebellar infarction and many patients with cerebellar hemorrhage will be initially under the care of a neurologist. The diagnosis of either entity can almost
The patient with cerebellar hemorrhage usually presents with the classic history of a headache of relatively abrupt onset frequently accompanied by nausea and vomiting. Very commonly, the patient or his or her family members
Patients with a lesion m the region of the anterior third ventricle and the foramen of Monro can deteriorate acutely, and in these instances, acute hydrocephalus musr be suspected. This is a common cause of sudden death in patients with colloid cysts of the third ventricle (Figure 52,1). These patients often have a history of abrupt headaches related to posture or to coughing or performing a Valsalva maneuver that produce an abrupt increase in intracranial pressures. An emergency ventriculostomy can be life saving in these cases. Patients who have an in-dwelling shunt for hydrocephalus can deteriorate acutely as a result of shunt malfunction. Again, when this occurs and the patient has lapsed into coma, the first step should be a "shunt tap"; by placing a small needle in the shunt reservoir, cerebrospinal fluid (CSF) can be freely extracted if the obstruction is disral. If this fails, usually because the obstruction is proximal, an emergency ventriculostomy is indicated even before the CT scan is obtained.
PRINCIPLES OF NEUROSURGERY
will give a history of inability to walk due to instability that develops soon after the headache. When examined, these patients have striking truncal ataxia and often cannot even sit on the examining table to be examined; they can practically never walk. In addition, they frequently have nystagmus and signs of cerebellar appendicular ataxia. When the patient is wide awake and the hemorrhage is not too large (usually 20
pro-UK group was 66% and only 18% in the control group (p < 0.001). Intracranial hemorrhage at 24 hours was observed in 10% of the pro-UK group and only 2% of the control patients (/> = .06). The investigators concluded that IA rpro-UK significantly improved clinical outcomes at 90 days, despite increased frequency of early symptomatic intracranial hemorrhage (Furlan et al. 1999). The Emergency Managemenr of Stroke (EMS) Bridging Trial was a pilot study that suggested combined IV and IA therapies are feasible and safe and lead to higher rates of recanalization. The feasibility, safety, and efficacy of combined IV rt-PA and IA rt-PA were evaluated in this multicenter, randomized, placebo-controlled, doubleblinded trial (Lcwandowski et al. 1999}. Thirty-five patients were enrolled, with eighteen in the IV/IA group and seventeen in the placebo/IA group. Outcomes were measured by the Barthel Index, NIHSS, and modified Rankin Scale. There were no significant differences in outcomes between the two groups at 7 days, 10 days, and 3 months. Recanalization was better in the IV/IA group with statistical significance. It was determined that IV/IA rt-PA was feasible to use and had better recanalization rates. However, the combined therapy did not reveal improved clinical outcomes. There was not a statistically significant difference in the rate of symptomatic ICH between the two groups. In a study to determine the safety and efficacy of local IA thrombolysis with urokinase, Arnold et al. (2002) followed 100 consecutive patients with stroke caused by MCA occlusion. They found that the median NIHSS was 14 on admission. Excellent or good outcomes, a modified Rankin Scale score of 2 or less, were found in 5 9 % of patients with an Ml or M2 occlusion and 9 5 % of patients with an M3 or M4 occlusion. Fifty-six percent of patients had a
recanalization score (Thrombolysis in Myocardial Infarction [TIMI1 score) of 2, and twenty percent had a score of 3 (complete recanalization). They concluded that local IA thrombolysis with urokinase can be safe and efficacious (Arnold et al. 2002). As the randomized NINDS trial showed the beneficial effect of IV given t-PA in patients who present within the 3-hour time window for treatment, in most centers IA thrombolysis is frequently reserved for patients presenting with symptoms 3-6 hours after the onset of the ictus. For the IA use of thrombolytics, a superselectivc positioning of a microcathetcr adjacent to the clot is recommended. The endovascular approach allows fibrinolytic agents to be infused ptoximally, disrally, and within clots in main cerebral arteries. A higher local concentration of fibrinolytic agents is achieved, thus reducing systemic exposure to thrombolytics. In addition, a mechanical disruption of the clot with the microwirc and catheter can be accomplished. The collateral blood supply and the vascular system distal to the occluded atca can be visualized simultaneously, and a sense for the degree of recanalization gained (Saver 2001). IA thrombolysis has provided better early recanalization rates (60-80%) than IV therapy (20-60%) (del Zoppo 1997; Jahan et al. 1999; Saver 2001). Recanalization is graded according to the TIMI grade (T1M1 Study Group 1985). Grade 0 no recanalization; grade 1 minimal recanalization; grade 2 partial recanalization; and grade 3 complete recanalization. Modified Rankin Scale scores, Barthel indices, and NIHSS may all be used to assess patient outcomes over follow-up periods. Inclusion and exclusion criteria for IA thrombolysis are listed in Tables 53.6 and 53.7. Conventional IV or IA chemical thrombolysis is time consuming, with a significant risk of hemorrhagic transformation of ischemic strokes. Mechanical thrombolysis may afford more rapid and complete relief of cerebral ischemia, with decreased hemorrhagic transformation. Devices for revascularization in acute stroke have the potential risks of producing showers of distal emboli, vessel perforation, and damage to vessel walls with secondary platelet aggregation. Other strategies that may play a larger role in the future include various devices to remove clots, such as laser energy,
Table 53.6: criteria
Acute stroke intra-arterial thrombolysis inclusion
Clinical diagnosis of ischemic stroke Computed tomographic exclusion of hemorrhagic stroke Four-vessel angiography that reveals vessel occlusion that correlates to clinical stroke Significant long-term neurological deficit can be expected without treatment lime from symptoms to intervention is less than 6 hours No contraindications {laboratory findings) against the use of thrombolytics
PRINCIPLES OF ENDOVASCUI.AR THERAPY
Tabic 53.7: criteria
Acute stroke mtra-arterial thrombolysis exclusion
Mild symptoms (deficits that are quickly resolving) Sustained hypertension of > 180/100 mm Hg Hemorrhage on computed tomography or magnetic resonance imaging Known vascular malformation or tumor Recent history of stroke, trauma, or surgery
ultrasound, photo acoustic laser energy, rheolytic thrombectomy, clot retticvers (including snarclikc devices, excision and aspiration), and suction thrombectomy. Cathetet-hascd methodologies include hypothermia for neuroprotection, with heat exchangers placed in the inferior vena cava and systems that provide controlled induction, maintenance, and reversal of hypothermia. Other devices provide increased cerebral perfusion with intra-aortic balloons, hyperoxygenated perfusion using fluorocarbon and othct major oxygen carriers. Functional recovery of stroke includes rehabilitation with physical, occupational, and speech therapy. Stem cell research is ongoing with human bone matrow stem cell gtafting and neuronal growth hormones to replace neuronal loss. It is apparent the histotical perspective on the treatment of acute sttoke has dramatically changed over the last decade and will continue to expand with neuroendovascular technologies. National analysis was reported by Nilasena and coworkers (Nilasena et al. 2002) from the National Stroke Project of the U.S. Centers for Medicare and Medicaid Service. They analyzed 14,295 inpatient Medicare medical records from a national sample of patients with acute stroke who were treated between April 1998 and March 1999. Fibrinolytic therapy was employed in only 1,7% of patients. In a study of Cleveland hospitals, only 1.8% of patients received IV t-PA (Kat/an et al. 2000). Furthermore, the 5-year recurrence rate for stroke has been reported anywhere from 2 4 - 4 2 % (Sacco et al. 1982, 1994; Petty et al. 1998; Stapf and Mohr 2002). The etiology of the stroke must be addressed to minimize the risk of an additional stroke. Vasospasm Vasospasm associated with SAH accounts for major morbidity and mortality in approximately 2 0 % of patients who initially survive an aneurysm rupture. It is considered one of the most preventable types of ischemic brain injury by prevention care and newer interventional techniques. It typically presents within 3-14 days after the initial hemorrhage and is usually greatest in severity at 7 days posthemorrhage. It can result in extensive cerebral and brainstem infarction and death. The etiology of cetebral vasospasm is directly related to the rupture of an aneurysm and hemosiderin products. However, a cascade of events results in a decrease in CBF. The events are likely related to
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the disturbed balance between vasoconstriction (mediated by endorhclin-1) and vasodilatation (mediated by NO), but have not been clearly elucidated. Compensatory mechanisms of autoregulation, collateral flow, and increased oxygen extraction eventually become exhausted and ischemic neurological damage ensues. The potential end result of prolonged vasospasm is cerebral infarction. Smooth muscle cells in the arterial wall undergo sustained contraction between 4 and 14 days (peak 7 days) after the initial hemorrhagic event. Subsequently, collagen is deposited in the adventiria and there is thickening of the intima, which may last for several weeks (Chan et al. 1995). Cerebral vasospasm has been reported to occur in 6 0 - 8 0 % of all patients with SAH. Almost 3 0 % of patients are thought to have symptomatic manifestations (Heros, Zervas, and Varsos 1983; Kassell et al. 1985, 1990; Srinivasan et al. 2002). Patients with vasospasm may present with symptoms, and transcranial Doppler studies may reliably determine vasospasm at the patient's bedside in a noninvasive fashion, Conventional angiography is the gold standard for determining vasospasm. Several other studies have been proposed to evaluate regional CBF that include singlephoton emission CT (SPECT), positron emission tomography (PET), xenon CT scan, and radioactive xenon clearance. Prevention of vasospasm is attempted through maintaining normovolemia, normothermia, and normal oxygenarion. Volume contraction can predispose patients to vasospasm; hence, careful monitoring of fluid status is paramount. Prophylactically, an oral calcium-channel blocker, nimodipiue, is given for 21 days following SAH to prevent vasospasm (Allen et al. 1983; Pickard et al. 1989). Other preventive modalities being investigated include thrombolytic therapy via intracisternal injections, aspiration and irrigation at time of craniotomy, intraoperative sodium chloride lavage, and early ventriculostomy to control intracranial pressure (Newton, Krawczyk, and Lavine 2002). When patients become symptomatic and vasospasm is suspected as the culprit, hypertensive, hypervolemic, and /jemodilution (triple H) therapy is most commonly administered, However, symptoms may coincide with rebleeding or hemorrhage and should be distinguished with head CT. The role of endovascular approaches to the treatment of vasospasm becomes foremost in the case of failure of conventional therapies. In patients at risk for pulmonary edema, myocardial infarction, or other medical risk factors preventing triple-H therapy, endovascular techniques including mechanical and/or pharmacological treatment options should be initiated. Mechanical Therapies. Balloon angioplasty has been shown to be effective in the treatment of vasospasm secondary to SAH. Zubkov, Nikiforov, and Shustin
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(1984) first described this technique in 1984, As with other treatment options in the endovascular field, advances in balloon, catheter, microcatheter, and imaging technologies have expanded the application, efficacy, and safety of this technique over the course of the last several years (Figure 53.5). Before treatment, a CT scan should be obtained to rule out hemorrhage or large infarct that could potentially be enhanced through repcrfusion. Intracranial pressure and arterial blood pressure are monitored throughout the procedure. Balloon angioplasty is performed with a lowpressure (2 atm), soft, compliant silicon microballoon.
Angioplasty has been shown to have long-lasting effects, possibly due to stretched and torn collagen fibers (Yamamoro, Smith, and Klag 1992), rupture of the internal elastic lamina, and stretched smooth muscle fibers (Chan et al. 1995; Srinivasan et al. 2002). Many investigators have reported improved clinical outcomes after mechanical angioplasty for vasospasm (Higashida et al. 1989; Newell et al. 1989; Eskridge et al. 1990; McDougall et al. 1997; Maybcrg 1998). Transluminal balloon angioplasty has been shown to improve neurological outcomes in 6 0 - 7 0 % of treated patients (Eskridge et al. 1998; Rosenwasser et al. 1999). Furthermore, complete vessel revascularization is
FIGURE 53.5 (A) Right hemiparcsis and aphasia associated with moderate to severe vasospasm of the CI and C2 segments of the internal carotid artery (ICA), and the Ml segment of the middle cerebral artery (MCA), and Al segment of the anterior ccrchral artery after coiling of a ruptured ICA terminus aneurysm {arrows). {Arrows in [A| reveal the extent of spasm. Note the decreased caliber of the ICA.) (B, C) Balloon angioplasty of the distal ICA and the Ml segment (arrows). (D) Improved distal perfusion after angioplasty of the ICA and Ml {arrows).
PRINCIPLES OF ENDOVASCUI.AR THERAPY
seen in virtually all cases and imaging studies, such as SPEC! and transcranial Doppler, correlate with clinical improvement (Mayberg 1998). Currently, however, angioplasty can address only larger proximal vessels (>1.5 mm in diameter). Improved microcirculation is seen due to removal of the proximal increased impedance, with subsequent increased perfusion pressure. The potential complications of angioplasty include vessel rupture, dissection, or occlusion, as well as ICH, which is extremely rare in experienced centers and if appropriate material is used (American Society of Interventional and Therapeutic Neuroradiology 2001; Newton et al. 2002). Hypetplasia with subsequent narrowing of the artery is not seen. Vasospasm of the smallet caliber distal vessels is not amenable to angioplasty. However, the most commonly used pharmacotherapy has been the use of IA papaverine. Papaverine is a phosphodiesterase inhibitot that causes smooth muscle telation possibly through decreasing the level of intracellular calcium (Mathis, Jensen, and Dion 1997; Milburn et al. 1998; Srinivasan et al. 2002). Superselective injections of 100-300 mg of papaverine ( 3 % solution) ovet 30-60 minutes may be delivered close to the target vessel. Its effect has been observed only transiently, which requires repeated injections. Infusions should be avoided below the ophthalmic artery to avoid pupillary dilatation, which may be misconsttued as evidence of neurological decompensation. Other side effects of papaverine include seizure, respiratory depression (if the infusion is given below the posterior inferior cerebellar artery), and increased intracranial pressure. Therefore intracranial pressure and arterial blood pressure should be monitored during its administration.
HEMORRHAGIC STROKE Aneurysms Intracranial
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ruptured aneurysms. Most patients have a single unruptured aneurysm that is identified incidentally during the workup of conditions such as headache, cerebrovascular ischemic event, cranial nerve deficits, convulsive disorder, ill-defined spells, aneurysm mass effect, subdural hemorrhage or ICH, brain tumor, and neurological degenerative disease. The diagnosis of an unruptuted inttactanial aneurysm is made after suggestive findings on CT (40%) and MRI (37%) (International Study of Unruptured Intracranial Aneurysms Investigators 1998). The various types of imaging modalities and their utility in detecting aneurysms are listed in Table 53.8. Juvela, Porras, and Poussa (2000) followed the natural history of intracranial aneurysms for an average of nearly 20 years in 142 patients with 181 unruptured aneurysms. The average annual incidence rate of ruptute was 1.3%, and the relative risk of rupture increased with the size of aneurysms. Smoking, size of aneutysm, and patient age were the most important risk factors for rupture. The International Study of Unruptured Intracranial Aneurysm (LSUIA) investigarots provided the most comprehensive study on the natural history of unruptured aneurysms. They reported a retrospective study of 1449 patients with 1937 aneurysms. Patients without a history of SAH (group 1, « = 727) were separated from those with a histoty of SAH from a separate aneurysm (group 2, n — 722), In group 1, the study revealed a cumulative tate of rupture of 0.05% per year for aneurysms that were less than 10 mm in diameter at the time of diagnosis. The tate was 20 times higher for aneurysms greater than 10 mm in diameter {nearly 1% per year). The rate of rupture in group 1 was 6% for the first year for giant aneurysms (>25 mm). Size and location of aneurysms were predictive factots of future rupture in group 1. Posterior circulation aneurysms were more likely to rupture independent of size. Group 2 included patients with a history of SAH who had the ruptured aneurysm properly treated and a second nonruptured aneurysm. The rupture rate for the untreated
Aneurysms
Studies have shown overall prevalence rates of intracranial aneurysms that vaty from 0.2-9.9%. The mean of 5% would correlate to nearly 15,000,000 Americans with an intracranial aneurysm. Approximately 10 of every 100,000 aneurysms will rupture per year, which equates to nearly 30,000 cases in the United States per year. The vast majority of aneurysms do not rupture, thereby presenting the need to classify patients into two gtoups: those with ruptured inttacranial aneurysms and those with unruptured intracranial aneurysms. The clinical management of these patient groups is evolving with the advent of ncuroendovascular therapeutics. Unruptured Intracranial Aneurysm. Patients with unruptured intracranial aneurysms far outnumber those with
Table S3.8: aneurysms
Diagnostic studies for detection of intracranial
CT examinations with slice thicknesses of 5-10 mm; however, small aneurysms may not be visible even with IV contrast (Hsiang et al. 1396; Bederson et al. 2000) CT angiography shows aneurysm sizes as small as 2 mm with sensitivity of 77% and specificity of 87% CT angiography for size >3 mm has specificity of 97% and 100%, respectively (Hope et al. 1996) MRl/MRA: Good for screening with sensitivity of 69-93%, particularly for aneurysms >3 mm (Korogi et al. 1996) Intra-arte Ha I angiography: Gold standard, but risks include complication rate of about 5%, neurological event of about 1%, and permanent neurological deficit of about 0.5% (Rinneetal. 1993; Ronkainen et al. 1998) CT = computed tomography; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
aneurysm was 11-fold higher at 0.5% per year for aneurysms less than 10 mm in diameter than for similar aneurysms in patients who had not suffered an SAH. The rupture rate was less than 1% per year for aneurysms greater than 10 mm in diameter in both groups. Surprisingly, the size was not an independent risk factor for group 2 aneurysms. The location of the aneurysm and the age of patients were independent factors for rupture; specifically, basilar tip aneurysms provided a 5.1 relative risk and older age was ,i 1 .3 1 relative risk for rupture. Since the publication of this report, Wiebers et al. (unpublished data) have prospectively studied a larger cohort and the critical aneurysm size has now been redefined as 6 mm. This confirms the earlier observation made by McCormick and Acosta-Rua (1970) that 5-mm aneurysm size seems to be critical for an increased risk of rupture, Indications for the treatment of unruptured intracranial aneurysms are listed in Table 53.9 (Bederson, Awad, and Wicbcrs 2000, revised by authors). Surgical Treatment. Surgical outcomes were prospectively studied in the ISUIA report; 972 patients underwent intracranial surgery in group 1, and 198 patients in group 2, The overall morbidity and mortality rate at 1 month for patients in group 1 was 17,5%. At 1 year, the overall rate was 15.7%, with only 15.6% of patients at their baseline neurological status. Furthermore, 3,8% of patients died from surgical-related complications. Mortality rates of direct surgical treatment of unruptured intracranial aneurysms have been reported as low as 0% and as high as 7%. Morbidity rates have been reported as low as 4% and as high as 15.3%. Unfortunately, various studies have established different criteria for morbidity and even mortality, depending on the time period of follow-up. The ISUIA study has been recognized as the most
Table 5.1.9: Indications for the treatment and management of unruptured aneurysms 1. Treatment of small intra caver nous internal carotid artery aneurysms generally is not indicated. Treatment of large symptomatic ones should be individualized based on patient age, severity, and progression, in addition to alternatives. 2. Symptomatic intradural aneurysms of all sizes should heconsidered for treatment, with large or giant carrying higher risks for surgery. .). Cdtxisiiiij; aneurysms nf all sizes in patients with subarachnoid hemorrhage from a separate aneurysm warrant treatment. Aneurysms at the basilar tip have high risk of rupture. Patient age, medical condition, and neurological status and relative risks should he considered. 4. Young patients with aneurysms approaching .5-6 mm should receive special consideration. Also, unique characteristics include aneurysms with daughter sacs, hemodynamic features (high-flow impingement zone, for example, internal carotid artery terminus aneurysm); familial considerations deserve special treatment consideration, 5. Asymptomatic aneurysms >5 mm should be strongly considered for treatment.
comprehensive study on this issue (International Study of Unruptured Intracranial Aneurysms Investigators 1998). Specific risk factors for poor surgical outcomes have been grouped into the following categories and subcategories: patient characteristics (age, symptoms, and medical condition), aneurysm characteristics (size, location, and morphology), and other factors (hospital and surgical team experience). Endovascular Treatment of Unruptured Intracranial Aneurysms. Preliminary results of endovascularly treated unruptured intracranial aneurysms have revealed lower morbidity and mortality rates when compared with surgery. However, the rates of incomplete aneurysm obliteration and re-canalization arc current challenges tin this field. More than 120,000 aneurysms have been treated with the Guglielmi detachable coil (GDC) system. In a case series of 42 unruptured aneurysms that were treated with an endovascular approach, Wanke et al. (2002) found a morbidity rate of 4.8% and a mortality rate of 0%, with a follow-up range of 6-S3 months. Murayama et al. (1999) reported a morbidity rate of 4 . 3 % in 109 treated patients. In a blinded review of patients with aneurysms that were deemed amenable to both coiling and clipping, 68 patients were treated with surgery and 62 were treated with endovascular coil embolization. The rates of complications were 3 4 % in the surgical arm and 8% in the endovascular arm (Johnston et al. 2000). A retrospective study of patients with unruptured intracranial aneurysms in California reported the outcomes of surgically treated patients versus endovascularly treated patients. Adverse outcomes were more common in patients treated with surgery (25%, n = 1699) than in those with EVT (10%, n = 370). Remarkably, a testimony to improved procedures and materials, the frequency of adverse outcomes declined with statistical significance from 1991 to 1998, whereas the surgical adverse outcomes did not decline. Deaths occurred in 3.5% of surgeries and 0.5% of endovascular treatments (Johnston et al. 2001) (Figure 55.6). A cohort study of patients with unruptured intracranial aneurysms from 1994 to 1997 were evaluated and found to have significantly more adverse outcomes with surgery (18.5%, n = 2357) versus EVT (10.6%, n = 255). Adverse outcomes were defined as death or transfer to a rehabilitation hospital or nursing home at the time of discharge. The results were not altered after adjustments were made for age, sex, race, transfer admissions, emergency room admissions, and year of treatment (Johnston et al, 1999). In the infancy of endovascular neuroradiology, it was widely believed that only posterior circulation aneurysms were amenable to coiling. It was also thought that aneurysms with mass effect would suffer great effects from the mass of platinum coils. However, the last 10 years have brought exponential growth in the field in terms of biotechnology, materials, and the understanding of fluid flow. A call has been made for a randomized controlled trial for unruptured intracranial aneurysms with surgical
PRINCIPLES OF ENDOVASCULAR THERAPY
101.1
FIGURE 53.6 (A) Twice-ruptured .5-mm bilobed anterior communicating artery aneurysm in a 51 -year-old man who presented with a Hunt and Hess grade of 1. (B, C) Coiling of the aneurysm with complete obliteration [arrows). (D) The aneurysm remains completely occluded on 6-month follow-up angiography. clipping, endovascular coiling, or medical management Oohnston et al. 1999, 2001; Broderick 2000). The American Society of Interventional and Therapeutic Neuroradiology has, for management purposes, categorized aneurysms as either ruptured or unruptured. This classification can be further expanded to indicate endovascular treatment for therapeutic purposes, including treatment with parent vessel sparing or parent vessel occlusion (Tables 53.10, 53.11, and 53.12). The indications for endovascular treatment of aneurysms follow general guidelines based on aneurysm morphology, medical stability of the patient, and the risks of endovascular procedure versus clipping. The overall goal is to prevent aneurysm rupture
or rebleed, or to stabilize or decrease the symptoms of mass effect caused by large or giant aneurysms. Successful outcomes are dependent on the degree of aneurysm exclusion from the overall circulation. Degree of exclusion
Table 53.10: Indications for endovascular treatment in unruptured aneurysm Poor surgical candidate due to medical risk factors High surgical clipping risk due to location or size Failed clipping attempt Patient/family refusal of open surgery Multiple aneurysms that would require several craniotomies
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Table 53.11: Indications for endovascular treatment with parent vessel sparing in ruptured aneurysm Poor surgical candidate due to medical risk factors Poor clinical grade High surgical clipping risk due ro location or size Failed clipping attempt Significant vasospasm in vascular distribution removed from aneurysm location
by coiling will be based on the anatomy of the circulation (access and tortuosity leading to aneurysm), aneurysm morphology (specifically neck size), and collateral circulation. Aneurysms with a small neck ( type ol neurological disease, especially stroke, TBI, thoracic SCI, and myasthenia gravis.
Spasticity Mechanisms. The most important UMN problems that cause disability are the decrement in motor control associated with dyssynergic patterns of muscle activation and the coactivation of agonist and antagonist groups during movements, as well as paresis, slow movements, loss of dexterity, and fatigability. During rehabilitation, the signs that tend to be treated include the flexor posture of the arm and extensor posture of the leg, sometimes with dystonia, rigidity, and contractures; and exaggerated cutaneous and autonomic reflexes with involuntary flexor and extensor spasms. Hypertonicity can also be the consequence of interactions between central and peripheral factors. The mechanical resistance to a passive change in a joint angle arises from the elastic and viscous properties of muscle, tendon, and connective tissue and from reflexively mediated stiffness. Some investigators have proposed that secondary changes in spastic muscle, such as an increase in connective tissue and loss of muscle fibers or change in their properties, explain at least some of the increased stiffness in patients. Hyperexcilability of motoneurons probably plays a larger role. A number of ill-defined mechanisms could alter membrane properties and morphologically and physiologically reorganize spinal circuits, leading to hypertonicity. A variety of neurotransmitters act within these
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
Table 54.18:
Clinical measures of spasticity
Ash worth Scale 1 No increase in tone 2 Slight increase, producing a catch when joint is moved in flexion or extension 3 More marked increase in tone hut easily flexed 4 Considerable increase; passive movement difficult 5 Affected part rigid in flexion or extension Spasm Score 0 No spasms 1 Mild spasms induced by stimulation 2 Spasms less than 1/hr 3 Spasms more than 1/hr 4 Spasms more than 10/hr
systems, although their net effects are uncertain. Thus drug interventions produce hard-to-predict changes in tone and spasms. Assessments. For routine assessments and for clinical trials of a uti spasticity interventions, a mini her of measures of hypcrtonicity have been used. The Ashworth Scale (Table 54.18) has had good interrater reliability in studies of stroke, SCI, and MS. The relationship between this score and disability is not so evident. A clenched, plegic hand may lead to disability if pain ot maceration of the palm develops, but a treatment that changes the Ashworth score from 4 to 3, and certainly from 3 to a lower score, is unlikely to offer any benefit. Other measurement techniques require instrumentation (Dobkin 2003). Treatment
of Spasticity
Therapists usually can manage pathologically increased tone in patients with hemiplegia by aiming to maintain notmal length of the muscle and soft tissue across a joint and helping patients to avoid abnormal flexor and extensor patterns at rest and during movement. Spasticity should be treated more aggressively when it interferes with nursing care and perineal hygiene or contributes to contractures and pressure sores. Treatment is often needed for patients with myelopathies, who endure painful spasms or involuntary flexor or extensor trunk and leg movements during transfers and after minor cutaneous stimulation. After SCI, spasticity is more prominent with incomplete than complete motor and sensory impairments, especially with cervical and upper thoracic lesions. It can be useful to lessen spasticity when ir appears to restrain voluntary upper or lower limb movements by co-contraction of agonist and antagonist groups. Hypertonicity has potential value. For example, spasms can dceteasc muscle atrophy and bone dcmineralization and increase venous return. An extensor thrust can provide the rigidity needed for weight-bearing stance. Learning to induce an extensor spasm can assist bed transfers in patients with a myelopathy. Determining how and when hypertonicity interferes with a patient's activities is the most useful
way to determine whether an intervention is needed. Bouts of clonus and flexor and extensor spasms during ambulation, driving, wheelchair push-up pressure releases, transfers, self-care activities, bed mobility, sleep, and sexual activities can be counted over the course of a day or week. Any intervention should aim to greatly lessen recurrences. Nociception can exacerbate hypcrtonicity and trigger flexor and extensor spasms and dystonic postures. A painful shoulder can cause the hemiplegic arm to flex at the elbow and wrist. Even an ordinarily innocuous stimulus, such as tight clothing or sunburn, can abruptly increase tone, much as it can cause autonomic dysreflexia in the patient with a cervicothoracic SCI. Treatable pain stimuli include bowel and bladder distention, urinary tract infection, epididymitis, joint pain especially on range of motion, unrecognized fractures, pressure sores, ingrown toenails, and deep venous thrombosis. Resistance exercises, though generally useful during rehabilitation, can increase flexor or extensor tone, especially if the exercise brings out associated movements. An overall approach to the management of pathological hypertonicity and spasms includes reversing any noxious stimulus, using physical interventions before adding drug trials, and reserving more invasive techniques such as nerve blocks and orthopedic or neurosurgical procedures to a few recalcitrant situations. Physical Modalities. Slow stretching movements and daily passive range-of-motion exercises reduce motion-sensitive symptoms of spasticity. Static stretching with splints and serial casting can reduce stretch reflex activity and contractures. Muscle cooling, tendon vibration, pressure exerted over a tight muscle belly, postural adjustments, loading a limb by weight-bearing on an extended arm or, for paraplegics, standing in a support frame (Figure 54.9), and EMG BFB can complement a stretching program. Electrical stimulation of motor and sensory nerves, muscles, and dermatomes by a variety of paradigms may reduce tone at the ankle and knee and in the forearm and finger flexors. A single session of stimulation usually decreases resistance and clonus for a few hours. Pharmacotherapy. Conttolled trials of antispasticity agents have varied widely in the target symptoms managed and the outcome assessments used. Usually, only a particular neurological disease is considered. Functional gains related to locomotion and upper limb use for any UMN disease often are marginal. However, a medication that prevents disabling spasms may improve quality of life. Table 54.19 lists useful first- and second-line drugs. After a SCI, about 2 5 % of patients arc discharged with an antispasticity agent, and half use medication by 1 year. Patients with American Spinal Injury Society (ASIA) gtades A and D (see Chapter 56C, Table 56C.2) are less likely to have been treated than those with grades B and C. Baclofen, tizanidine, and clonidine are especially useful in reducing
PRINCIPLES AND PRACTICES OF NEUROLOGICAL REHABILITATION Tabic 54.19:
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Dosages of medications for symptomatic spasticity
Drug First-Line Use Diazepam Dantrolene Baclofen Clonidine
Dosage
Ti/.anidine Gabapentin
2 mg bid—15 mg qid 25 mg bid—100 mg qid 5 mg bid-40 mg qid mg tid 0.05 mg qd-0.2 qd2 mg bid—8 tug qiu 400 mg tid-900 mg qid
Occasionally Useful Additions Intrathecal baclofen L-dopa or carbidopa Phcnytoin Phenobarbital Threonine Cyprobepradine Chlorpromazinc Mannol
50-150 pg rrial dosages 25 or 100 mg bid, respectively Serum concentration 10-20 ng/dl. Serum concentration 10-30 ug/dL 500 mg-2.5 m tid 4 mg bid—-H mg qid 10 mg qd-50 mg tid 2.5 mg qd-tid
paretic leg. L-dopa may be of value in these patients and in selected adults after stroke or SCI. These drugs can also cause sedation, confusion, hypotension, bowel and bladder dysfunction, and other central and systemic side effects. Great care must be taken when using them in the patient who has a pseudobulbar palsy and is at risk for aspiration. Whenever a drug appears to be useful, it is worth tapering the dosage down from time to time so that the patient can help reassess continued benefits.
FIGURE 54.9 A patient with quadnplegia from a spinal cord injury uses a standing wheelchair to try to reduce ankle and knee contractures and overall muscle tone. Subjects who can use their upper extremities may use a wheelchair like this to perform tasks while upright, such as washing dishes.
clonus and extensor spasms caused by myelopathy. The latter two drugs are a-2 agonists that inhibit the excitatory influences of peripheral sensory inputs on motoneurons. Medications with short-lasting effects such as tizanidine may be especially useful in limiting spasms during sleep or brief activities, such as ttansferring from wheelchair to bed. For refractory spasms and pain, intrathecal baclofen given by an implanted, programmable pump infusion has generally replaced a surgical myelotomy, intrathecal morphine, and electrical spinal stimulation. It has also replaced selective dorsal rhizotomy, except in some children with spastic diplegia from cerebral palsy. Dantrolene tends to be most useful in managing hypertoniaty of the upper extremity after stroke and TBI. Less than 0.5% of users develop hepatotoxicity after several months of intake. Baclofen, dantrolene, and the benzodiazepines can cause muscular weakness and difficulty with weight-bearing. Children with cerebral palsy and patients with hemiplegic stroke often need their by perron icity to ambulate on a
Chemical Blocks. Chemical agents, such as phenol, have been injected into the lumbar theca, nerve, motor point, or muscle to lessen inappropriate muscle co-contraction, spasms, and dystonic postures. Because motor point blocks can partially spare voluntary movement and could reduce reciprocal inhibition when given to an antagonist muscle, they could improve some aspects of motor control. Intramuscular infiltrative injections of 5 0 % cthanol or botulinum toxin reduce features of spasticity for about 3 months. Botulinum injections have seemed most efficacious for the wrist and finger flexors and plantar flexors of the ankle. Interpretation of the results of clinical trials using botulinum toxin requires attention to how well the outcome measure reflects clinical effectiveness for an important problem. Is a change in ease of passive range of motion, as in the Ashworth Scale, as meaningful as an increase in functional use of the limb? A few trials in children with cerebral palsy and spastic diplegia reveal modest \0% increases in walking speed after injections. The great majority of studies report a 1 - or 2-point decrease in the Ashworth Scale score and support this finding by offering a global physician score that, in reality, probably reflects a perception of a decrease in tone around one or more joints. A randomized trial compared injection of type A toxin into forearm muscles with vehicle injection in patients after stroke who scored 3 or more for the wrist and
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
2 or more for the fingers (Brashear et al. 2002). A statistically significant decrease in the Ashworth score occurred at 6 and 12 weeks (e.g., a change from 0.1 in controls to 0.8 in the finger flexors of the treated group). Significant changes were also found in the Disability Assessment Scale, which was said to reflect functional disability. This disability is only a subjective measure of change in hand hygiene, pain, positioning, and dressing that does not require use of the hand. It would be easy to misinterpret the data as revealing better functional use of the hand after botulinum toxin injection, but the real meaning is that with the wrist and finger flexors loosened, the hand was easier to keep open passively. Trials of botulinum toxin that are sponsored by the industry have not included a conttol intervention that uses rehabilitative passive or active range-of-motion or treatments for pain that may decrease tone. Also, these studies have not tried to maintain the effect of greater passive ranging by adding physical therapy after an injection to try to prolong benefit. Surgical Interventions. A variety of surgical procedures, including tendon lengthening, tenotomy, and tendon transfer, can correct deformities induced by spasticity and improve function. A gait analysis with EMG helps determine which procedure might aid mobility. Physical therapy must follow any surgery. Tenotomy of the hip adductors and iliopsoas and tendon lengthening of the hamstrings, Achilles, and toe or finger and wrist flexors are among the more common interventions. Lower-extremity surgeries are performed most often in children with cerebral palsy, although the data are difficult to interpret in terms of meaningful clinical gains. Achilles tenotomies for Duchenne's muscular dystrophy and a variety of foot surgeries, including triple arthrodesis, for Gharcot-MarieTooth disease may be beneficial. Posterior rhizotomy has been carried out especially in children with spastic diplegia. Selective division of posterior nerve rootlets of the second lumbar to second sacral level is based on intraoperative EMG responses of lower extremity muscles to posterior nerve rootlet stimulation. Youngsters with the most dramatic functional improvements are bright, ambulatory patients with spastic diplegia who have minimal fixed contractures and good strength. Some clinicians argue that such patients would do well with any intensive therapy. Indeed, controlled trials suggest that the intervention is no better than routine physical therapy in terms of functional walking (McLaughlin et al. 2002).
THERAPIES FOR IMPAIRMENTS AND DISABILITIES Therapeutic exercise and the neurodevelopmcnral approaches have traditionally received the most attention from PTs and OTs. Newer approaches, developed from concepts related to neuroplasticity, motor control, and
motor learning, arc merging with these. Success in retraining during rehabilitation, regardless of the primary approach, requires attention to many confounding variables. These include the characteristics of a task; how learning is reinforced; the patient's mood, motivation, attention, and memory for carryover of what is taught; environmental distractions; and family support. All can influence how motor and cognitive programs are built, shaped, and refined as the patient acquires a new skill. The daily practices of most individual neurological therapists reveal an eclectic, problem-oriented approach, A few wellspecified approaches to therapy are being assessed in clinical trials.
Locomotor Training Observation of rhe gait cycle for temporal asymmetries of the legs and kinematics at the hip, knee, and ankle during the stance and swing phases reveals deviations that the clinician can identify and use to help train patients (Dobkin 2003). Table 54.20 lists the easiest ones to look for as the patient walks on a flat surface. The timing of loading the stance leg and flexing the swing leg from its 10 degrees of extension is one of the important sensory inputs to the spinal cord for initiating the swing phase of gait. The notion of task-oriented training has led to small trials of treadmill training and related walking activities in patients with hemiplegic stroke. The specificity of the training improves the speed of walking, leg strength, and fitness and may reduce the energy cost of walking. The addition of partial body weight support to treadmill training (BWSTT) has shown promise in patients with stroke and SGI and in patients with Parkinson's disease and cerebral palsy. Subjects wear a mountain climbing harness that is attached to an overhead lift. The amount of weight borne by the lower extremities is adjusted to optimize the stance and swing phases of gait. One or more therapists
Table 54.20: Stance Phase Pelvis Hip Knee Ankle
Swing Phase Pelvis Hip Knee Ankle
Easily observed components of the gait cycleLateral and horizontal shift to the stance leg Extension to about II) Slight flexion upon loading Extension at midstance Flexion at foot pushoff Dorsiflexion to 10" at heel contact Dorsiflexion as the lower leg moves over the foot Plantarflexion to 20 with a propulsive rocker motion of the foot for pushoff Drop at toe off, then forward rotation Flexion to 20° to "shorten" the leg Flexion to 65° to "shorten" the leg, then extension just before heel contact Dorsiflexion to 10s for heel strike
PRINCIPLES AND PRACTICES OF NEUROLOGICAL REHABILITATION
may manually assist the lower extremities and pelvis during step training to optimize the step pattern. In theory, BWSTT allows the spinal cord and supraspinal locomotor regions to experience sensory inputs that are more like ordinary stepping than the atypical locomotor inputs created by compensatory gait deviations and difficulty with loading a paretic limb (Dobkin 1999). More normal proprioceptive and cutaneous input may improve the timing and increase the activation of residual descending locomotor outputs on the motor pools. In patients with complete SCI, FMG activity appears to he derived from the neural circuitry of the lumbosacral motor pools that recognize the sensory inputs provided by BWSTT, Sensory inputs related to the level of loading and to treadmill speed have been shown to modulate the EMG output during BWSTT in which the legs arc fully assisted during the step cycle. Most important, BWSTT allows massed practice with many repetitions guided by the cues of the therapist. This approach should enhance motor re lea ruing. In patients with stroke, single case studies and small clinical trials also suggest that BWSTT can increase the likelihood of achieving more independent ambulation and at greater speeds than by conventional therapy (Dobkin 1999). Gait symmetry clearly improves during treadmill step training. A Canadian randomized trial compared BWSTT with treadmill training without support during inpatient rehabilitation starting an average of 70 days after a stroke in 100 patients who could flex the affected hip. Average treadmill speeds did not exceed 1 mph. The trial showed a significantly greater overground speed in those managed with BWSTT (34 cm per second compared with 25 cm per second). Patient selection, duration of support before full weight bearing is allowed at faster treadmill speeds, practice paradigms, and the associated use of orthotics must In: better defined. Aims of this task-specific intervention include greater independence in walking and attaining walking speeds that permit home and community ambulation. The threshold velocity for home ambulation is 40 cm per second (45 cm per second equals 1 mph). Therapy ought to aim for faster walking speeds and for more energy-efficient traveling distances to permit unlimited community activities. Commtinin ambulation requires a walking velocity of 60 to 80 cm per second, or more than 1.5 mph. Therefore task-oriented training on a treadmill must exceed 1.5 mph. Note that typical disability measures such as the FIM and BI assess only the level of independence to walk 150 feet at any velocity. BWSTT did not improve overall locomotor-related outcomes in several randomized inpatient trials. The great range in time of onset of stroke to entry, slow treadmill training speeds for the BWSTT group, variations in the duration of therapy across patients, and lack of an intention-to-treat analysis make these trials less valuable. Training at treadmill speeds of about 2 mph lead to faster overground walking speeds than training at slower speeds, regardless of the
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initial overground walking velocity of a patient with stroke (Sullivan et al. 2002). BWSTT is also being combined with functional neuromuscular stimulation (FNS) with surface or implanted electrodes for patients will) chronic stroke. The results to date show modest improvements in walking speed and kinematics within subjects, but the design of clinical trials with the combined approach seems premature, given that the optimal use of BWSTT has not yet been demonstrated. Robotic devices may prove useful in assisting patients and taking the physical burden of step training off therapists. Multiccntcr trials of BWSTT are in progress for acute SCI (Dobkin 1999) and stroke using faster treadmill training speeds and better-defined training strategics than in previous trials. Temporal features of the gait cycle in patients with stroke and Parkinson's disease have been enhanced by bicycling and by rhythmic auditory stimulation that seems to entrain stepping.
Constraint-Induced Movement Therapy This strategy calls for forced use of the affected upper extremity and gradual shaping of a variety of functional movements to overcome what is theorized as learned nonuse of the paretic limb. Learned nonuse might derive from unsuccessful early attempts to use the affected limb after a stroke. The primary intervention uses a variety of techniques that prevent the use of the unaffected arm byplacing it in a sling or glove and having the patient practice skills and ADLs with the affected arm. The first rendition of this approach for the upper extremity has been promoted by Taub ct al. (1999) with a course of 6-7 hours of massed practice with the affected arm and the restraint for 2 weeks. In these patients with chronic stroke who could dorsiflex the wrist at least 10 degrees and extend the fingers of the paretic arm, about half of the improvement in daily use was evident within the first several days of restraint of the unaffected arm combined with therapy, which suggests that a latent capability had succumbed to learned nonuse. Gains in the amount of hand use are accompanied by cortical reorganization of the hand region, consistent with the effects of practice. Other investigators have been working to eliminate the restraint and decrease the intensity of practice with a therapist. One acute trial of the approach showed positive results (Dromerick et al. 2000), and a multiccnter trial called EXCITE for patients who are 3-9 months post-stroke is in progress. The most important aspect of this approach is massed practice. Styles of practice, such as the use of shaping and reinforcement schedules and the most cost-effective practice intensity, are works in progress. The notion of constraint with therapy has been invoked for a few treatments for walking and aphasia because the underlying style of therapy aims for massed practice of
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
specified activities and attempts to optimize responses and limit patient errors (Pulvermuller et al. 2001). The practice paradigm seems more important than concerns about restricting the use of an unaffected arm, leg, or language response.
Instrumented Biofeedback BFB includes a variety of instrumented techniques that try to make the treated subject aware of physiological information that can be used to better train an activity. Electromyographic BFB to improve upper and lower extremity muscle activity, decrease co-contraction of muscles, and increase functional movements has been used across many upper and lower moroneuron diseases. Its efficacy usually is modest at best. Across controlled trials of ambulation after stroke, electromyographic BFB seems most useful as a way to increase ankle dorsiflexion. EMGtriggcred neuromuscular stimulation initiated by a voluntary movement such as slight wrist extension of a paretic hand has led to functional gains for hand grip in some studies. BFB can improve performance during training but not necessarily when visual or auditory guidance is stopped.
Acupuncture A variety of acupuncture methods are widely used in China and Korea after stroke. Reports from these countries are impossible to interpret in terms of efficacy. Several small Western trials that treated subjects who had moderate hand paresis after a pure motor stroke showed gains in speed of hand manipulation or ADLs with the intervention. Bettercontrolled trials have not shown clear benefit (Johansson et al. 2001). A review of nine Western controlled trials with 53$ patients, carried out by investigators from a department of complementary medicine in Britain, concluded that no compelling evidence shows acupuncture to be effective for stroke rehabilitation. Despite 12 positive randomized trials reported in the Chinese literature, the results of very well-designed clinical trials do not support the use of acupuncture as a general intervention during stroke rehabilitation. Studies focused on particular types of dysfunction have yet to be carried out in a well-designed fashion.
Robotics In addition to robotic trainers to assist stepping ptactice, unilateral and bimanual practice with the upper extremities may be enhanced with robotic and mechanical assistive devices. Devices aim to allow subjects to ptactice movements to increase motor control and functional use of the
arm with only intermittent therapist oversight. The MITMANUS manipulates a patient's pareric elbow and shoulder much as a therapist might provide hand-overhand therapy for reaching in a plane over a Moror. Power and control at the shoulder and elbow improve with robotic training, consistent with the greater intensity of practice using those muscle groups. A device that allows movement in multiple planes and incorporates the hand may be of greater value for training.
Functional Neuromuscular Stimulation FNS systems can provide a hand grasp and release in C5 and C6 quadriplegics (Peckham et al. 2001). The commercially available FrecHand (NeuroConrrol, Ohio) ncuroprosthesis uses electrodes implanted in muscles of the opposite shoulder to control an external device that allows patients to complete upper limb grasp, pinch, and release tasks. The device has been less successful in reaching potential users than one might have expected. The first commercial surface electrode-driven device for grasping is the Handmastcr (NESS Ltd. Ra'anana, Israel), which has found some use in quadriplegic patients with at least CS intact and in hemipJcgic patients with poor hand function, FJectrodcs attached to a molded forearm orthosis that teaches across rhe wrist stimulate the wrist and finger flexors and extensors in synchrony. The external conttol unit operates from a button managed by the patient for the level of output that allows grasp, holding, or release. FNS sysrems have been used more often to aid standing and ambulation. Used alone or combined with an RGO or with other assistive and bracing devices, these systems can allow walking as an exercise and in some instances permit stepping for distances involved in movement indoots. However, a lengthy strengthening and fitness program must precede the use of these devices. The only commercial device to assist stepping, the Patastep System (Sigmetics, Inc.}, uses six surface electrodes to stimulate the gait cycle as subjects hold onto a rolling walker. Stimulation of the quadriceps muscles and pushoff with the arms permits standing up. Constant stimulation maintains standing. A step button on the walker stops quadriceps firing as one leg srarts its swing phase and activates a triple flexion response by peroneal nerve stimulation. The patient releases the button after the hip flexes and switches on the quadriceps stimulator for stance. The other leg is then stimulated to aid swing. Other patients with a complete UMN SCI may exercise with a bicycle ergometer called the ERGYS (Therapeutic Technologies, Inc., Tampa, Florida), which uses bilateral surface electrodes over the quadriceps, hamstrings, and gluteal muscles to sequentially activate leg forces on the pedals. As muscle strength increases, contractions are made against greater ergometer resistance, and muscle bulk builds.
PRINCIPLES AND PRACTICES OF NEUROLOGICAL REHABILITATION Neural Prostheses Direct electrical stimulation of the brain and spinal cord and the use of neural signals to control brain-computer interfaces have become increasingly feasible. Spinal cord stimulators placed over the dorsal spinal cord in the epidural space reduce some types of central pain and hypertonicity after SCI. Stimulation of the upper lumbar cord has also produced rhythmic leg movements in subjects with complete SCI. Stimulation with four dorsally placed lumbar electrodes reportedly improved the gait pattern of a patient with spastic quadriparcsis. Walking speed and endurance increased beyond what had been accomplished with BWSTT alone. Electrode microarrays are in experimental stages for direct spinal cord stimulation, perhaps of spinal primitive modules described earlier, Nerve cuffs placed around a portion of a peripheral nerve provide a permanent electrochemical interface to selectively initiate or record electrical signals or modulate the nerve's responses. Their initial experimental use has been for ankle dorsiflexor stimulation during walking. Some estimates suggest that up to 2 million Americans may currently be without any voluntary control due to ALS, a locked-in syndrome after stroke or trauma, MS, cerebral palsy, or muscular dystrophy. A direct braincomputer interface can be configured to substitute for neural control of muscles. Many of the technical challenges have been addressed or clever solutions are in the making to take command signals derived from brain electrical activity to control a neuroprosthesis or robotic device (Wolpaw et al. 2002). Signals are acquired from field potentials over the surface of the scalp, dura, or subdural regions or from the spike potentials of small clusters of neurons picked up by microelcctrode arrays from motor cortex or cognitive planning regions. Selected signals are digitized and processed by algorithms to extract specific features, such as the amplitude of an evoked potential or of a specific rhythm from sensorimotor cortex, or the firing rate of cortical spikes. A translation algorithm takes the particular electrophysiological features chosen to give simple commands to a device, such as a word processor or keyboard, a Web site, or an upper extremity neuroprosthesis.
Pharmacological Adjuncts Neurotransmitters and neuromodulators given in pharmacological dosages may augment the activation of a network during a specific task, but determining the doseresponse ratio that has positive effects and no adverse effects takes much study. Human clinical trials have been small, and most investigators screen 10-50 subjects to meet entry criteria. Several trials of dextroamphetamine, methylphenidate, and i.-threodopa have revealed motor gains when combined with motor therapies, but others have not;
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a trial with l.-dopa revealed modest gains in motor function (Scheidtmann et al. 2001). A promising approach is to use functional imaging to help detect changes in response to a drug and other therapy (Boroojerdi et al. 2001).
THERAPIES FOR COGNITIVE AND BEHAVIORAL DISABILITIES Overview of Cognitive Therapy Cognitive and behavioral disorders are common with a recent stroke or TBI and in MS, Parkinson's disease, and degenerative diseases. Table 54.21 lists some of the cognitive impairments dealt with by the rehabilitation team. These can seriously impede gains in mobility, ADLs, and community reintegration. Prospective studies of patients with an acute stroke reveal that 15-35% have greater memory impairments 3 months to 1 year after onset than age-matched controls. Cognitive dysfunction is
Table 54.21: rehabilitation
Cognitive impairments managed during
Language Aphasia Affective expression Attention Alertness Speed of mental processing Awareness of disability and impairment Focused attention on a single stimulus Sustained attention to a task Selective attention during distraction Divided or alternating attention between tasks Memory Retrograde, antegrade Immediate, delayed, cued, and recognition recall Learning Visual, verbal, and procedural or skill Perception Visual Auditory
Visuospatial Executive Planning Initiation Organization skills Maintaining goal or intention Conceptual reasoning Hypothesis testing and ability to shift responses Self'appraisal Self-monitoring Intelligence Verbal IVrforuiiiTiLV Problem solving Abstract reasoning
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Nl IIROI.OCIOU INVESTIGATIONS AND RELATED CI.INICAI. NEUROSCIENCES
especially common after TBI. Greater severity and duration of impairments are associated with a lower Glasgow Coma Score on acute admission and longer duration of posttraumatic amnesia. Up to one half of patients with an SCI have cognitive impairments from an associated TBI that may not be obvious early in their care. The amount and rate of recovery of neuropsychological functions vary with the sophistication of the measures used; type and severity of impairment; type, severity, and distribution of lesions; time since onset; and age at onset and follow-up. More subtle factors such as the interactions of diseases, associated sensorimotor and cognitive impairments, and premorbid intellect and education can affect the efficacy of a particular therapeutic approach and the natural history of gains. Comparisons between interventions often are confounded by the intensity and duration of treatment, lack of specification of the treatment methods, personal infractions between the therapist and patient, and success of the family's ability to reinforce desired behaviors.
202 yearly. By one month after stroke, 165 survivors were potential candidates for speech therapy, A prospective, community-based Danish study of acute stroke found that 3 8 % of 881 patients were aphasic on admission, with 2 0 % of the admissions rated as severe on the Scandinavian Stroke Score. Nearly one half of the severe aphasics died soon after onset, and one half of the mild aphasics recovered by 1 week. Only 18% of community survivors were srill aphasic at the time of their rehabilitation hospital discharge. Up to 2 8 % received early speech therapy as needed. Patients were retested for 6 months. Ninety-five percent with a mild aphasia reached their best level of recovery at 2 weeks, those with a moderate aphasia peaked at 6 weeks, and patients with severe aphasia reached best language function within 10 weeks. Only 8% of the severe aphasics fully recovered by 6 months on the scoring system used. The best predictor of recovery was less severe aphasia close to the time of the stroke.
General management approaches include training in particular functional adaptive skills, behavioral modification, and remediation of specific cognitive processes (Cicerone et al. 2000). In the adaptive approach, therapy tries to circumvent the effects of cognitive impairments on targeted daily activities. Repetition, cues that are both internal and environmental, and cognitive assistive devices are used for training. Learning to do a particular task usually does not generalize to other tasks that are not closely telatcd. Behavioral modification techniques are most often used in acute and transitional living settings for patients with TBI. Rewards are given for accomplishing a task or reducing antisocial actions. In the cognitive remediation approach, the subcomponents or hierarchical organization of a given cognitive skill are addressed. Tbe strategy assumes that at least some of the parallel and hierarchical neural networks for cognitive processes are understood. More often, the techniques used emphasize interventions meant to boost intact domains to help compensate for more impaired ones. Few studies show the benefit of a particular approach or combination of approaches over another interventional style for most cognitive impairments. Techniques usually merge as the team experiments with interventions that address the most deleterious problems. Indeed, outpatients wkh a TBI are the most likely group to need multimodal programs that stress ttaining in task-specific skills by remediative techniques, awareness about impairments and limitations, and skills needed for independent living and work,
Treatments
Aphasia The incidence of language disorders has varied across studies of patients with stroke and TBI. In a British health districr of 250,000 people, new cases of aphasia numbered
Treatments for aphasia average 45-60 minutes, arc provided up to three times a week in most studies, and rarely exceed this number in community practices. The family tries to continue what therapists recommend at home. Twenty percent to 5 0 % of aphasic patients have partial features of rhe rraditional aphasia subtypes (see Chapter 12). For rehabilitation therapy, the broadly defined features used to classify patients often do not address in enough detail tbe underlying disturbances of language, so they may not be optimal for directing treatment. A neurolinguistic assessment of aphasia aims to specify the types of representations or units of language, such as simple words, word formation, sentences, and discourse that arc abnormally processed during speech, auditory comprehension, reading, and writing. For each unit, the therapist ascertains how the disturbance affects linguistic forms such as phonemes, syntactic structures, and semantic meanings. Speech therapists most often attempt to find ways to circumvent, deblock, or help the patient compensate for defective language function by using a great variety of stimulation-facilitation techniques (see Table 54.4). These include visual and verbal cueing techniques, such as picture matching and sentence completion tasks, along with frequent repetition and positive reinforcement as the patient approaches the desired responses. Initial treatments also use tasks that relate to self-care, the immediate environment, and emotionally positive experiences. To prevent withdrawal and isolation, ir is especially important to quickly find a way to obtain reliable verbal or gestural "yes-no" responses. Behavioral techniques, particularly for patients with TBI, can be used to improve skills in maintaining eye contact, initiating and staying on a topic, turn-taking
PRINCIPLES AND PRACTICES OF NEUROLOGICAL RF.HABI1 ITATION
during conversation, adapting to listener needs, and using speech to warn, assert, request, acknowledge, or comment. Beyond the stimulation-facilitation approach to therapy, a variety of theoretical models for therapy have been proposed, such as the modality, linguistic, processing, functional communication, and minor hemisphere mediation models. Therapy techniques have been designed for specific aphasia syndromes and neurolinguistic impairments as well. Examples of a few of the available specificapproaches for particular problems follow. The efficacy of melodic intonation thcrapv (MIT) has been especially good. In MIT, therapists and patients meiodically intone multisyllabic words and commonly use short phrases while the therapist taps the patient's left hand to mark each syllable. Gradually, the continuous voicing and tapping are withdrawn. MIT works best in Broca's aphasics with sparse or stereotyped nonsense speech and good auditory comprehension. If a single sound, word, or phrase overwhelms any other attempted output, the Voluntary Control of Involuntary Utterance Program can help the patient gain control over perseverative intrusions. The agrammatism of Broca's aphasia has been treated with the Helm Elicited Language Program for Syntax Stimulation, which tries to build increasingly more difficult syntactic constructions. The therapist uses a standard series of drawings of common activities and provides a brief verbal description that ends with a question. The question contains a target sentence. As the patient's responses with target words improve, the patient is asked to complete the story without having heard the target sentence. Some patients with minimal or stereotyped output and impaired comprehension have improved with multiple input phoneme therapy. This 22-step hierarchical program huilds from an analysis of phonemes produced spontaneously by the patient to attempts at eliciting a target phoneme, followed by blends of consonants, then multisyllabic words, and eventually simple sentences. Some mute or nonfluent aphasics can acquire a limited but useful repertoire of gestures using, for example, American Sign Language. Comprehension in global and Wernicke's aphasics has been managed with the Sentence Level Auditory Comprehension Program. It trains patients to discriminate consonant-vowel-consonant words that are the same or differ by only one phoneme (e.g. "bill, pill, fill"). They then try to associate the word sounds with the written word and later try to identify the target word embedded in a sentence. For global aphasics, nonverbal communication using pantomime has decreased limb apraxia and improved auditory comprehension through a technique called Visual Action Therapy. The technique called Promoting Aphasics' Communicative Effectiveness emphasizes the ideas that need to be conveyed in face-to-face interactions rather than linguistic accuracy. It aims to develop any modality that can be used to transmit a message, including
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hand and facial gestures and drawing. The handbook and program called Supported Conversation for Aphasic Adults (Pictographic Communications Resources, Aphasia Centre, North York, Ontario, Canada) was designed for the nonaphasic conversation partner to facilitate interaction with global and nonfluent people. Electronic devices that provide delayed auditory feedback by about 200 milliseconds after the aphasic person makes each phoneme can be tried to improve awareness of paraphasic errors and intelligibility. Pharmacological
Adjuncts
A few studies suggest that intensive therapy combined with a drug that enhances vigilance or learning may benefit patients who have adequate language comprehension. Piracetam, a derivative of y-aminobutyric acid but with no GABA activity, may facilitate cholinergic and aminergic neurorransmission. A randomized, placebo-controlled trial included 50 moderately aphasic patients who had a stroke a mean of 10 months before starting the 6-week intervention of 10 hours of speech therapy weekly. The drug-treated group had a significantly better total score on the Aachen Aphasia Test, alrhough the clinical impact is not clear. In a randomized trial of 24 patients, use of piracetam was also associated with some language subtest gains and higher cerebral blood flow in left hemisphere language regions during a word repetition task. Other cholinergic agents have improved naming in patients with moderately severe Wernicke's aphasia or dysnomia, especially by reducing perseveration. Amphetamine and dopaminergic agents have improved aspects of language in several small studies but not all. Short-term trials of such agents can be carried out with parallel therapy and standardized tests in individual patients. Outcomes A metaanalysis was performed on 55 trials of speech therapy in aphasics with a stroke. Significant effects were found for treated patients at all stages of recovery, with the greatest outcome found when therapy was started in the acute stage. Treatments of more than 2 hours per week gave greater gains than lesser amounts of therapy. Severe aphasics showed large gams when treated by a speechlanguage pathologist. An inadequate number of studies were found to allow demonstration of any difference in treatment effects for differing types of aphasia. The Cochrane Library's systematic review of group trials in stroke (http://update-software.com/cochrane.htm) concludes that speech and language therapy for aphasic people after stroke has not been shown to be clearly effective or ineffective in a randomized clinical trial. Still, even a delayed pulse of a specific language therapy often improves a goal-directed aspect of aphasic communication in individual patients.
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINIC!AL NEUROSCIENCES
Memory Disturbances Memory disturbances can have a profoundly negative influence on compensation and new learning in the patient undergoing neurorehabilitation. An inpatient team depends on teaching that can he encoded and retrieved. When sustained attention is impaired, even motor and functional gains may be affected. Frequency of Memory Disturbance Across Diseases The frequency and risk factors for memory toss and dementia caused by one or more strokes have become increasingly appreciated. The prevalence of memory disturbance in population- and community-based studies is nine times greater in the first year after a stroke than in an agecontrolled group and twice as great each subsequent year. Other studies find a risk of about 2 0 % 3 months after a stroke. The frequency of dementia rises with increasing age and varies with the definition used. Even a mild aphasia may affect verbal memory and can interfere with verbal learning during rehabilitation. Memory impairments after TBI have been related to the time between injury and assessment, to the nature of the memory task, and to the severity of the injury. Tasks that require divided attention are especially useful to tease out executive dysfunction caused by a TBI. Natural history studies have reported varying outcomes. For example, in a group of 102 patients with TBI (ages 10-60 years) who were hospitalized for any period of unconsciousness, for post-trauma tic amnesia (PTA) of more than 1 hour, or for evidence of cerebral trauma, at 1 month the TBI group performed significantly worse on the Wcchsler Memory Scale and the Selective Reminding Test than a control group. Those who could not follow a command for the longest times beyond 24 hours after injury scored below the controls on more subtests of the Wechsler Memory Scale. Tests of orientation and short-term memory were inferior in their ability to reveal memory deficits compared with tests that required storage of new information for later use. At 1 year, patients performed better than they had at 1 month after onset. Treatments Most rehabilitative efforts to improve attention and to encode new information or recognize and retrieve memories are used for people with TBI. Previous exposure to verbal and especially to nonverbal information, with cues and prompts, can allow many amnestic patients after TBI to recall that information, a phenomenon called priming. Priming does not require semantic processing for encoding. It is specific to the properties of the input and relies on perceptual representations stored by modaliryspeeific memory subsystems, such as those that process word forms and visual objects. Tests of recognition
memory are especially sensitive methods for detecting residual memory in patients with severe amnesia. This implicit memory neocortical mechanism can even support the rapid acquisition of novel verbal and nonverbal material. It is independent of the hippocampal and diencephalic structures that relate to amnesia. Priming seems especially useful during rehabilitation to enhance procedural memory for skill acquisition. Cognitive remediation of amnestic disorders aims to train paricnts in using the subcomponent processes that underlie declarative and nondcelarative memory. Therapists can then take a restorative or compensatory approach to affect particular memory skills for functionally important activities, For example, therapists may address attentional impairments that could interfere with memory training by strategies for improving focused, sustained, selective, alternating, and then divided attention. Impairments in encoding and recall of information are then addressed. This approach uses associative and external cues that arc meant to prompt an action after increasingly longer intervals. It also uses aids such as memory notebooks. Some patients with TBI underestimate their memory and emotional impairments, even as they acknowledge physical and other cognitive problems. Without insight or concern, they deny having the impairment and withdraw or become angry with attempts at rehabilitation. The rehabilitation team must provide the counseling and insight therapy needed to overcome this. After a moderate to severe TBI, repetitive driils can have little impact on general recall or on memory outside of the training session. External aids such as a calendar and appointment diary and internal strategies such as rehearsal and visual imagery help most patients. The devices listed in Table 54.22 are helpful if patients can be cued to use them. Computers have been used extensively in cognitive remediation and skill training. Although software programs abound for working on reaction times, aspects of attention, language, problem solving, and other cognitive tasks, almost no data demonstrate the efficacy of this approach. Some patients have learned tasks such as data entry, database management, and word processing by taking advantage oi preserved cognitive abilities, including [Inability to respond to partial cues and acquire procedural information, even in the presence of a marked amnestic syndrome. This knowledge often does not generalize to even modest changes in the tasks. Through procedural memory, verbal and visual mnemonic strategies have been used to teach subjects a computer graphics program. Cooking and vocational tasks were taught with an interactive guidance system that cued each subtask to build up to the desired task. Pharmacological
Adjuncts
Studies of single subjects and small groups suggest that the drugs in Table 54.2.3 may benefit some patients with
PRINCIPLES AND PRACTTCFS OE NEUROLOGICAL REHABILITATION Table 54.22:
Aids and strategies for memory impairment
External Reminders by others Tape recorder Note written on hand Time reminders Alarm clock or phone call Personal organizer or diary Calendar or wall planner Orientation board Place reminders Labels Codes (colors, symbols) Person reminders Name tags Clothes that offer a cue Organizers Lists Personal organizer or diaryNumbered series of reminders Items grouped for use Radio pager Handheld computer [menial Mental retracing of events Visual imagery Alphabet searching Associations to what is already recalled Rehearsal Eirst-letter mnemonics Chunking or grouping of items amnestic and attentional impairments. TBI may lead to damage in a particular neurotransmitter system, such as cholinergic neurons. Presynaptic cholinctgic neurotransmission was abnormal in a human postmortem study of TBI. Therefore rehabilitation trials of cholinergic enhancing drugs such as donepezil and cytidme diphosphocholine Table 54.23: Possibly useful medications for attentional and memory impairments Cholinergic agonists Physostigmine Tacrine
Donepezil Merrifonate Cytidine diphosphocholine Choline and lecithin precursors Catecholamine agonists Dextroamphetamine Methylphenidate i.-dopa Amantadine Bromocriptine and other dopamine receptor agonists Desipraminc Nootropics Pramiraceram Piracetam Neuropeptides Vasopressin and analogues
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seem warranted. Replacement therapies fot other neurotransmittets, such as bromocriptine and noradrenergic agents, have a few human case studies to commend them. The divetsity of lesions after TBI (e.g., diffuse axonal injury, dorsolateral prefrontal cortex, hippocampus) necessitates an empiric, often individualized approach to pharmacotherapy. Outcomes Although memory-related processes are found to improve over the first 3 months after a stroke, reports on the natural history of ongoing cognitive sequelae suggest that both inpatient and outpatient rehabilitation efforts must pay ongoing attention to the need for compensatory aids and other strategies for these patients. After mild TBI, memoty usually recovers by 3 months. This varies with the test used to measure severity, the time from injury to testing, and the comparison group. The most impaired patients 1 year after a serious TBI are initially unable to follow a command finmore than a day and have post-traumatic amnesia for more than 14 days and a Glasgow Coma Score of 8 or less. One year after a severe closed head injury, patients followed in the Traumatic Coma Data Bank had greater impairments in vetbal and visual memoty and in other neurobehaviors, such as naming to confrontation and block construction, compared with normal controls. Selective rather than global cognitive impairments were likely at 1 year. Memory was disproportionately impaired compared with overall intellectual functioning in 1 5 % of the moderately injuted and 3 0 % of the severely injured patients. After moderate to severe TBI, children plateau in recovery by 1 year after onset, with little change in the next 2 years, and do not catch up to their peers in tetms of memoty, problem-solving ability, and academic performance. Late changes do evolve in some. In a long-term outcome study of mostly young adults, Wilson and colleagues reassessed 26 patients who had a TBI causing 1 hour to 24 weeks of coma, followed by rehabilitation. Five to 10 years later, 5 8 % wete unchanged, 3 1 % performed better, and 1 1 % did worse on the Rivermead Behavioral Memory Test and Wechsler Memory Scale. Many needed to tcly on memory aids.
Hem i-In attention Hennattentional disorders can arise from any node in the cottical-limbic-reticLilar network, which directs attention and integrates the localization and identification of a stimulus and its importance to the person. Unilateral neglect arises from injuries of the posterior parietal cortex; the ptefrontal cortex, which encompasses the frontal eye fields; and the cingulare gyrus. These regions include representations for sensation, for motor activities such as visual scanning and limb explotation, and for motivational televance, respectively. Subcortical areas such
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
as the thalamus, striatum, and superior colliculus coordinate the distribution of attention. Atrophy of frontal white matter and the diencephalon contributes to persistent anosognosia. The anterior and posterior extent of a lesion may also produce impairments in attentional and intentional processes that contribute to neglect. Therefore the most severe and subtle hcmiattentional disorders can be expected in focal stroke and more diffuse TBI. Frequency of Hetni-lnattention Across
Diseases
Community-based studies of stroke survivors detect visual neglect in 10-30% of patients. The neglect is modestly associated with poorer ADL scores and slower recovery, although severe neglect is rare beyond 6 months. Visual neglect is greater in right than left hemisphete strokes. Right-sided inattention, when looked for, has been detected in 15—40% of nonaphasic patients with acute left cerebral infarcts, although it is clinically most prominent after right brain injury. Patients with anosognosia, visual neglect, tactile extinction, motor inipersistence, or auditory neglect have the lowest BI scores at 1 year, even after the data are adjusted for initial ADL scores and for poststroke rehabilitation. Recovery across reports has been most rapid in the first 2 weeks, regardless of the side of stroke, and has plateaued at 3 months, when most patients have little visual neglect. Severe visual neglect and anosognosia in the first week tend to predict some level of persistent impairment at 6 months. Many patients have more subtle and lingering impairments that depend on the test used to detect them. ¥OT example, early after a right hemisphere stroke, a group of patients showed a strong and consistent rightward attentional bias in addition to an inability to reorient their attention leftward. Twelve months later, the attentional bias continued, but they could fully reorient to left hemispacc when performing line bisection and cancellation tasks.
Tabic 54.24:
Interventions for hemi-inartention
Multisensory visual and sensory cues, then fading cues Verbal elaboration ot visual analysis Environmental adaptations (bed position, red ribbon at left book margin) Computer training Video feedback Monocular and binocular patches Prisms Left limb movement in left hemispacc Head and trunk midline rotation Vestibular caloric stimulation Contralesional cervical nerve stimulation Reduction of hemianopic defects Pharmacotherapy Source: Adapted with permission from Dobkin, B. 2003, The Clinical Science of Neurologic Rehabilitation, Oxford University Press, New York.
and clever ways rehabilitationists have tried to manage hemi-inattcntion. For example, prisms have been used to transform sensorimotor coordinates, and passive prosthetics can be worn during tabletop activities. A 10-degree prism that shifts objects to the right in a patient with left hemi-inattention causes the patient to reach to the left when the glasses are removed. After adaptation to wearing the prism for 5 minutes, the patient's internal visual and proprioceptive map apparently realigns in the direction opposite to the optical deviation. The aftereffects of the prism may include significant improvement in drawing objects and performing cancellation tasks in left hemispace and in ADLs for days or more (Frassinetti et al. 2002). Noradrenergic and dopaminergic stimulants including methylphenidate and bromocriptine are especially worth trying in recalcitrant cases.
Behavioral Disorders Treatments The initial choice of an intervention may depend on the proposed mechanism of unilateral neglect or hemispatial inattention. For example, the patient can be treated for an underaroused right hemisphere that has difficulty processing sensory inputs. After a right brain injury, a powerful bias of the left hemisphere for attention to contralateral space could lead to an imbalance and necessitate a way to lessen the bias. A selective inability to disengage from inputs from ipsilatcral space might need to be addressed. Other strategies might have to be developed if the mental representation of contralesional space has been degraded or if a unilateral impairment m the activation of motor programs delays or prevents the intention to move to the contralesional side. If the initial theory-based intervention is not successful, then others should be tried. Table 54.24 lists some of the traditional
A great variety of behavioral changes can follow any hypoxic-ischemic injury or TBI. Alterations in personality have been reported in up to 7 5 % of patients 1-15 years after a TBI and tend not to improve beyond 2 years after onset. Table 54.25 lists some of the more common changes. Agitated motor and verbal behaviors, though not easy to define or treat after TBI, are found in more than 1 0 % and restlessness in 3 5 % of patients during acute inpatient rehabilitation. As cognition improves, agitation declines, but directed and nondirected aggressive, impulsive behavior may evolve. Persistent aggression and emotional dyscontrol suggest premorbid mood and behavioral disorders. Interventions include a medical assessment for exacerbating problems such as pain and drug-induced confusion, behavioral modification with positive and consistently applied reinforcements, a structured milieu, individual and group psychotherapy, and medication {Table 54.26).
PRINCIPLES AND PRACTICES OF NEUROLOGICAL RLHAH1LTTATJON
Table 54.25: Potential changes in behavior and personality after traumatic brain injury and cerebral hypoxia Disinhibition [mpulsivity Aggressiveness Irritability Lability Euphoria Paranoia Lack of self-criticism and insight Irresponsibility and childishness Egoocntricity Selfishness Sexual inappropriateness Self-abuse Poor personal habits Apathy, indifference Indecision Lack of initiation
Blunted emotional responses Poor self-worth Passive dependent)
Hypoarousal sometimes improves with stimulants such as methylphenidate and amphetamine or with dopamine agonists. Aggressive behavior sometimes is decreased dopaminergic or noradrenergic receptor blockade. Beta blockers can decrease irritability. A randomized trial of propranolol with a dosage escalation to 420 mg a day showed a reduction in the intensity of agitation, but not the frequency of episodes, compared with placebo. Hypomaiiic behavior may respond to lithium. Anticonvulsants such as carhamazepine sometimes prevent outbursts related to episodic dyscontrol.
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and in 2 5 % of age- and sex-matched controls. In a population-based cohort of Swedish stroke patients whose mean age was 73 years, the prevalence of maior depression was 2 5 % at hospital discharge, 3 0 % at 3 months after sttoke, 16% at 1 year, 1 9 % at 2 years, and 2 9 % at 3 years. In this and many other studies, a left anterior infarct, dysphasia, and living alone contributed to the prediction of depression upon discharge. At 3 months, greater dependence in ADLs and relative social isolation were associated with depression. Few social contacts at 1 and 2 years contributed. Anxiety is another stroke-related affective disotder. Although less often studied, a generalized anxiety disorder was present in 2 8 % of recent stroke victims and was associated with greater social isolation and greater dependence in ADLs. Apathy was found in about one quarter of patients within 10 days of a stroke, associated with greater cognitive impairment, poorer ADLs, and some cases of major but not minor depression. Depressed people with an SCI report spending more time in bed and fewer days out of the house and receiving more personal care assistance than better-adjusted patients with SCI at 2 - 7 years after injury. Suicide rates may be 2-4 times that of the general population within 5 years of SCI. Anxiety and depression can also arise from a posttraumatic stress disorder associated with the event that led to the SCI. Of patients with TBI, 2 5 - 6 0 % ate diagnosed with depression. Left anterior injuries, as in unilateral stroke, are associated with an early, ttansient depression. However, other focal and diffuse injuries make it difficult to relate mood disorders to specific diseases. Late-onset depression has been associated with premorbid psychiatric history and lower psychosocial function. Poor social adjustment can cause long-term depression and anxiety.
Affective Disorders Incidence
Treatment
Depression is very common after a stroke. The communitybased Framingham Study diagnosed depression in 4 7 % of 6-month stroke survivors, with no difference found in the incidence between those with left- and right-sided lesions,
Clinicians should manage mood disorders aggressively, especially when progress in rehabilitation falls short of expectations. In general, patients with depression respond to all classes of antidepressant medications and can be managed with the judicious care in dosing that is usually taken with an older adult. For example, by 6 weeks after starting fluoxetine or citalopram, two thitds of depressed subjects after a stroke recover, compared with about 1 5 % given placebo. The same medications can help alleviate pseudobulbar emotional incontinence with its involuntary weeping, grimacing, and laughing. Close clinical monitoring for adverse reactions to the antidepressants is important during inpatient and outpatient rehabilitation. These include sedation, insomnia, anticholinergic effects on bowel, bladder, and salivation, orthostatic hypotension, cardiac arrhythmias, anxiety, extrapyramidal symptoms, and a serotonin svndrome.
[able 54.26: Drut; interventions for aggressive behavior, restlessness, and episodic dyscontrol Anticonvulsants (carhamazepine, valproate, gabapentin) Beta blockers (e.g., propanolol) Lithium Antidepressants (e.g., amitriptyline, fluoxetine) Stimulants (e.g., methylphenidate, pemoline) Neuroleptics (e.g., risperidone) Benzodiazepines (e.g., clonazepam) Clonidine Calcium channel blockers
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
FUNCTIONAL OUTCOMES WITH REHABILITATION The most important outcomes for the rehabilitation team include the degree of independence in ADLs and community living. Thus functional measures that reflect the burden of care needed and the quality of life achieved by people with neurological disabilities are used in outcome studies more often than measures of change in sensorimotor and cognitive impairments. The scores on the FIM at admission for inpatient rehabilitation and at discharge offer an interesting snapshot of a large number of patients with stroke, TBI, and SCI from American institutions that participate in the Uniform Data System for Medical Rehabilitation. Over the past 10 years, the time from onset of neurological illness to transfer for rehabilitation has dropped about 2 5 % , and the length of stay in rehabilitation has followed a similar course in the United States.
Stroke A metaanalysis of 36 trials carried out before 1992 showed that the average patient who received a program of focused stroke rehabilitation or a particular procedure performed better than about 65% of the patients in the comparison group. Larger treatment effect sizes were associated with earlier timing of the intervention and younger age. This trend has continued over the past 10 years. Specific interventions for a well-defined functional disability, such as for improving functional use of an affected hand, walking, strength of a muscle group, balance, speech intelligibility, or community activities, show a moderate benefit. Rehabilitation studies of patients with stroke generally show that 5 0 % of 6-month survivors have no motor impairment, 7 0 - 8 0 % can walk 150 feet alone, and 5 0 70% are independent in ADLs using the BI. These gains in subjects with the best outcomes do not imply that they can walk efficiently in the community. However, most studies suggest that 5 0 - 7 5 % of survivors do not return to their prestroke level of activities in the community. Table 54.27 shows admission and discharge data about ADLs measured by the 7-part FIM, compiled from publications from the Uniform Data System. Ambulation A community-based population study in Copenhagen prospectively followed 800 acute stroke survivors. On admission, 5 1 % were unable to walk, 12% walked with assistance, and 3 7 % were independent. In the same facility, all who needed rehabilitation received services for an average total stay of 35 ± 41 days. At discharge, 2 2 % could not walk, 14% walked with human assistance, and
Table 54.27: Typical uniform data system for medical rehabilitation data for first stroke admissions, 2000
Mean Subs cores Self-care Sphincter Mobility Locomotion Communication Social cognition Total Functional Independence Measure score Age (yr) Onset (days) Stay (days) Discharge (%) Community Long-term care Acute care
Admission
Discharge
3.5 3.7 3.0 2.1 4.2 3.5 62
5.2 5.4 5.0 4.3 5.2 4.6 86
70 12 20 76 15 7
76 14 6
64% of survivors walked independently by BI criteria. Recovery of ambulation correlated directly with leg strength. About 80% of those who were initially nonwalkers reached their best walking function within 6 weeks, and 9 5 % achieved this within 11 weeks. If patients walked with assistance at stroke onset, 8 0 % reached their best function within 3 weeks and 9 5 % within 5 weeks. With rehabilitation, 3 4 % of the survivors who had been dependent and 6 0 % of those who initially needed assistance achieved independent walking for at least 150 feet. Life table analysis of patients from different impairment groups reveals a somewhat different pattern of gains. During their rehabilitation, 9 0 % of patients with a pure motor (M) deficit become independent in walking 150 feet by week 14 after stroke onset, but only 3 5 % of those with motor and proprioceptive (SM) loss by week 24, and 3% of those with motor, sensory, and hemianopic deficits (SMH) by week 30. The probability of walking more than 150 feet with assistance increases to 100% with M impairment by week 14. It increases to 9 0 % in those with SM loss by week 26 and with SMH deficits by 28 weeks. At 1 month and 6 months after stroke for all survivors, 5 0 % and 8 5 % , respectively, of M subjects recover walking, 4 8 % and 7 2 % of SM subjects recover, and 1 6 % and 3 8 % of SMH subjects walk without human assistance (Patel et al. 2000). Although many patients become independent in gait, sttoke patients who needed rehabilitation most often have self-selected walking speeds that peak in 3-6 months at one third to one half of normal for age. Speed is a good reflection of the overall gait pattern and, as noted earlier, reflects capabilities for walking in the home and community. Self-Care Skills In the Copenhagen Stroke Study, ADLs measured by the BI were assessed weekly in the hospital and at 6 months.
PRINCIPLES AND PRACTICES OF NEUROLOGICAL RLHAWLITATION
Twenty percent of survivors had a severe disability and 8% a moderate disability after a mean hospital stay of 37 days. Functional recovery peaked by 13 weeks after stroke onset in 95%. The highest BI score was reached within 13 weeks by those with moderate impairments and within 20 weeks in those with severe impairments by the Scandinavian Stroke Scale. A Bl score greater than 60 is associated with a home discharge. Using the impairment grouping schema, the cumulative probability of reaching a BI score greater than 60 and greater than 90 at 6 months after stroke is 9 5 % and 7 0 % , respectively, for M subjects, 8 5 % and 6 2 % for SM subjects, and 5 2 % and 3 5 % for SMH patients (Patel et al. 2000). Similarly, about 65% of inpatients during rehabilitation achieve a BI score greater than 95 by 15 weeks if they have only M deficits and by 26 weeks with SM loss. Only 10% score that high with SMH deficits after 18 to 30 weeks. However, 100% achieve a score greater than 60 by 14 weeks with M loss only, 7 5 % by 23 weeks with SM deficits, and 6 0 % by 29 weeks with SMH loss. For patients admitted for stroke rehabilitation, the admission BI or FIM score predicts later burden of care. The FIM score on admission positively correlates with discharge FIM and negatively correlates with length of stay, except in patients under age 50. The largest FIM change over time occurs in patients with admission FIM scores of 40 to 80. Patients with admission scores grearer than 80 and age less than 55 years routinely return home. A score of less than 40 and age greater than 65 leads to a nursing home discharge for 6 0 % .
Spinal Cord Injury The Uniform Data System database shows that the average age of patients with traumatic SCI is 43 years old. The mean rime from onset to admission for rehabilitation is 22 days, and length of stay is about 33 days. The FIM score increases from about 63 to 89. ASIA A (sensorimotor complete) and B (sensory present) subjects from trauma become ASIA C (less than useful motor return) in only about 1 0 % of patients during inpatient rehabilitation after a cervical or thoracic SCI. These patients tend to regain some sensorimotor function one level below the initial level of impairment. Gains may be a bit better for these ASIA-lcvcl patients with conus and cauda equina injuries. A clinical trial of CM, ganglioside found the following changes in 760 patients between 72 hours after a traumatic SCI of the cervical or thoracic cord and 26 weeks. About 8 0 % of patients with a central cord injury were able to walk at least 25 feet. Only 4% of ASIA A patients at onset recovered any ability to walk, whereas 4 0 % of ASIA B subjects regained this function. At least 7 0 % of ASIA C subjects recovered unlimited walking. ASIA A patients almost never recovered normal bowel and bladder function. Overall, about 1 5 % of subjects recovered these functions.
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Self-care skills depend especially on the level and completeness of an SCI. For patients with complete lesions at C4 or above, ventilatory support and assistive devices are needed along with physical help. With C5 intact, selffeeding is achieved with devices such as a balanced forearm orthosis and wrist splints with attachments for utensils. Patients use a power wheelchair by a hand control. With C6 intact, wrist extension allows the thumb and fingers to oppose without or, better, with a tenodesis orthosis. Upper extremity dressing, self-carheterization, manual wheelchair propulsion, and sliding board transfers are feasible. With C7 intact, these activities are performed more efficiently, and use of a suppository for the bowel program is feasible. With C8 intact, long finger flexion permits most ADLs to lie accomplished from a wheelchair. The strength of the lower extremities determines the amount of work that must be performed by the upper extremities for support, which in turn determines the energy cost and feasibility of ambulation. A study using the ASIA Motor Score found rhat 20 of 23 incomplete tetraplcgics who had an ASIA lower extremity motor score of 10 or more (the maximum normal score is 50 for five muscle groups of each leg on a 5-poinr scale of strength) at 1 month after injury became community ambulators with crutches and orthoses by 1 year. They subsequently achieved nearly effortless community ambulation if the lower extremity motor score improved to at least 30. In comparison, scores of 20 or less were associated with limited ambulation at slower average velocities, highct heart rates, greater energy expenditure, and greater peak axial loads on assistive devices. Paraparetic community ambulators usually need to have pelvic control with at least movement against gravity in the hip flexors and at one knee extensor so that they need no more than one KAFO for a reciprocal gait pattern. Patients need encouragement and resources to be able to return to work or school. Those with education beyond high school are far more likely to return to work and stay employed. Aging with SCI poses problems for many. One fourth of patients who sustained their injuries 20 or more years ago evolve a greater need for physical assistance over the years, especially for help with transfers. They report shoulder pain, fatigue, weakness, weight gain, and a decline in the quality of life more often than patients who do not need more assistance. Clinical surveillance is needed to anticipate when a pulse of therapy for an increasing impairment or disability or a change in assistive devices or wheelchair is needed.
Traumatic Brain Injury In general, after moderate to severe TBI, self-care and mobility improve from admission to inpatient rehabilitation to discharge, and gains are maintained or continue to increase for about 6 months. About 5 0 % return to work at
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NEUROLOGICAL INVESTIGATIONS AND RELATED CLINICAL NEUROSCIENCES
6 months. Socialization and leisure activities generally do not return to premorbid levels. Table 54.28 shows some of the characteristics of injury and rehabilitation in a well-defined group of American patients that did not include children. In a group of 2 4 i consecutive admissions to a rehabilitation unit, a significant inverse relationship was found between the Glasgow Coma Score and the duration of coma, along with a strong positive relationship between the duration of coma and post-traumatic amnesia (PTA). Of 119 patients with diffuse axonal injury, no one in a coma for more than 2 weeks or with PTA for more than 12 weeks had a good recovery by the Glasgow Outcome Score at 1 year after injury. Two thirds of the small subgroup with coma for more than 2 weeks improved to moderate disability when the coma lasted 2-4 weeks. Only one third achieved this level if in coma for more than 4 weeks. Eighty percent of patients with PTA for less than 1 weeks had a good recovery, and half with PTA lasting 2-8 weeks were moderately disabled 1 year after admission. At another inpatient facility, patients who had a Glasgow Coma Score of 3-7 within 24 hours of onset had lower admission and discharge FIM scores for motor and cognitive function duting their rehabilitation. In many communities, about 10% of patients return to former jobs, and fewer than 3 0 % are employed 2 years after severe TBI.
Parkinson's Disease Perhaps even more than with other chronic and progressive neurological diseases, with Parkinson's disease an exercise prescription can help patients maintain range of motion, flexibility, proximal strength, mobility, and fitness. Parkinsonian patients can reduce their symptoms and Table 54.28:
improve their function with focused physical and occupational rehabilitation therapies. Speech therapy improves prosody, breath support for speaking, and intelligibility. Patients have been trained to increase the speed of a skilled movement such as buttoning, although with more practice than normal controls need. Also, twice-a-weck practice for 3 months in whole body movements such as sitting, kneeling, standing up, and throwing, along with problemsolving for these activities, improves the speed of movements needed for mobility in moderately disabled Parkinsonian patients. A randomized crossover study compared regular activity with 1 hour of repetitive stretching, endurance, balance, gait, and fine motor exer cises in moderately disabled patients. Exercises were performed three times a week for 4 weeks with a progressive increase in the number of repetitions. The total United Parkinson's Disease Rating Scale score and the ADL and motor subscores, particularly the bradykinesia and rigidity components, significantly improved with exercise. Without an ongoing formal exercise program, these gains were lost 6 months later.
Multiple Sclerosis Evaluating the impact of rehabilitation in MS presents difficulties because it is a chronic condition continuing over many decades that is variable, unpredictable, and subject to spontaneous improvement during the first 15 years in many patients. A study of patients with rclapsing-and-remitting MS at onset found that the median time to reach a score of 4, 6, and 7 on the Kurtzke Disability Status Scale was 11, 2 3 , and 33 years, respectively. The scores represent a change from limited walking up to 500 m (EDSS 4), to walking with unilateral support no more than 100 m
Traumatic Brain Injury Model Systems Project, 1989-2000 (2553 cases)
Variable
Onset
Mean age, years % Male % Vehicle-re) a ted % Alcohol-related % Employed % Living ar home % Loss of consciousness % Post-traumatic amnesia >30 days 8-29 days 1-7 days Mean lowest Glasgow Coma Score Duration of coma, days Acute hospiral stay, days Rehab inpatient stay, days Total Functional Independence Measure score Disability Rating Scale
36 75 52 41 59 97 94 98 34 34 8 7 3.8 22 56 12.6
Source: Traumatic Brain Injury National Data Center (www.thims.org).
Rehabilitation discharge
1 Year after injury
24 85
32 97 6
115 2.9
PRINCIPLES AND PRACTICES OF NEUROLOGICAL REHABILITATION without rest (EDSS 5), to walking no more than 10 m while holding objects for support (EDSS 6). Patients with progressive disease from onset declined at 0, 7, and 13 years, respectively. Thus plenty of opportunities arise for rehabilitative interventions for specific disabilities. Quasi-experimental studies suggest a benefit from inpatient rehabilitation in MS. For example, in a srratified, randomized, wait list, controlled study involving 66 patients with progressive MS, the treatment group underwent a mean of 25 days of multidisciplinary inpatient rehabilitation. At 6 weeks, the neurological status in both groups remained the same. The treated group showed significantly lower levels of disability than the control group. Despite a decline in neurological status over the following year, the group maintained its gains in disability for 6 months and in quality of life for 10 months. A randomized trial compared 3 weeks of inpatient rehabilitation with a home exercise program in 50 patients. No change in impairment was seen in either group. However, the rehabilitation arm showed a benefit in disability in the FIM motor domain for self-care and locomotion (which could include wheelchair use), which persisted for 15 weeks. Improvement in quality of life (SF-36) in the mental composite score was also present for 9 weeks. These results emphasize the importance of continuity of care between the rehabilitation environment and the community and social service sectors, if the needs of the person with MS or with other chronic neurological diseases are to be met effectively over the longer term. The effect of an extended outpatient rehabilitation program on symptom frequency, fatigue, and functional status was studied in 46 patients with progressive MS. The 26 patients in the nonrandomized treatment arm received rehabilitation day services for 5 hours, 1 day per week. Although this program did not have any effect on functional status, significant benefits were seen in both in a reduction of symptom frequency at 1-year follow-up and in the incidence of fatigue compared with that of a waitlisted group. Although not yet studied by a scientific design, a day program may include general physical fitness exercises, practice in ADLs, group recreation, gardening, and local travel that help maintain or build self-care and community skills, along with psychosocial supports for clients and caregivers.
Other Diseases Critical illness polyneuropathy and myopathy from sepsis and organ transplantation have become a common cause of diffuse weakness, deconditioning, and disability that necessitates inpatient rehabilitation. Exercise management is similar to that of patients with Guillain-Barre syndrome. Nearly all patients with critical illness-induced weakness improve their strength from movement only against gravity at admission to offering resistance in proximal muscles
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within 3 weeks of the inpatient stay. As soon as feasible, these patients need to enter a milieu that encourages them to assist themselves, stay out of bed, and do light resistance exercises throughout the day. Patients are encouraged to work their arms and legs against the resistance of a stretchablc rubber Theraband for 10 repetitions in various planes every hour, even when resting in bed, or to do isometric exercise with a family member. The average length of stay needed to achieve the ability to stand up and walk 50 feet or more with an assistive device is about 18 days. Light resistance and conditioning exercises ought to be part of any maintenance program for people with diseases of the motor unit as well, along with instruction from therapists if greater disability evolves.
SUMMARY The essence of neurological rehabilitation is the ability to recognize and solve problems in everyday he a 1th-related activities faced by patients and their caregivers. Rehabilitation efforts attend to the details of the physical and cognitive impairments and disabilities of patients and their desire to participate more independently. The clinician must survey the patient's needs and anticipate complications by promoting prophylactic measures. Physical and cognitive interventions, supplemented by psychosocial supports and drug trials, aim to extend the quality of life of disabled patients. The design and institution of clinical trials for theory-based interventions have progressed more in the past 5 years than at any time in the past 50 years. These trials will lead to a solid base of therapies for specific needs. The success of incorporating biological interventions for neural repair and pharmacological memory-enhancing molecules into clinical practice will depend heavily on clinicians' ability to offer well-defined treatments that foster activity-dependent plasticity during the retraining of important skills.
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Dobkin, B. 1999, "Overview of treadmill locomotor training with partial body weight support: A neurophysiologically sound apptoach whose time has come for randomized clinical trials," Neurorebabilitatson and Neural Repair, vol. 13, pp. 157-165 Dobkin, B. 2003, The Clinical Science of Neurol'ogic Rehabilitation, Oxford University Press, New York Dromerick, A., Edwards, D., et al. 2000, "Does the application of constraint-induced movement therapy during acute rehabilitation reduce arm impairment after ischemic stroke?" Stroke, vol. 3 1 , pp. 2984-2988 F'eydy, A., Carlier, R., et al. 2002, "Longitudinal study of motor recovery after stroke: Recruitment and focusing of brain activation," Stroke, vol. 33, pp. 1610-1617 Frassinetti, F., Angeli, V., et al. 2002, "Long-lasting amelioration of visuospatial neglect by prism adaptation," Brain, vol. 125, pp. 608-623 Grariano, M., Taylor, C, et al. 2002, "Complex movements evoked by microstimulation of precentral cortex," Neuron, vol. 34, pp. 841-851 Haltiner, A., Newell, D., et al. 1999, "Side effects and mortality associated with use of phenytoin for early posttraumatic seizure prophylaxis," / Neurosurg, vol. 9 1 , pp. 588-592 Johansson, B., Haker, F„, et al. 2001, "Acupuncture and transcutaneous nerve stimulation in stroke rehabilitation: A randomized, controlled trial," Stroke, vol. 32, pp. 707-713 Jorgensen, H., Kammersgaard, L., et al. 2000, "Who benefits from treatment and rehabilitation in a stroke unit? A communitybased study," Stroke, vol. 3 1 , pp. 434-439 Kwakkel, G., Wagenaar, R., et al. 1999, "Intensity of leg and arm training after primary middle cerebral artery stroke: A randomised trial," Lancet, vol. 354, pp. 191-196 Macko, R,, Smith, G., et al. 2 0 0 1 , "Treadmill training improves fitness reserve in chronic stroke patients," Arch Phys Med Rebabil, vol. 82, pp. 879-884
McLaughlin, J., Bjomson, K., ct al. 2002, "Selective dotsal rhizotomy: Meta-analysis of three randomized controlled trials," Dev Med Child Neurol, vol. 44, pp. 17-25 Patel, A., Duncan, P., et al. 2000, "The relation between impairments and functional outcomes posrsttoke," Arch Phys Med Rehahil, vol. 8 1 , pp. 1357-1363 Peckham, P., Keith, M., et a I. 2001, "Efficacy of an implanted neuroprosthesis for restoring grasp in tetraplegia: A multiccnter study," Arch Phys Med Rebabil, vol. 82, pp. 1380-1388 Powell, j . , Heslin, J., ct al. 2002, "Community based rehabilitation after severe traumatic brain injury: A randomised controlled trial," / Neurol Neurosurg Psychiatry, vol. 72, pp. 193-202 Pulvermuller, F., Neininger, B., et al. 2 0 0 1 , "Constraint-induced therapy of chronic aphasia after stroke," Stroke, vol. 32, pp. 1621-1626 Salazar, A., Warden, D., ct al. 2000, "Cognitive rehabilitation for traumatic brain injury: A randomized trial," JAMA, vol. 283, pp. 3075-3124 Scheidtmann, K., Fries, W., et al. 2001, "Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: A prospective, randomised, double-blinded study," Lancet, vol. 358, pp. 7K7-790 Sullivan, K., Knowlton, B., et al. 2002, "Step training with body weight support: Effect of treadmill speed and practice paradigms on post-stroke locomotor recovery," Arch Phys Med Rehabil, vol. 83, pp. 683-691 Taub, F^., Us watte, C, et al. 1999, "Constraint-induced movement therapy: A new family of techniques with broad application to physical rehabilitation—a clinical review," Rehahil Res Dev, vol. 36, pp. 237-251 Wolpaw, J., Birbaumcr, N., et al. 2002, "Brain-computer interfaces for communication and control," Clin Neurophysiol, vol. 113, pp. 767-791
INDEX Page numbers followed by "f" denote figures, "t" denote tables, and " 6 " denote boxes
A Abaca vir, 1587t Abdominal examination, for coma evaluations, .SO Abduccns nerve brainstem syndromes of, 2111 extra-axial posterior fossa syndromes of, 2111-2112 lesions of, 275 neuroanatomy of, 2111 neurons of, 277 nucleus of, 277 Abdueens nucleus ipsilateral, 708 lesion of, 706 Abetalipoproteinemia, 80.lt, 1699, 1826, 2176, 2336 Abscess brain actinomycosis and, 1505 in AIDS patients, 1597f antibiotics for, 1487 in children, 1102 clinical features of, 1484 computed tomography of, 1484 corticosteroids for, 1487 diagnosis of, 966, 1484 differential diagnosis, 1485, 1487 frontal lobe, 1484 hematogenous spread of, 1484 magnetic resonance imaging of, 1484, 1485f-1486f meningitis-related, 1476 neurosurgical treatment of, 966, 966f pathogens associared with, 1484-1485 predisposing causes of, 1484 sites of, 1484 treatment of, 1487 diffusion-weighted magnetic resonance imaging of, 527, 528f epidural characteristics of, 596-597, 967 cranial, 1488, 1489f spinal, 1489-1490, 2213-2214 intracerebral, 559 pituitary, 966-967 psoas, 2293 retroperitoneal, 452 spinal epidural, 1489-1490 Absence seizures characteristics of, 17-18 clinical features of, 1961-1962 complex partial seizures vs., 19c description of, 17-18, 19t electroencephalography findings, 469, 470f, 1962 Absence syndromes, 1965 Abulia, 104t clinical features of, 44, 44t definirion of, 118 Accmthamoeba spp., 1556t, 1565-1566 Ac a nthocy tic syndromes, 1086
Acceleration concussion, 1116 Accessory deep peroneal nerve, Acetaminophen adverse effecrs of, 932t half-life of, 932t pain management using, 931, 932t Accra «>lamide, 1241, 1749, 1758, 1 860, 2044 Acetylcholine in Cajal Retzius cells, 1773 cellular sites of, 889 chemistry of, 889-890 description of, 515, 889, 2443 disorders associated with, 882t distribution of, 889-890 galanin and, 905 neuronal uptake, 889 neuropeptide colocalization with, 902t slow release of, 889-890 synaptic space diffusion of, 890 Acetylcholine receptors antibodies against, 2446 description of, 404 diseases associated with, 892, 893t muscarinic description of, 404 disorders associated with, 893t neuronal, 891-892 rypes of, 892 nicotinic description of, 404 disorders associated with, 893t muscle, 890-891 neuronal, 891 structure of, 890-891 pharmacology of, 891f regulation of, 892 Acetylcholinesterase, 889-890 Acetylcholinesterase inhibitors, Alzheimer's disease treated with, 1915-1916 Achondroplasia, 2196, 2196r Acinetobacter, 1484 Acoustic neurinoma brainstem auditory evoked potentials findings, 482, 482f-483f description of, 547, 548f neurosurgical treatment of, 977 Acoustic neuroma, 5, 1336 Acoustic reflex testing of, 744-745 threshold, 250-251 Acquired demyelinating polyradiculoneuropathy, 2280-2281 Acquired horizontal gaze palsy, 715 Acquired immunodeficiency syndrome. see also Human immunodeficiency virus central nervous system lymphoma in, 562f, 563, 1418 cerebral infarction caused by, 1219 computed tomography uses, 560-563 cryptococcosis, 563, 563f
Acquired immunodeficiency syndrome (Continued) cytomegalovirus, 562-563, 836 delirium caused by, 37 dementia, 835, 888t discovery of, 1581 fungal infections caused by, 1545-1546 gender disrribution of, 1581 global prevalence »f, 1581 highly active antiretroviral therapy for, 1585-1586 language disorders in, 158 magnetic resonance imaging uses, 560-563 mortality rates, 773 neurological complications of brain abscess, 1597f cryptococcal meningitis, 1590f, 1590-1591, 1593t cytomegalovirus encephalitis, 1591-1592 description of, 1582c, 1582-1583 neurosyphilis, 1591 primary central nervous system lymphoma, 1594 progressive multifocal leukoencephalopathy, 1594, 1596 ventriculoencephalitis, 1591-1592 neurological diseases associated with, 775 neuropathologies! complications of, 1582 prevalence of, 1581 progressive multifocal leukoencephalopathy, 562 sleep disturbances in, 2034-2035 toxoplasma encephalitis, 560-562, 561f Acquired immunodeficiency syndrome-associated neuropathy, 413 Acquired protein C deficiency, 1226-1227 Acquired stuttering, 163-164 Acrodystrophic neuropathy, 2360 Acromegaly, 860, 860r, 866, 1095, 2379 Acrylamide, 1710 Acrigraphy, 2042 Actinomycosis, 1505-1506 Action myoclonus, 317, 332-333 Action potentials calcium-dependent, 909 compound muscle aging effects, 496 amplitude of, 492, 1189 area of, 492 axon loss mononcuropathy findings, 499 decrement in, 516 definition of, 491 demyelinative mononeuropathy findings, 499 duration of, 492 F wave, 512 Lambert-Eaton myasthenic syndrome findings, 2456 Martin-Grubcr anastomosis effect on, 496-497 in neuromuscular junction disorders, 517i motor unit i
ii
INDEX
Action potentials {Continued) amplirude of, 507 duration of, 508 firing patterns, 509 interference pattern, 509 morphology of, 507-509 phases of, 508-509 recruitment frequency, 509 recruitment ratio, 509 stability of, 509, 509f voluntary, 507-509 sensory nerve aging effects, 496 amplirude of, 493-494 definition of, 491 nerve conduction study measurements, 493^194 temporal dispersion effects, 497-^98, 498f Action tremor description of, 288, 302 gait disturbances caused by, 333 of legs, 333 Activation-induced cell death, 820 Activities of daily living adaptive aids for, 1032t neurological rehabilitation for, 1029 Schwab-England Scale of, 296, 297t-299t Acupuncture, 1058 Acute central cord syndrome, 361, 1155-1157, 1156f, 1170 Acute coronary syndrome, 951 Acute demyclinating transverse myelitis, 967 Acute disseminated encephalomyelitis characteristics of, 553, 553f, 825, 838 clinical features of, 1660 diagnosis of, 1661-1662 differential diagnosis, 1659t history of, 1659 idiopathic, 1660 laboratory features of, 1660-1662 lesions associated with, 1661, 16611 measles-induced, 1660 postvacci nation, 1659-1660 recovery from, 1660 treatment of, 1662 Acute hemorrhagic leukoencephalitis, 1662 Acute infantile spinal muscular atrophy, 381 Acute inflammatory demyelinating polyneuropathy, 414t, 825. see also Guillain-Barre syndrome Acute inflammatory demyelinating polyradiculoneuropathy, 414t, 415, 1593t, 2387. see also Guillain-Barr syndrome Acute intermittent porphyria, 1829 diagnosis of, 109-110 psychiatric disturbances associated with, 109-110 Acute lymphoblastic leukemia, 1450 Acute motor axonal neuropathy, 2343f Acute motof neuron disease, 1529 Acute mountain sickness cerebral edema caused by, 1755 description of, 1665 Acute myocardial infarction, 1211-1212 Acute necrotizing myopathy, 1469
Acute pain history-taking, 929-930 interview-raking, 929-930 physical examination for, 930 Acute pandysautonomia, 2338 Acute phase proteins, 810 Acure promyelocyte leukemia, 1253 Acute respiratory failure, 948 Acute transverse myelitis, 1663 Acyclovir herpes simplex encephalitis treated with, 834, 1518 renal insufficiency caused by, 1518 viral infections treated with, 1518, 1521t Acylcarnitinc profile, 1812t Addison's disease, I 09N Adenomas, pituitary characteristics of, 545, 546f, 861t, 1095 imaging of, 1399f management of, 1419 Adenovirus, 1541 Adenylosuccinate lyase deficiency, 1828 Adenylyl cyclase, 861-862 A die's syndrome, 223-224, 227 Adolescents headaches in, 2103-2104 human immunodeficiency virus-associated progressive encephalopathy in, 1608-1609 inborn errors of metabolism in, 1820-1821 migraines in, 2103-2104 pregnancy, 1309 tension-type headaches in, 2104 Adrenal glands Addison's disease, 1098 coma evaluations, 60-61 disorders "i in adults, 1098 in children, 1111 glucocorticoid deficiency, 1111 pheochromocytoma, 1098 Adrenergic receptors central, 897-898 clinical role of, 898, 899t physiology and pharmacology of, 897-898 Adrenocorticotropic hormone, 860 Adrenoleukodystrophy, 554, 805t, 1948 Adrenomyeloneuropathy, 2228, 2334-2335 Ad son'5 test, 435 Adult hcxosaminidase-A deficiency, 2260-2261 Adult-onset hydrocephalus, 1759-1760 Adult-onset primary focal and segmental dystonia, 2156-2157 Adult respiratory distress syndrome, 1137 Advanced sleep-phase syndrome, 2024 Aedes aegypti, 1538 Affective agnosia, 154 Afferent pupillary defect, 730-731, 731t Afibrinogenemia, 1227 Afiptia feUs, 1504 African trypanosomiasis cerebrospinal fluid findings, 1563 clinical features of, 1562-1563 description of, 2007 diagnosis of, 1563 epilepsy and, 1970 geographic distribution of, 1562 incidence of, 1562
African trypanosomiasis [Continued] pathogenesis of, 1562 pathology associated with, 1562 relapses, 1563 sleep effects, 2035 treatment of, 1563-1564 Agcncrase. see Amprenavir Agenesis, corpus callosum, 564, 565f, 1777r, 1782-1783 Age of patient electroencephalography and, 476 magnetic resonance imaging findings based on, 548 nerve' conduction studies and, 496 Aggression in Alzheimer's disease, 88 in epilepsy, 99 in Huntington's disease, 94, 95t neurological disorders associated wirh, 86t post-stroke occurrence of, 100 Agnosia affective, 154 auditory assessment of, 138 characteristics of, 136 nonverbal, 136-137 positron emission tomography evaluation of, 137 pure word deafness, 137 sound impairments associated with, 137 definition of, 131-132 object, 129 tactile anatomic considerations, 138-139 assessment of, 139 definition of, 138 somarosensory cortex and, 138-139 somesthetic function impairments in, 138 stages of, 138 verbal auditory, 1806 visual apperceptive associative agnosia vs., 131-132 characteristics of, 132 perceptive categorization deficit, 133, 133f share perception impairments, 132, 132f simultanagnosia, 133 syndromes related to, 132-133 assessment of, 136 associative apperceptive agnosia vs., 131-132 brain damage patterns in, 134-135, U5f definition of, 133-134 dissociations in, I 34 lesions that cause, 134-135 neuropathology of, 134-135 with prosopagnosia, 134, 135 f pure alexia, 134 syndromes related to, 135-136 historical investigations of, 131 Agrammatism, 145 Agraphia alexia with, 151-152, 154t, 1204 alexia without, 151, 153t, 1208 characteristics of, 153-154 pure alexia without, 151, 153t
1NDF.X
Aicardi's syndrome, 805t, 178.^ AI P. see Acute intermittent porphyria Air-hone gap, 253 Akathisia description of, 317-318 restless legs syndrome vs., 2023t Akinesia assessing for, 1 1 8 - 1 1 9 erosscd response task assessments, 118 definition of, 117 diagnosis of, 117-1 IS directional, 1 1 8 - 1 1 9 endo-evoked, 1 1 8 - 1 1 9 exo-evoked, 1 1 8 hemisparial, 119 in parkinsonism, 300 Parkinson's disease, 122 spatial, 118 temporoparietal lesions a n d , 122 testing for, 1 1 8 - 1 1 9 types of, 118 Akinetic mutism, 67 Akinetic-rigid gait, 3 3 0 - 3 3 1 , 3 3 1 t Alanine, 1683 Albendazole, for parasitic infections, 1556t, 1572, 1 5 7 5 - 1 5 7 6 Alhinism, 7 3 8 Alcohol consumption ataxia caused by, 2 1 6 9 brain tumors a n d , 1337 stroke risks a n d , 1199 Alcoholic dementia, 1944 Alcoholic neuropathy, 1705, 2 3 7 5 - 2 3 7 6 Alcoholism cerebellar degeneration associated with, 1706 neurological complications of, 1705t nutritional diseases associated with alcoholic neuropathy, 1705 description of, I 7H-1 Marchiafava-Bignami disease, 1706 tobacco-alcohol amblyopia, 1 7 0 5 - 1 7 0 6 serotonin a n d , 9 0 I t Wernicke's encephalopathy and, 1702-1703 Alert, 43 Alexia with agraphia, 1 5 1 - 1 5 2 , 154t, 1204 aphasic, 152-153 pure descriprion of, 134 without agraphia, 151, 153t without agraphia, 151, 153t, 1208 Alien hand syndrome, 68 Alkylating agents antitumor effect of, 1404 brain tumors treated with, 1404—1405, 1409 nitrogen mustards, 1404 nitrosoureas, 1404 nonclassic, 1 4 0 4 - 1 4 0 5 procarbazine, 1 4 0 4 - 1 4 0 5 thio-TEPA, 1404 Alleles, 783 Allelic heterogeneity, 7 8 3 , 7 9 2 Allochiria, 120 Allodynia, 3 8 7 , 2 3 0 3 , 2 3 0 8 Ally! chloride, 1 7 1 0 - 1 7 1 1 Ahnotriptan, 2 0 8 2 t Alobar holoprosencephaly, 1777t, 1780
Alopecia, 2 3 0 5 Alpha c o m a , 4 7 4 , 475f, 1670 Alpha-i-fucosidase-1, 803t Alpha m o t o n e u r o n s , 2 2 2 9 Alpha rhythm, 4 6 6 , 467f Alphavirus, 1516t Altered peptide ligands, for multiple sclerosis, 8 2 4 - 8 2 5 Alternating hemiplegia of childhood, 3 4 0 , 2104 Alternating skew deviation, 7 2 0 Altitude insomnia, 2 0 1 3 Aluminum exposure, 1714 Alzheimer's disease aggression in, 88 /{-amyloid fragment in, 1 9 1 3 - 1 9 1 4 amyloid precursor protein associated with, 1 9 0 5 - 1 9 0 6 , 1913 apathy in, 8 7 - 8 8 apolipoprotein F, allele a n d , 1 9 0 6 , 1910 aurosomal dominant, I 909 behavioral symproms associated with description of, I 906 management of, 1910 biochemical changes associated with, 1913-1914 cell loss i n , 1912 cerebral amyloid angiopathy a n d , 1255 cerebral atrophy associated with, I 4 HI clinical features of aphasia, 1907 apraxia, 129, 1907 delusions, 1 9 0 7 - 1 9 0 8 depression, 1907 description of, 1906 hallucinations, 1 9 0 7 - 1 9 0 8 memory loss, 1 9 0 6 - 1 9 0 7 m^identification syndromes, 1907 personality changes, 1908 psychotic symptoms, 1 9 0 7 - 1 9 0 8 visuospatial impairment, 1907 clock drawing test evaluations, 6 8 3 - 6 8 4 , 685f cognitive impairments in description of, 1 14 mild, 1908 cognitive map of, 687f conceptual apraxia associated with, 129 constructional praxis in, 6 8 7 delusions in, 88 dementia clinical features of, 6 8 9 t conceptual apraxia associated with, 129 frontotcmporal dementia vs., 6 8 9 t magnetic resonance imaging findings, 549 demographic factors, 1906 depression in, 8 7 , 9 1 , 111, 1916, 2 0 4 9 description of, 8 6 - 8 7 , 1616 D o w n s y n d r o m e a n d , 1915 electroencephalography evaluations, 4 7 7 epidemiology of, 1906 familial patterns, 1909 fronrotemporal dementia vs., 689t, 1919 generics of, 1 9 0 9 - 1 9 1 0 hallucinations in, 8 8 , I I 1 histologic features of, 1912 history of, 1 9 0 5 - 1 9 0 6 imaging of, 1 9 1 0 - 1 9 1 1 , 1 9 l l f inflammatory m a r k e r s in, 1914
Alzheimer's disease (Continued) laboratory studies, 1909 language deficits in, 158, 6 8 6 - 6 8 7 late-onset familial, 1909 magnetic resonance imaging findings, 5 4 9 , 1910, 1911f memory impairment associated wirh Creurzfeldt-Jakob disease-related memory disorder vs., 1622 description of, 6 8 6 treatment of, 8 7 3 - 8 7 4 mild cognitive impairments in, 6 8 5 , 1908 Mini-Mental State Examination findings, 6 7 9 , 680f, 6 8 6 , 1908 muscarinic receptors a n d , 893r neuritic plaques in, 19 12 neurofibrillary tangles in, 1 9 1 1 - 1 9 1 2 neuroimpging of, 1 9 1 0 - 1 9 1 1 , 191 If UL'urokisiical examination tor, 1908-1909 n e u r o p a t h o l o g y findings, 1 9 1 1 - 1 9 1 2 , 1913f n e u r o p s y c h i a t r y symptoms description of, 1 9 0 7 - 1 9 0 8 management of, 1910 neuropsychological findings, 6 8 6 - 6 8 7 ncurorransmitter abnormalities in, 1914-1915 pathologic findings, 1 9 1 1 - 1 9 1 2 , I913f positron emission tomography of, 6 6 9 , 669f, 1 9 1 0 - 1 9 1 1 presenilin 1, 1906, 1909 presenilin 2, 1906, 1909 prevalence of, 1 I I progression of, 686f, 1909f psychosis in, 8 8 - 8 9 , 89f, 90t, 111 schizophrenia vs., 90r sequelae of, 86 serotonin's role in, 901t single-photon emission computed tomography of, 6 6 9 , 1910 sleep disorders in, 2 0 3 0 - 2 0 3 1 , 2 0 3 9 tau protein in, 1913 treatment and management of acetylcholinesterase inhibitors, 1915-1916 furure rypes of, 1 9 1 6 - 1 9 1 7 urinary inconrinence in, 4 2 3 ventricular enlargement associared wirh, 1910 visuoperceptual ability deficits in, 6 8 7 white-matter lesions in, 1910 A m a n t a d i n e , 8 9 5 , I 5 2 1 t , 1626, 1654 Amaurosis fugax, 178, 1 2 0 3 - 1 2 0 4 , 2066-2067 Amblyopia tobacco-alcohol, 1 7 0 5 - 1 7 0 6 vision loss caused by, 182 American Adulr Reading Test, 678 American Neuropsychiatric Association, 85 American trypanosomiasis, 1564, 2392-2393 Amino acid metabolism disorders, 1823-1825 Aminoacidurias, 1773 j'-Aminoburyric acid binding of, 8 7 9 chemistry of, 879 description of, 879
Volume I p p . 1-1070 • Volume II p. 1071-2546
iv
INDEX
y-k mi no butyric acid [Continued) disorders associated with, 882t distribution of, 879 epilepsy and, 1973-1974 neuropeptide col oca ligation w i t h , 902t receptors For clinical role of, 8 8 1 , 881t G A B A A , 879-880 G A B A B , 879-880 GABAc, 879-880 genetic anomalies that affect, SSI modulators of, 881 structure of, 880f types of, 879-880 Aminoglycosides, bacterial meningitis treated with, 1481t i* - A mino- 3 - h yd roxy- 5 - met h y I is ox a zole-4propiomc acid receptors, see AMPA receptors Amiodarone, 1076, 2382 Amitnpryline, 1655, 2097-2098 Amnesia anrerograde, 69 posttraumatic, 1062 retrograde, 69 transicnr global delirium caused by, 38
description of, 71 onset of, 1202 transient ischemic" attacks and,
1202-1203 l ran malic lira m injury related, 698 Amnestic mild cognitive impairment, 1908 Amnestic shellfish poisoning, 1736t, 1739-1740 Amnestic syndrome anterior communicating artery aneurysm rupture, 69 definition of, 69 features of, 69t Wernicke-Korsakoff syndrome, 69 Amniotic fluid embolism, 1225-1226 Amoebiasis, cerebral, 1566 Amoebic infections, 1564—1565 AMPA receptors description of, 884-885, 1132 pharmacology of, 886 Amphotericin B, 1547t, 1552-1553, 1556t, 1591 Ampicillin, for bacterial meningitis, 1480t Amprenavir, 1587t Amslcr's grid chart, 733f Amusia, 137
Amygdala, 68 Amyloid neuropathy characteristics of, 2358f description of, 414 sexual dysfunction and, 429 Amyloidosis apolipoprotein A l , 2330 desenprion of, 1088 gelsolin, 2330-2331 Gers rma tin -Stra u ss Icr -Schei n ker synd rome and, 1621 primary systemic, 2356-2357 prion diseases and, 1617 transrhyrerin, 2329-2331, 2330t Amyloid precursor protein, 1905-1906, 1913
Amyotrophic lateral sclerosis age of onset, 2247 atypical features of, 2251-2252 behavioral disturbances i n , 97 blood tests for, 2253 characteristics of, 172 chromosomal aberrarions, 803t classification of, 22521 dementia i n , 2251 depression in, 97 diagnosis of, 383-384, 2253-2254 differential diagnosis, 2254 dysphagia i n , 172 electrodiagnostic examination for, 2253 enteroviruses and, 1529 epidemiology of, 2247 etiology of, 2247 familial autosomal dominant, 2258-2259 clinical features of, 2259 description of, 2247, 2258
genetics of, 2258 juvenile, 2259-2260 pathogenesis of, 2258-2259 fasciculations i n , 2251 footdrop in, 2250f fron to temporal dementia and, 688, 1922 glutamate excirotoxicity and, 2247 history of, 2246-2247 human immunodeficiency virus and, 1540 immunological abnormaliries associated w i t h , 2248 inclusion body myopathy vs., 384 in ..in i'i nor, abnormalities associated w i t h , 2248, 2249f laboratory studies of, 2252-2253 lower motor neuron-type weakness, 379 magnetic resonance imaging of, 2253 muscle weakness associated w i t h , 383-384, 2249-2250 natural history of, 2252 needle electrode examination for, 2253 needle electromyography diagnosis of, 511-512 nerve conduction studies for, 512 neurofilamenr dysfunction i n , 2248-2249 paraneoplastic, 2262 personality disturbances i n , 97 prognosis for, 2252 pseudobulbar palsy associated w i t h , 2250 radiculopathies that simulate, 2282 rehabilitation for, 871 signs and symptoms of, 8 sleep disorders and, 2031 spastic-flaccid dysarthria in, 162 sporadic clinical features of, 2249-2251
etiology of, 2247 pathogenesis of, 2247-2249 susceptibility genes, 2249 symptomatic treatment of, 869-870 tongue atrophy i n , 380f trearment of ethical and legal issues, 2256 guidelines for, 2254t, 2256t home care, 2258 hospice care, 2258 initial, 2254-2255 mulridisciplinary team approach, 2256
Amyotrophic lateral sclerosis (Continued) neurotrophic factors, 2255 nutritional care, 2257 percutaneous endoscopic gastroscopy, 2257 pharmacological, 2255 physical rehabilitation, 2256-2257 respirarory care, 2257-2258 speech and communication management, 2257 varianrs of, 2247 Amyorrophic lateral sclerosis-parkinsonismdementia complex, 2260 Amyorrophy benign focal, lower motor neuron diseases clinical features of, 2236 differential diagnosis, 2237 etiology of, 2236 laboratory studies, 2236-2237 pathogenesis of, 2236 trearment of, 2237 diabetic leg pain associated with, 454 monoplegia and, 347-348 monomelic, 348 Anal sphincter, 1173-1174 Anaplasia, 1342 Anaplastic astrocytomas characteristics of, 1348 imaging of, 1376, 1377f-1378f management of, 1413 optic pathway, 1382f Anaplastic large cell medulloblastoma, 1426 Anaplastic oligodendrogliomas, 137ft, 1381f, 1414 Anatomic localization, 7-8 Ancrod, 1238-1239 Andersen's syndrome, 2490 Andersen/Tawil syndrome, 1848t, 1852, 1855-1856 Androgen-insensitivity syndrome, 2244 Anemia, megaloblastic, 1086 Ancncephaly, 1776, 1777r Anesthesia saddle, 1158 sensory ataxia and, 417 Anesthesia dolorosa sensory loss and, 871 trigeminal neuralgia and, 983, 2101 Aneurysm(s) anrerior communicating artery, 69, 1013f, 1270 aortic, 1078 aottic dissection, 1315 arreriovenous malformations caused by, 1015 basilar tip, 612f carotid artery, 1277f, 2109 cerebral computed tomography angiography of, 619, 621 management of, 957 mycotic, 1077, 1077f fusiform, 1015f internal carotid artery cavernous portion of, 1020 petrous portion, 620f-621f, 1020 intracranial causes of, 1271-1274
INDEX Aneurysm(s) [Continued) clinical manifestations of, 1269-1270 computed tomographic angiography of, 621 computed tomography of, 1270-1271, 1271f diagnostic studies for, 101 It dissecting, 1274 in Ehler-Danlos syndrome, 1878, 1878f endovascular treatment of, 969-970, 971f, 1012-1013 epidemiology of, 1274 familial occurrence of, 1271-1274 fusiform, 1274 headaches caused hy, 2062 incidence of, 1011 laboratory studies, 1270-1271 magnetic resonance imaging of, 1271 microsurgical clipping of, 970 natural history of, 1011-1012 neurosurgical treatment of, 969-970 pathogenesis of, 1271-1274 physical findings of, 1270 prevalence of, 1011 ruptured, 1014, 1269 saccular, 1271-1274 signs and symptoms of, 1269 surgical classification of, 1273t surgical treatment of, 1012, I012t 3D contrast-enhanced magnetic resonance angiography evaluations of, 611 3D rime-of-flight magnetic resonance angiography evaluations, 610 treatment of, 1275, 1279-1281 unruptured, 1011-1014, 1280-1281 intranidal, 1293f lumbosacral ple\opaihy and, 2293
middle cerebral artery, 619f, 635 mycotic, 1272
oculomotor nerve, 2108 saccular, 1271-1274 spinal cord ischemia caused by repair of, 1315 traumatic, 1272-1273 Aneurysmal subarachnoid hemorrhage cardiac abnormalities in, 1276 cerebral blood flow effects, 1279 cognitive dysfunction after, 1275 complications of, 1275-1276 course of, 1274-1275 delayed ischemic deteriorarion after, 1279 description of, 661-662, 1014 epidemiology of, 1274 familial history of, 1274 hyponatremia associated with, 1276 ischemic complications, 1280 neuropsychological deficits secondary to, 1275 pathogenesis of, 1271-1274 physical findings of, 1270 pulmonary edema caused hy, 1275 rebleeding after, 1276-1279 recurrence prevention, 1276-1279 seizures associated with, 1275 treatment of, 1275 vasospasm associated with, 1279-1280
Angelman's syndrome genetics of, 81t, 787, 805t seizures in, 787 Angiitis, granulomatous, 1080 Angioendothcliomatosis, 1224 Angiofibromas, 1869 Angiogenesis glioma stimulation of, 1409 inhibitors of, 1409 Angiography cerebral arteriovenous malformations, 569, 569f central nervous sysrem vasculitis evaluations, 1324 headache evaluations, 270 indications, 530-531 intracerebral hemorrhage, 1252 leptomeningeal metastases evaluation, 1453 sleep disturbances and disorders evaluarion, 2042 stroke evaluations, 1234 technique for, 531 computed tomography advantages of, 617 applications of acute ischemic stroke, 618-619 carotid artery stenosis, 616-617, 617f carotid dissection, 617-618 cerebral aneurysms, 619, 621 internal carotid artery aneurysms, 620f-621f intracranial circulation, 618-621 middle cerebral artery stenosis, 619 steno-occlusivc disease, 619 disadvantages of, 617 methods of, 616 endovascular therapy and, 993 in[raoperative, 989 magnetic resonance, see Magnetic resonance angiography polyarteritis nodosa findings, 1104 stroke evaluations, 1234, 1307 subarachnoid hemorrhage evaluations, 1271 subarachnoid hemorrhage indications, 968 Angiokeratoma corporis diflusum, 1224 Angioma cavernous clinical features of, 972, 973f description of, 569 natural history of, 973 neurosurgical treatment of, 972-973 venous, 569-570, 570f, 970, 972, 972f, 1285, 1286f Angiomyolipomas, 1872, 1874f Anglos trongyliasis, 1573-1574 Angiostrongyhis cantonensis, 1557t, 1573-1574 Angiotensin, 85 It Angle-closure glaucoma, vision loss caused hy, 178 Angular gyrus syndrome, 19.35r Anhidrosis, 2418 Anismus, 425 Anisocoria algorithmic evaluation of, 225f description of, 223-224 episodic, 224 evaluation of, 225f, 225-226
v
Anisocoria (Continued) laboratory investigations, 227 poorly reactive pupils without, 224 Anklc-brachial index, 1209 Ankle-foot orthosis, 1033, 1033f, 1035 Anomia, 143 Anomic aphasia, 149-150, 150t Anorexia nervosa, 855 Anosmia, olfactory groove meningioma and, 259 Anosognosia, 1204 Anoxia coma after cardiopulmonary arrest-related, 1668-1669, 1669t delayed deterioration, 1668 description of, 1666-1667 epilepsy after, 1668 management of, 1671-1672 memory acquisition, 1667 movement disorders, 1668 persisrent vegetative state, 1667 recovery from, 1667 sequelae of, 1668 drug abuse-related, 1725 syncope caused by, 16 Anoxic/ischemic encephalopathy cerebral edema and, 1667 sequelae of, 1668 Anrerior cerebral artery anatomy of, 631 A'l segment, 631, 632f A2 segment, 631, 632f azygous, 632 branches of, 631, 632f-633f infarction of, 339, I204f ischemia of, 24 neurological symptoms, 632 syndromes of, 1204 variants of, 632 Anterior choroidal artery infarction, 281f Anterior choroidal artety syndtome, 1204-1205 Anterior cingulate circuit description of, 86 disruption of, 87t-88t Anterior communicating artery anatomy of, 631 aneurysm of, 69, 1013f, 1270 perforating branches of, 631 segments of, 631 Anterior cord syndrome, 1157, 1157f Anterior horn cells, 2229 Anterior horn syndrome, 361 Anterior inferior cerebellar artery anatomy of, 636f disorders associated with compromise of, 638t occlusion of, 1207 Anterior inferior cerebellar artery syndrome, 1205 Anterior interosseous nerve, I 180-1 INI Antetior interosseous nerve syndrome, 3441, 345, 2313-2314 Anterior ischemic optic neuropathy bilateral, 189 diagnosis of, 187 unilateral optic disc edema caused hy, 186-187 vision loss caused by, ISO, I SOi
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vi
INDEX
Anterior median spinal vein, 1.314 Anterior pituitary gland blood supply to, 856 disorders of acromegaly, 860, 860t, 866 Cusking's disease, 8 6 0 - 8 6 1 excessive thyroid-stimulating hormone secretion, 861 gigantism, 860 gonadotropin secretin;; rumors, 861 hyperprolactinemia, 859t, 8 5 9 - 8 6 0 hypophysitis, 862 growth h o r m o n e effects, 8 5 8 , 8 5 8 t hyperfunction of, 8 5 9 - 8 6 1 hyperprolactinemia, 859t, 8 5 9 - 8 6 0 hypofunction of, 8 5 8 - 8 5 9 hypothalamic conrrol of, 8 5 7 - 8 5 8 insufficiency of, 858, 858t tumors of, 8 6 1 - 8 6 2 Anterior radicular arteries, 1314f Anterior spinal arteries, 6.35 Anterior spinal artery syndrome, 3 6 0 - 3 6 1 Anterior sulcal arteries, 1 3 1 3 - 1 3 1 4 Anterior temporal lobectomy, 1989 Anterograde amnesia, 69 Anthrax, 1503 Antibiotics bacterial meningitis riv.irrd with, l 4 " S i , 1479-1482, 1481t-1482t brain abscess treated with, 1487 diphtheria treated with, 1512 endocarditis treated with, 1507 spinal epidural abscess treated with, 1490 syphilis treated with, 1496t, 1498 Antibodies, 8 1 0 Ann body-mediated enhancement, 8 4 0 Anticardiolipin antibodies, 1 2 2 7 - 1 2 2 8 , 1228f Anticholinergics abuse of, 1723 detrusor overactivity treated with, 7 5 6 , 758 motion sickness treated with, 7 4 7 psychoactive effects of, 1723 spinal cord disease treated with, 758 Anticoagulants, see also specific drug deep venous thrombosis treated with, 1367 intracerebral hemorrhage secondary to, 1253-1254 stroke prophylaxis using, 12.36 Anticonvulsants, see also specific drug ataxia caused by, 2 1 7 0 brain tumor-related seizures treated with, 1366t cognitive effects, 695 migraine treated with, 2085 pain management using, 936, 2 3 1 0 properties of, 916 sodium channels and, 9 1 2 traumatic brain injury prophylaxis, 1140 tremors treated with, 1654 types of, 1366t Amiepileptic drugs behavioral effects of, 1980 benzodiazepines, 1 9 8 1 - 1 9 8 2 brain turn or-related seizures treated with, 1366, 1366t calcium channels a n d , 913
Antiepileptic drugs {Continued) cognitive effects of, 1980 ethosuximide, 1982t, 1983 felbamate, 1982t, 1983 gabapentin, 1982t, 1 9 8 3 - 1 9 8 4 lamotrigine, 1982r, 1984 levetiracetam, 1982t, 1984 long-term effects of, 6 9 5 oxcarbazepine, 1982t, 1 9 8 4 - 1 9 8 5 phenobarbital, 1 982t, 1985 phenytoin, 1982t, 1985 during pregnancy, 2 5 3 8 - 2 5 3 9 primidone, 1982t, 1985 sodium channel binding of, 9 1 1 - 9 1 2 tiagabine, 1982t, 1 9 8 5 - 1 9 8 6 topiramate, 1982c, 1986 valproic acid, 1982t, 1986 vigabattin, 1982t, 1 9 8 6 - 1 9 8 7 zonisamide, 1982t, 1 9 8 7 Antifolates, 1405 Antifungal agents, 1552 Ami gen-presenting cells, 8 1 0 Antigen receptor gene, 8 1 2 - 8 1 3 Antiglutamatc decarboxylase antibodies, 2172 Antihistamines, for dizziness, 7 4 7 Antimicrobial agents description of, 147.3 tubercular meningitis treated with, 1492t Antimictotubule agents, 1 4 0 5 - 1 4 0 6 Antincuronal antibodies description of, 4 5 8 in paraneoplastic neurological syndromes, 1461-1463, 1462t in vasculiris, 2371 Antineuronal nuclear antibody, 2 3 6 6 Ami phospholipid antibodies, 1227 Antiphospholipid antibody syndrome, 2542 Antiphospholipid antibody syndromes, 1 0 8 9 - 1 0 9 0 , 1090f, 1221 Antipsychotic agents delirium treated with, 40 dementia with Lewy bodies treated with, 1926 Ami-Purkinje cell antibodies, 4 5 8 Antirctroviral therapy agents used in, 1587t highly active, 1 5 8 5 - 1 5 8 6 h u m a n immunodeficiency virus tteated with, 1 5 8 5 - 1 5 8 6 , 1587t Antirheumatic agents, 1082 Antirhrombin-III deficiency, 1226 Antititin antibodies, 2 4 4 5 a 1-Antitrypsin deficiency, 1 3 0 4 - 1 3 0 5 Antiviral drugs cytomegalovirus treated with, 8 4 7 h u m a n immunodeficiency virus treated with, 8 4 7 - 8 4 8 Anti-Yo, 1463 Anti-Yo antibody, 828 Anton's syndrome, 180 Anxiety cholecystokinin a n d , 9 0 4 definition of, 104t in h u m a n immunodeficiency virus, 92 insomnia caused by, 20 11 in multiple sclerosis, 96, 96t neurological disorders associated with, 86t pathophysiology of, 8 8 1 t post-stroke occurrence of, 100
Anxiety [Continued) after sttoke, 1065 systemic lupus erythematosus a n d , 110 traumatic brain injury-related, 101 treatment of, 1065 in vascular demenria, 91 Aortic arch branches of, 6 2 5 - 6 2 6 , 626f digital subtraction angiography of, 626f diseases of, 1078 Aortic diseases aneurysms, 1078 aorritis, 1 0 7 8 - 1 0 7 9 claudication caused by, 1078 coarctation of the a o r t a , 1079 description of, 1078 spinal cord ischemia caused by, 1078 subclavian steal syndrome, 1079 Aortic dissection, 1315 Aortic stenosis, 1 1 0 1 - 1 1 0 2 Aortic surgery-related complications, 1079 Aortitis, 1 0 7 8 - 1 0 7 9 Aortoarteritis, transient emboligenic, ID"1) Apathetic hyperthyroidism, 109, 1095 Apathy in Alzheimer's disease, 8 7 - 8 8 definition of, 8 7 , 104t in H u n t i n g t o n ' s disease, 95 neurological disorders associated with, 86t in Parkinson's disease, 93 in vascular dementia, 91 Aphasia a n o m i c , 1 4 9 - 1 5 0 , 150t basal ganglia lesions as cause of, 150 Broca's agrammatism associated with, 1061 description of, 1 4 4 - 1 4 5 , 145t treatment of, 1061 clinical tests of, 1 5 6 - 1 5 8 , 157f cognitive thetapy for duration of, 1060 melodic intonation therapy, 1061 outcomes, 1061 pharmacological ad|uncrs, 1061 stimulation-facilitation techniques, 1060-1061 studies of, 1060 conduction, 149, 149t crossed, 1 4 3 , 154 definition of, 141 degenerative diseases and, 158 differential diagnosis, 1 5 8 - 1 5 9 dysphasia vs., 141 frontotemporal demenria a n d , 1921 global, 1 4 8 - 1 4 9 , 149t hemorrhagic strokes as cause of, 158 hesitant speech in, 143 investigation of, 1 5 6 - 1 5 8 , 157f left hemisphere t u m o r s as cause of, 158 mixed, 148 primary progressive, 1 5 5 , 157f, 1921 progressive nonflucnt, 689 pure w o r d deafness, 148 recovery and rehabilitation of, 159 rehabilitative treatment for, 1034, 1034t seizures as cause of, 159 speech therapy for, 159 subcortical, 150-151 symptoms of, 14.3 t h o u g h t disturbances vs., 141
INDEX Aphasia {Continued} transcortical, 150, 151t treatment of, 872, 1034, 1034t Wernicke's bedside features of, 146t causes of, 67 clinical features of, 39t, 145-146 delirium and, 38 language disturbances in, 146 lesions associated with, 146-147 magnetic resonance imaging of, 146f-148f psychiatric manifestations of, 146 pure word deafness and, 137 Sentence Level Auditory Comprehension Program for, 1061 Aphasic alexia, 152-153 Aphemia, 145, 163 Aplastic anemia, 1107 Apnea congenital myasthenic syndrome with, 2455-2456 obstructive sleep assessments of, 2021 in children, 2037 consequences of, 2020 definition of, 2018-2019 description of, 1053, 2007, 2017 epidemiology of, 2019-2020 evaluation of, 2021 excessive daytime sleepiness associated with, 2021 hypertension in, 2020 natcolepsy and, 2015 neural factors associated with, 2020 pathogenesis of, 2020 polysomnography in, 2039 signs and symptoms of, 2021, 2021t terminology associated with, 2017-2019 treatment of continuous positive airway pressure, 2044-2045 intermittent positive pressure ventilation, 2045 mechanical devices, 2044-2045 overview of, 2045t pharmacological, 2044 surgical, 2045 ventilatory supports, 2045 upper airway resistance syndrome, 2019, 2019f Apneustic breathing, 53, 2019 Apolipoprotein Al, 804t Apolipoprorein Al amyloidosis, 2330 Apo-lipoprotein E, 1585 Apomorphine, 895 Apo morphine hydrochloride, for erectile dysfunction, 761 Apoplexy, pituitary, 858-859, 967 Apo ptosis antiapoptotic agents for, 1123 brain tumor treatments, 1411 cellular mechanisms for, 844
description of, 819-820 disorders of, 1765-1766 glial cell, 1765 neuroblasts, 1765 traumatic brain injury and, 1117, 1123
virus infection-induced, 843
Apparent diffusion coefficient, 524 Appercepti ve-associative distinction, 131-132 Apperceptive visual agnosia associative agnosia vs., 131-132 characteristics of, 132 perceptive categorization deficit, 133, 133f share perception impairments, 132, 132f si mu I tan agnosia, 133 syndromes related to, 132-133 Appetite food intake, 854 hypothalamic regulation ol, N54-S55 meal size, 854 Apraxia buccofacial, 1922 conceptual
in Alzheimer's disease-related dementia, 129 definition of, 123-124 knowledge impairments associated with, 129 pathophysiology of, 129-130 testing for, 129 conduction, 123, 127-128 definition of, 144 disassociation, 123, 128 ideational, 123, 128-129, 1936t ideomotor brain tumor-re I a ted, 125 convexity premotor cortex lesions and, 127 corpus callosum lesions and, 126 definition of, 123 hemispheric lesions associated with, 125, 128 inferior parietal lobe lesions and, 126 left hemispheric dysfunction and, 121, 128 pathophysiology of, 125-127 postural errors representative of, 125 righr hemispheric dysfunction and, 128 spatial errors representative of, 125 supplementary motor area lesions and, 126-127 testing for, 125 timing errors representative of, 125 vascular lesions and, 1936r lack of recognition of, 124 limb-kinetic definition of, 123 pathophysiology of, 124 testing for, 124 types of, 124 ocular motor, 714 of lid opening, 230-231, 231 f of speech definition of, 141, 163 features of, 163 testing for, 163 oral-buccal-lingua I, 163 parkinsonism testing, 301 pathology associated with, 130 progressive, 1922 Aprosodies, 154 APUD cells, 867 Apudomas, 867-868 Aqucductal stenosis, 566, 567f Ara-C, 1110, 1405
vii
Arachnoid cysts, 2057-2058 Arachnoid granulations, 643 Arachnoiditis, 1162
chronic adhesive, 2219-2220 Arboviruses California virus, 1531t, 1532 characteristics of, 833, l517t, 1531t Colorado tick fever virus, 832t, 1531t, 1533 definition of, 1529-1530 Eastern equine encephalitis virus, 153It, 1532 Japanese encephalitis virus, 832t, 1515, 1520t, 1532 Kyasanur Forest disease virus, 1533-1534 louping ill virus, 1533 Modoc virus, 1533 Murray Valley encephalitis, 1533 Powassan virus, 1531t, 1533 Rift Valley fever virus, 1534 rocio virus, 1534 St. Louis encephalitis virus, 1530, 153It tick-borne encephalitis virus, 1533 Venezuelan equine virus, 1531t, 1532-1533 Western equine encephalitis virus, 832t, 833, 1531t, 1532 West Nile virus, 832t, 1520t, 1530-1531, 1531t Arcus senilis, 49 Area cerebrovasculosa, 1776 Arenavindae, 832t, 843t Arenaviruses, 1537-1538 Argentine hemorrhagic fever, 1538 Arginase deficiency, 1825t Argininosuccinate lyase, 804t Argininosuccinic lyase deficiency, 1825t Argininosuccinic synthase deficiency, 1825t Arm pain causes of brachial neuritis, 438 carpal tunnel syndrome, 439 complex regional pain syndromes, 440-441 extramedullary lesions, 436-437 median nerve entrapment, 434 nerve roots, 433-434 plexus, 434 posterior interosseous nerve entrapment, 440 spinal cord-related, 435^136 syringomyelia, 436 ulnar nerve entrapment, 434 ulnar nerve entrapment at elbow, 439^140 devices for, 1033f history-taking, 433-434 physical examination for description of, 434-435 motot signs, 434-435 sensory signs, 435 tendon reflexes, 435 Arnold Chiari malformations. see Chiari malformarions Aromaric L-amino acid decarboxylase deficiency, 1829 Arousal alterations of, 43, continuum of, 43 hypertension effects on, 48
Volume I pp. 1-1070 • Volume II p. 1071-2546
viii
INDEX
Arrhinencephaly, 1780, 1781 Arrhythmias, 951 syncope caused by, 1 2 - 1 5 Arsenic poisoning, 50, 1 7 1 4 - 1 7 1 6 Arterial blood gases, 943 Arterial blood pressure, see Blood pressure Arterial occlusive disease, 6 1 8 - 6 1 9 Artcriogcnic embolisms, 1209 Arteriovenous fistulae, 1318 Arteriovenous malformations aneurysms and, 1015 angiographics 11 y occult, 9 7 2 aphasia caused by, 158 capillary telangiectases, 1285 cavernous malformations, 1285 in children, 1300 description of, 1285 epidemiology of, 1 2 8 6 - 1 2 8 8 signs and symptoms of, 1 2 8 6 - 1 2 8 8 stereotactic radiosurgical therapy for, 1294 treatment of, 1294 cerebral angiography of, 569, 569f classification of, 1285 clinical features of, 974f clinical manifestations of, 1288 computed tomography of, 1289, 1290f course of, 1290, 1 2 9 3 - 1 2 9 4 definition of, 1285 embolization for, 974 e ndt>v a scu 1 a r e m hoi i ?.a t i on of, 1015—1016, 1296t epidemiology of, 1014, 1288 frontal, 1017f frontal lobe, 1293f functional imaging of, 1 2 8 9 , 1290f grading of, 974 headaches associated wirh, 1015, 1288, 2062-2063 hemorrhagic stroke caused by, 1 0 1 4 - 1 0 1 6 illustration of, 1017f incidence of, 974 intra-arterial digital subtraction angiography of, 6 1 2 - 6 1 3 intracerebral hemorrhage associated with, 1015, 1 2 5 2 - 1 2 5 3 , 1288 intracranial hemorrhage associated with, 1290 intramedullary, 1318 intraventricular hemorrhage caused by, 1264 laboratory studies of, 1289, 1290f magnetic resonance angiography of, 1289, 1291 f magnetic resonance imaging of, 1 2 8 9 , 129 If metabolic findings, 1289 microsurgical excision of, 1296t mortality rates, 9 7 4 , 1292 natural history of, 974 neurosurgical treatment of, 9 7 3 - 9 7 5 parenchymal, 2 0 6 2 parietal lobe, 1292f pathological characteristics of, 1285 physical findings of, 1288 physiology of, 1289 in pregnancy, 1296, 2 5 4 0 prevalence of, 1014 prognosis for, 1290, 1 2 9 3 - 1 2 9 4 radiographic features of, 1015
Arteriovenous malformations {Continued) radiosurgery for, 9 9 0 , 1296 seizures associared with, 1288, 1294 signs and symptoms of, 1288 Spcrzlcr-Martin grading scale for, 1294t
spinal classification of, 984 description of, 5 7 0 myelopathy vs., 985 neurosurgical treatment of, 984—985 surgical treatment of, 1 2 9 4 - 1 2 9 6 temporal, 1295f 3D contrast-enhanced magnetic resonance angiography of, 6 1 3 treatment of, 9 7 4 - 9 7 5 , 1 0 1 5 - 1 0 1 6 , 1288, 1294-1296 true, 1285 venous angiomas, 1285 in Wy b u r n - M a s on disease, 1896 Arteritis cranial, 1 2 2 0 - 1 2 2 1 fungal, 1219 giant cell, 1080 amaurosis fugax, 2 0 6 6 - 2 0 6 7 corticosteroids for, 2 0 6 9 course of, 2 0 6 8 definirion of, 2065 epidemiology of, 2 0 6 8 etiology of, 2 0 6 8 immunology of, 2 0 6 8 laboratory studies, 2 0 6 7 pathogenesis of, 2 0 6 8 pathology of, 2 0 6 7 - 2 0 6 8 , 2068f physical findings of, 2 0 6 6 - 2 0 6 7 physiology of, 2 0 6 7 polymyalgia rheumatica, 2 0 6 6 prognosis of, 2068 symptoms of, 2 0 6 5 - 2 0 6 6 , 2 0 6 7 t treatment of, 2 0 6 8 - 2 0 6 9 Takayasu's in children, 1104 description of, 1220 neurological complications of, 1104 syncope associated with, 16 temporal, 2 0 6 7 Artery of the pterygoid canal, 6 2 9 Arthritis of hand, 443 osteoarthritis cervical, 2 2 0 7 spinal, 2204 reactive, 2 2 1 7 , 2 2 1 8 t rheumatoid in adults, 1080, 1082, 1082f cervical spine, 441 headache in, 2 2 1 5 juvenile, 1 1 0 4 - 1 1 0 5 neurological complications of, 1 0 8 0 , 1 0 8 2 , 1082f, 1 1 0 4 - 1 1 0 5 , 2215-2216 pathogenesis of, 2 2 1 5 peripheral neuropathy in, 2 3 7 3 - 2 3 7 4 systemic presentation of, 2 2 1 5 Atthrogryposis, 396 Arrhrogryposis congenita multiplex, 3 9 6 - 3 9 7 , 39Ht Articulation disorders, 1804 Ascaris lumbricoides, 1557t Ascending pharyngeal artery, 6 2 7 , 6 2 8 t Ascending reticular activating system, 32
Aseptic meningitis, 1 5 8 7 - 1 5 8 8 Ashworrh Scale, for spasticity assessments, 1054, 1054t Aspartylglycosaminuria, 1822t Asperger's syndrome description of, 1794 diagnostic criteria for, 1795t ourcome for, 1795 Aspergillosis, rhinocerebral, 1549f Aspergillus, 1 5 4 8 - 1 5 4 9 , 1551 Asphyxia, 2 5 1 5 Aspiration dysphagia a n d , 1 6 9 - 1 7 0 , 1049 Parkinson's disease, 171 after stroke, 170 Aspirin adverse effects of, 9 3 2 t half-life of, 932t mechanism of action, 1235 pain management using, 9 3 1 , 9 3 2 t stroke prophylaxis using, 1 2 3 4 - 1 2 5 5 Assist-control mode ventilation, 949 Association cortex definition of, 65 heteromodal, 66 uni modal communication in, 66 definition of, 65 Associative visual agnosia apperceptive agnosia vs., 1 3 1 - 1 3 2 brain d a m a g e patterns in, 1 3 4 - 1 3 5 , 135f definition of, 1 3 3 - 1 3 4 dissociations in, 134 lesions that cause, 1 3 4 - 1 3 5 neuropathology of, 134—135 with prosopagnosia, 134, 135f pure alexia, 134 syndromes relared to, 1 3 5 - 1 3 6 Asterixis, 2 5 , 3 1 5 , 1 6 7 3 Asthenopia, 2 1 2 Astrocytes description of, 1 5 8 5 , 1680, 1752 radial glial cell transformation into, 1768 Astrocytomas anaplastic characteristics of, 1348 imaging of, 1376, 1377f-1378f management of, 1413 optic p a t h w a y , 1382f brainstem, 539f-540f, 5 3 9 - 5 4 0 cerebellar, 5 3 8 in children, 1 4 2 6 , 1 4 2 6 t - 1 4 2 7 t circumscribed, 1349 classification systems for, 13.30c desmoplastic cerebral astrocytoma of infancy, 1429 diffuse characteristics of, 1344f, 1 3 4 7 - 1 3 4 8 imaging of, 1374—1376 high-grade, 1432 juvenile pilocystic, 1385, 1390f, 1426-1428 low-grade characteristics of, 5 3 2 in children, 1 4 3 0 - 1 4 3 1 imaging of, 1330 management of, 1412 magnetic resonance spectroscopy evaluations, 671f-673f
INDEX Astrocytomas {Continued) metabolic polymorphisms associated with, 1339t pilocystic characteristics of, 975 imaging of, 1 3 4 9 - 1 3 5 0 , 1350f management of, 1412 spinal, 5 8 0 subependymal giant cell characteristics of, 5 4 1 , 1350, 1 3 8 1 , 1413 in children, 1 4 2 8 - 1 4 2 9 imaging of, 1381 management of, 1413 in tuberous sclerosis, 1871 Toxoplasma gondii a n d , 1338 Astrogliosis, 1092, 1092f Ataxia acquired causes of, 2 1 6 9 - 2 1 7 2 , 2170t age at onset, 2 9 0 t alcohol, 2 1 6 9 algorithm for, 2184f anticonvulsants, 2 1 7 0 antiglutamate decarboxylase antibodies and, 2172 approach tu, 290 29 I autoimmune causes of, 2 1 7 1 - 2 1 7 2 autosomal dominant clinical features of, 2 1 7 8 - 2 1 7 9 description of, 2 1 7 7 - 2 1 7 8 gene mutations in, 2 1 8 0 - 2 1 8 1 genetics of, 2 1 7 8 t imaging of, 2 1 7 9 laboratory studies of, 2 1 7 9 , 2 1 7 9 t neuropathology of, 2 1 7 9 pathogenesis of, 2 1 8 1 - 2 1 8 2 phenotype-genotype correlations in, 2180-2181 autosomal recessive, 2 1 7 2 - 2 1 7 7 balance problems a n d , 325 brain imaging abnormalities associated with, 2 9 2 t causes of, 2 9 0 t - 2 9 2 t cerebellar cognitive function assessments, 290 description of, 2 8 7 , 1 6 6 3 features of, 327t gait disturbances in, 2 8 8 , 3 2 7 , 327t intention tremor i n , 288 limb incoordination in, 288 muscle tone a n d strength abnormalities in, 2 8 9 neurological signs in, 2 8 8 - 2 9 0 nystagmus in, 289 oculomotor disturbances in, 2 8 9 pursuit disorders in, 289 saccade disorders in, 2 8 9 signs and symptoms of, 3 2 9 - 3 3 0 speech function in, 2 8 9 - 2 9 0 stance disturbances in, 288 chemotherapy, 2 1 6 9 - 2 1 7 0 Creutzfeldr-Jakob disease, 2 1 7 1 definition of, 287 diagnostic approach t o , 2 1 8 4 - 2 1 8 5 differential diagnosis, 2 9 2 t DNA repair defects that cause, 2 1 7 6 earlv onset ataxia with retained reflexes, 2176
Ataxia (Continued) familial episodic diagnosis of, 1860 forms of, 1859 myokymia associated with, 1859 pathophysiology of, 1 8 5 9 - 1 8 6 0 treatment of, 1860 Friedrich's characteristics of, 783f, 804t clinical features of, 2 1 7 3 genetic mutation associated with, 2173-2174 nerve conduction studies, 2 1 7 3 neuropathy associated with, 2 3 2 9 pathogenesis of, 2 1 7 4 point mutations in, 2 1 7 4 treatment of, 2 1 7 4 - 2 1 7 5 frontal lobe, 327t, 3 3 4 gait, 2 6 , 2 8 7 , 3 2 7 t with gluten sensitivity, 2 1 7 2 hemiparesis, 3 4 1 h u m a n immunodeficiency virus, 2171 hypothyroidism, 2169 infantile-onset olivopontocerebellar atrophy, 2 1 7 6 infectious causes of, 2 1 7 0 - 2 1 7 1 with isolated vitamin F. deficiency, 1699, 2175-2176 limb, 2 8 7 magnetic resonance imaging of, 2 9 2 t metals esposuiv, I I "0 mitochondrial diseases a n d , 2 1 7 7 neurological signs in, 2 8 8 - 2 9 0 oculomotor, 2 1 7 6 proprioceptive, 29 It sensory anesthesia a n d , 4 1 7 definition of, 4 0 9 features of, 3 2 7 t gait disturbances, 3 3 0 neurological signs in, 2 9 0 - 2 9 1 , 291t-292t symptoms of, 2 8 7 signs a n d symptoms of, 2 8 7 - 2 8 8 solvents, 2 1 7 0 spastic, 291t, 3 3 0 spinocerebellar, 1848t, 2179f, 2 2 6 0 sporadic with added nonccrcbellar deficits, 2183-2184 characteristics of, 2 1 8 2 - 2 1 8 3 cortical cerebellar atrophy, 2 1 8 3 definition of, 2 1 8 2 systemic signs associated with, 2 9 U toxic causes of, 2 1 6 9 - 2 1 7 0 treatment of, 8 7 2 truncal, 2 8 7 , 3 2 9 Ataxia-telangiectasia cancer risks, 1886 cutaneous features of, 1885 description of, 3 1 3 , 1 8 8 5 , 2 1 7 5 epidemiology of, 1885 genetics of, 1 8 8 6 , 2175 incidence of, 1885 laboratory diagnosis of, 1886 lymphoid malignancies a n d , 1886 neurological features of, 1 8 8 5 - 1 8 8 6 sinopulmonary infections in, 1886 Ataxic breathing, 53 Ataxic tremor, 3 0 2
ix
A t h e r o m a t o u s emboli, 1225 Atherosclerosis ankle-brachial index findings, 1209 aortic, 1200 cholesterol levels a n d , 1 1 9 8 - 1 1 9 9 homocysteine levels and, 1231 intracranial, 1 0 0 1 - 1 0 0 2 lipid-lowering strategies for, 1199 plaque carotid, 9 9 7 characteristics of, 9 9 7 internal carotid artery stenosis caused by, 6 5 5 , 9 9 7 intracranial, 6 5 5 - 6 5 9 , 661f spinal cord ischemia caused by, 1316 ultrasound evaluations, 6 5 1 , 652f smoking and, 1199 At hero thro mhos is, large artery, 1 2 0 9 - 1 2 1 0 , 1210f Athletes concussions in, 1144 "stingers" in, 1152 Atlantoaxial dissociation/dislocation, 1 1 5 3 , 2191-2192 Atlas occipitalization, 2 1 8 9 , 2190f Atonic seizures, 17, 1 9 6 3 Atrial fibrillation description of, 1074 epidemiology of, 1199, 1 2 1 3 nonvalvular, 1 I 99 stroke a n d , 1 1 9 9 , 1213 thromboembolism associared with, 1 2 1 2 - 1 2 1 3 , 1234 Atrial m y x o m a definition of, 1 2 1 3 embolisms associated with, 1213 syncope caused by, 15 Atrial natriuretic peptide, 8 6 3 , 958 Atrioventricular block clinical features of, 14 diagnosis of, 14 syncope caused by, 1 3 - 1 4 Atropine, 9 9 9 Attack rate, 7 6 3 Attention ascending reticular activating system, 32 deficirs of, in delirium, 30 schematic diagram of, 32f Attention deficit hyperactivity disorder clinical features of, 1 8 0 2 - 1 8 0 3 diagnosis of, 1 8 0 2 , 1802t dyslexia a n d , 1798 etiology of, 1803 evaluation of, 1803 genetic factors, 1 8 0 3 prevalence of, 1 802 psychostimulants for, 1 8 0 3 , 1803t signs of, 1803t Tourette's syndrome a n d , 9 5 , 692 treatment of, 1 8 0 3 , 1803t Atypical antipsychotics, for psychosis in Alzheimer's disease, 89 Atypical facial pain, 2 0 9 9 Atypical teratoid/rhabdoid t u m o r , 1356, 1426 Attdiological testing a b n o r m a l resulrs, 744 acoustic reflex, 7 4 4 - 7 4 5 brainstem auditory evoked potentials, 4 8 3 - 4 8 4 , 745 Volume I p p . 1-1070 • Volume II p. 1071-2546
x
INDEX
Audiological testing (Continued) central, 742 computed tomography for, 746 definitions, 743 description of, 7 4 2 - 7 4 3 elecrrocochleography, 746 elements of, 7 4 2 - 7 4 3 evoked potentials, 7 4 5 - 7 4 6 middle ear testing, 7 4 4 normal results, 743f ptirc-tone air thresholds, 2 4 9 , 743f speech reception threshold, 743 speech testing, 7 4 3 - 7 4 4 terminology associated with, 743 Audio logic assessments, 2 4 9 - 2 5 0 Auditory agnosia assessment of, [38 characteristics of, 136 nonverbal, 1 3 6 - 1 3 7 positron emission tomography evaluation of, 137 pure word deafness, 137 sound impairments associated with, 1 3 7 verbal, 1806 Auditory amusia, 1 3 7 Auditory brainstem evoked potentials. see Brainstem auditory evoked p< Hernials Auditory comprehension, 144 Auditory hallucinations, 31 Auditory nerve, 4 8 8 Auditory neuropathy description of, 2 4 7 diagnostic findings, 2 4 7 - 2 4 8 examination for, 2 4 8 - 2 5 2 Auerbach's plexus, 1173 Aura, 2 6 7 Australia bat lyssavirus, 1535 Autistic speerrum disorders clinical features of behaviors, interests, and activities, 1796-1797 cognition, 1795 communication disorders, 1796 intelligence, 1795 language, I 7')fi social dysfunction, 1796 social skills, 1796 developmental language disorders vs., 1794 developmental regression associated with, 82 diagnosis of, 1 7 9 4 - 1 7 9 5 etiology of, 1797 evaluation of, 1797 genetic findings, 1 7 9 4 - 1 7 9 5 hereditary factors, 1794 incidence of, 1794 medications fot, 1798r neuropathology associated with, 1797 outcome studies of, 1795 symptoms of, 1795 treatment of, 1797 tuberous sclerosis and, ] 797 Autoantibodies n: myasthenia gravis, 2 4 4 4 - 2 4 4 5 neuropathy a n d , 2 3 0 8 t paraneoplastic neurological syndromes and, 2367t
Autoimmune diseases B-cell mediated, 821 classification of, 8 2 1 - 8 2 2 environmental factors, 8 2 2 - 8 2 3 genetic factors, 8 2 2 mechanisms of, 8 2 1 - 8 2 2 paraneoplastic syndromes, 8 2 8 systemic lupus erythematosus, 821 T-cell mediated, 821 Autoimmune myasthenia gravis, 8 2 6 - 8 2 7 Automatic-voluntary dissociation, 164 Automatisms, 1957 Autonomic dysreflexia, 1175 Autonomic nervous system afferent pathways of, 2 4 0 3 , 2403f description of, 2 4 0 3 disorders of chronic a u t o n o m i c failure, 2 4 0 7 - 2 4 1 0 classification of, 2 4 0 5 - 2 4 0 6 extrapyramidal features, 2 4 0 8 localized, 2 4 1 1 - 2 4 1 2 primary, 2406t primary autonomic failure, 2 4 0 7 - 2 4 1 0 secondary, 24061 divisions of, 2 4 0 3 , 2404f dysfunction of cardiovascular system features, 2412-2416 drugs that cause, 2406t, 2411 in Guillain-Barre syndrome, 9 5 9 , 2 4 1 0 in malignancies, 2411 ncurally mediated syncope, 2 4 1 1 in parkinsonism, 2 9 6 , 3 0 2 peripheral, 2 4 1 0 - 2 4 1 1 psychiatric disturbances, 2 4 2 0 - 2 4 2 1 psychological disturbances, 2 4 2 0 - 2 4 2 1 secondary, 2 4 1 0 in spinal cord syndromes, 3 5 8 - 3 5 9 syncope caused by, 15 failure of clinical features cardiac dysrhythmias, 2 4 1 6 description of, 2 4 1 2 - 2 4 1 3 eyes, 2 4 2 0 , 2 4 2 9 - 2 4 3 0 facial vascular changes, 2 4 1 6 , 2418 gastrointestinal system, 2 4 1 8 - 2 4 1 9 , 2429 hyperhidrosis, 2 4 1 8 hypertension, 2 4 1 5 - 2 4 1 6 hypotension, 2 4 1 2 - 2 4 1 5 lacrimal glands, 2 4 2 0 reproductive system, 2 4 2 0 , 2 4 3 5 respiratory system, 2 4 2 9 , 2 4 3 5 sweating, 2 4 1 8 , 2 4 2 7 - 2 4 2 9 , 2 4 3 5 temperarure regulation, 2 4 1 8 urinary tract, 2 4 1 9 - 2 4 2 0 , 2 4 2 9 , 2 4 3 5 investigation of cardiovascular system, 2 4 2 2 - 2 4 2 7 goals, 2 4 2 1 guidelines for, 2 4 2 1 t muscle activity, 2 4 2 4 neurological deficits, 2 4 3 6 prognosis, 2 4 3 0 hyperactivity of, 35 neuroanatomy of, 2 4 0 3 - 2 4 0 5 parasympathetic outflow, 2 4 0 3 sympathetic outflow, 2 4 0 3 Autonomic neuropathy description of, 1098 paraneoplastic, 2 3 6 8
Autosomal d o m i n a n t ataxias clinical features of, 2 1 7 8 - 2 1 7 9 description of, 2 1 7 7 - 2 1 7 8 gene mutations in, 2 1 8 0 - 2 1 8 1 genetics of, 2 1 7 8 t imaging of, 2 1 7 9 laboratory studies of, 2 1 7 9 , 2 I 79t neuropathology of, 2 1 7 9 pathogenesis or, 2181 2 I Is2 phe no type-genotype correlations in, 2180-2181 Autosomal d o m i n a n t disorders, 7 8 1 - 7 8 3 , 782t, 800f Autosomal d o m i n a n t frontal lobe epilepsy, 2026 Autosomal d o m i n a n t frontotemporal dementia with m o t o r neuron disease, 2261 Autosomal d o m i n a n t nocturnal frontal lobe epilepsy, 1848t, 1 8 6 2 , 1975 Autosomal recessive ataxia of Charlevoix-Saguenay, 2 1 7 5 Autosomal recessive disorders, 782t, 783 Autosomal recessive hereditary inclusion body myopathy, 2 4 8 3 Axial compression fractures, 5 9 2 - 5 9 3 , 593f Axial muscle weakness, H69 Axillary nerve lesions, 3 5 6 t Axon(s) a n a t o m y of, 1181 degeneration of, 2 3 0 0 , 2300f, 2381 function of, 1 1 8 1 growth of, 1 7 7 0 outgrowth of, 1770 peripheral nerve, 1181 regeneration of, 1046, 1184, 1185f shearing of, 1 1 1 9 - 1 1 2 0 rraumaric brain injury effects, 1119 viral spread t h r o u g h , 841 Axonal injury, diffuse, 5 5 4 , 555f, 1129-1130 Axonal noncontinuity, 4 9 9 Axonal polyneuropathy chronic idiopathic, 2 3 0 8 nerve conduction studies of, 5 0 1 , 502f Axonal sensorimotor polyneuropathy, 1710 Axon loss mo n on eu to pa thy, 4 9 9 - 5 0 0 , 500f Axonotmesis, 4 9 8 ^ t 9 9 , 1 1 8 1 - 1 1 8 2 Axon sprouts, 1185 Azathioprine, 1 6 5 9 , 2 3 4 9 , 2 4 5 0 , 2506 Azoic antifungals, 1552 B B7, 816 Bacillus antbracis, 1503 Baclofen description of, 8 7 0 , 8 8 1 pain management using, 9 3 6 - 9 3 7 spasticity treated with, 1055t, 1654 Bacteremia, 1598 Bacterial e n d o t o x i n , 853 Bacterial infections abscess brain, see Bacterial infections, brain abscess cranial epidural, 1 4 8 8 , 1489f spinal epidural, 1 4 8 9 - 1 4 9 0 brain abscess antibiotics for, 1487
INDEX
Bacterial infections (Continued) in children, 1102 clinical features of, 1484 computed tomography of, 1484 corticosteroids for, 1487 diagnosis of, 9 6 6 , 1484 differential diagnosis, 1485, 1487 frontal lobe, 1484 hematogenous spread of, 1484 magnetic resonance imaging of, 1484, I485f-1486f meningitis-related, 1476 neurosurgical treatment of, 9 6 6 , 966f pathogens associated with, 1484-148.5 predisposing causes of, 1484 sites of, 1484 treatment of, 1487 aunpylobacR'riosis, 1 506 chlamydial infections, 1506-1.507 crania! epidural abscess, 1 4 8 8 ehrlichiosis, 1502 endocarditis, 1507 epidemic typhus, 1 5 0 0 - 1 5 0 1 filamentous actinomycosis, 1505-1.506 nocardiosis, 1505 legionellosis, 1.507 leprosy borderline, 1495 clinical features of, 1 4 9 4 - 1 4 9 5 complications of, 1 4 9 5 - 1 4 9 6 d i a g n o s i s . ill, I 4 ' * i
differential diagnosis, 1495 epidemiology of, 1 4 9 3 - 1 4 9 4 erythema nodosum leprosum, 1495 incidence of, 1 4 9 3 lepromarous, 1494 Mycobacterium leprae, 1493 prevention of, 1496 signs and symptoms of, 1 4 9 4 - 1 4 9 5 transmission of, 1494 treatment of, 1495 tuberculoid, 1 4 9 4 - 1 4 9 5 Lyme disease clinical features of, 1 4 9 8 - 1 4 9 9 description of, 5 5 9 , 1498 diagnosis of, 1499 neurological complications of, 1498-1499 treatment of, 1499 mycoplasma syndromes, 1507 nosocomial, 1475 pathogenic organisms that cause, 1476 pathways for, 1475 pertussis, 1 5 0 7 relapsing fever, 1 4 9 9 - 1 5 0 0 rheumatic fever, 1508 Rocky M o u n t a i n spotted fever, 1500-1501 salmonellosis, 1.506 septic venous sinus thrombosis, 1488-1489 shigellosis, 1.506 spirochetes. 1 4 % subdural empyema clinical features of, 1 4 8 7 - 1 4 8 8 computed tomography of, 1487, 1488f definition of, 1 4 8 7 diagnosis of, 14SH
Bacterial infections (Continued) treatment of, 1488 syphilis algorithm for, 1496t antibiotics for, 1498 clinical features of, 1 4 9 6 - 1 4 9 7 congenital presentation of, 1497 diagnosis of, 1496t, 1 4 9 7 - 1 4 9 8 etiology of, 1496 follow-up visits for, 1498 general paresis caused by, 1497 jarisch-Herxheimcr reactions, 1498 meningitis, 1497 neurosyphilis, 1497 secondary, 1496 tabes dorsalis, 1497 tertiary, 1 4 9 6 - 1 4 9 7 treatment of, 1496t, 1498 Treponema pallidum, 1496 visual system effects, 1497 toxic shock syndrome, 1504 tropical pyoinyositis, 1 5 0 4 - 1 5 0 5 tuberculosis epidemiology of, 1491 global prevalence of, 1491 meningitis, 1 4 9 1 - 1 4 9 2 , 1494f pathogenesis of, 1491 pathogens that cause, 1 4 9 0 - 1 4 9 1 spinal, 1 4 9 2 - 1 4 9 3 tuberculomas, 1492 vaccination, 1493 Whipple's disease, 1506 zoonotic anthrax, 1503 brucellosis, 1 5 0 2 - 1 5 0 3 cat-scratch disease, 1504 glanders, 1 5 0 3 melioidosis, 1504 pasteurellosis, 1503 plague, 1503 rat-hire fever, 1504 tularemia, 1 5 0 3 Bacterial meningitis adjunctive treatment of, 1482 age of patient a n d , 1 4 7 7 , 1478t algorithm for, 1479f cerebral dysfunction caused by, 1 4 7 7 cerebrospinal fluid findings, 1478 clinical features of, 1477 complications of, 1 4 8 2 - 1 4 8 3 cytokine's role in, 1482 definition of, 1476 diagnosis of, 1 4 7 8 - 1 4 7 9 differential diagnosis, 1 4 7 8 - 1 4 7 9 electroencephalography evaluations, 475^76 epidemiology of, 1476 global distribution of, 1476 Haemophilus influenzae, 1476 increased intracranial pressure in, 1482 infection mechanisms, 1476 inflammatory reaction caused by, 1 4 7 7 , 1752 neonatal causes of, 2.522 clinical features of, 2 5 2 2 description of, 1477 management of, 2 5 2 2 prognosis, 2522-2.523 pathogenesis of, 1 4 7 7
xi
Bacterial meningitis {Continued) parhoj'.cns rh.it cause antibiotic selection based on, 1479-1482 description of, 1476 signs and symptoms of, 1477 Streptococcus pneumoniae, 1476 stroke risks, 1303 subarachnoid space effects, 1477 transmission methods, 1477 treatment of adjunctive, 1482 antibiotics, 1478t, 1 4 7 9 - 1 4 8 2 , 1481t-1482t corticosteroids, 1482 duration of, 1482 Bacterial toxins botulism, 1 5 0 8 - 1 5 1 0 diphtheria, 1 5 1 1 - 1 5 1 2 tetanus, 1 5 1 0 - 1 5 1 2 BAEPs. see Brainstem auditory evoked potentials Ballot's syndrome, 1936t Ballism, 3 1 0 , 310t, 3 2 0 Ballismus, 2 1 5 3 - 2 1 5 4 Halo's concentric sclerosis, 1635 Bannwarth's syndrome, 2116 Barbiturates abuse of, 1 7 2 1 - 1 7 2 2 intracranial pressure lowered using, 1139 psychotropic effects of, 98t withdrawal from, 1722 Eardet-Riedl syndrome, 80.5t Barthcl Index, 1037, 1038t Bartonella bacilliformis, 1502 Bartter's syndrome, 1848t Basal ganglia a n a t o m y of, 2 1 2 6 , 2126f biochemistry of, 2 1 2 9 t , 2 1 2 9 - 2 1 3 0 disorders of dysphagia associated with, 1 7 1 - 1 7 2 Parkinson's disease, see Parkinson's disease sleep disorders associated with, 2031 d o p a m i n e levels in, 8 9 4 funcrional organization of, 2126f, 2126-2129 idiopathic calcification, 1930 internuclear connections of, 2126f, 2126-2129 lesions of aphasia caused by, 150 falls associated with, 26 hemiplegia caused by, 3 3 8 t neurotransmitters of, 2129t, 2 1 2 9 - 2 1 3 0 nuclei of, 142 pathways of, 2126f, 2 1 2 6 - 2 1 2 9 Basal veins of Rosenthal, 6 4 0 Basilar artery a n a t o m y of, 637f branches of, 280f, 6 3 6 embolism of, 279f occlusion of, 656 stenosis of, 659f trunk bifurcation, 6 3 7 Basilar impression, 2 1 8 9 - 2 1 9 0 Basilar migraine, 2 0 7 5 Basilar skull fractures, 1128, 1128f Basilar tip aneurysms, 612f Basscn-Kornzweig syndrome, 2336 Volume I p p . 1-1070 • Volume 11 p. 1071-2546
xii
INDEX
Battle sign, 49 Baylisacaris procyoms, 1557t B cell(s) accessory molecules for activating, 8 1 6 - 8 1 7 activation of, 8 1 6 - 8 1 7 description of, 8 0 9 , 811 function of, 810 immunoglobulin M expression, 811 inhibition of, 8 1 8 - 8 1 9 myasthenia gravis a n d , 826 T-hclpcr cells and, 816 B-cell lymphoma, 1 4 6 6 - 1 4 6 7 BCNU, 1404 Becker's muscular dystrophy, 805t ch a r a t tens tics of, 2 4 7 3 epidemiology of, 2 4 6 9 - 2 4 7 0 genetics of, 2 4 6 9 Behavioral disturbances Alzheimer's disease aggression, 88 apathy, 8 7 - 8 8 delusions, 88 depression, 87 description of, 8 6 - 8 7 hallucinations, 83 psychosis, 8 8 - 8 9 , 89f sequelae " I , Mi amyotrophic lateral sclerosis a n d , 97 description of, 85 differential diagnosis, 103 epilepsy and, 9 7 - 9 9 frontal-subcortical circuitry in, 8 5 - 8 6 Huntington's disease a n d , 9 3 - 9 5 multiple sclerosis and, 9 5 - 9 7 Parkinson's disease and, 9 2 - 9 3 prevalence of, 86t rehabilitation for, 1 0 6 4 - 1 0 6 5 stroke and, 9 9 - 1 0 0 Tourettc's syndrome and, 95 traumatic brain injury and, 101 Behavioral dyscontrol disorder, 101 Behcet's disease in adults, 1083 in children, 1 1 0 5 - 1 1 0 6 stroke caused by, 1220 Bell's cruciate paralysis, 1154, 1156t Bell's palsy characteristics of, 2 1 1 6 - 2 1 1 7 diahetes mellirus a n d , 2 3 6 2 - 2 3 6 3 during pregnancy, 2 1 1 5 , 2 5 3 4 prognosis for, 2 1 1 6 - 2 1 1 7 taste disturbances associated with, 2 6 3 Benedikt's syndrome, 341t, 1206, 2108t, 2120t Benign childhood epilepsy with centrotemporal spikes, 1959 Benign familial neonatal convulsions, 1848t, IS62 IS63, 1964 Benign focal amyotrophy clinical features of, 2 2 3 6 differential diagnosis, 2 2 3 7 etiology of, 2 2 3 6 laboratory studies, 2 2 3 6 - 2 2 3 7 pathogenesis of, 2 2 3 6 treatment of, 2 2 3 7 IV'in;;n hercdiian chorea, 21 V> Benign myalgic encephalomyelitis, 1542 Benign myoclonic epilepsy of infancy, 1964
Benign neonatal sleep myoclonus, 2037 Benign paroxysmal positional vertigo in children, 241 description of, 2 3 6 , 237f exercise therapy for, 7 4 6 - 7 4 7 Benign paroxysmal Torticollis, 2 1 0 4 Hcn/oilia/cpincs abuse of, 1721 administration of, 1 9 8 1 - 1 9 8 2 characteristics of, 1982t description of, 1 721 epilepsy treated with, 1 9 8 1 - 1 9 8 2 insomnia treated with, 2 0 4 8 metabolism of, 1981 pain management using, 9 3 6 - 9 3 7 psychotropic effects of, 98t status epilepricus treated with, 1968, 1969t withdrawal from, 1721 Benzrropine, 2 1 3 4 t Beriberi, 1 7 0 1 - 1 7 0 2 Best corrected visual acuity, 728 Beta-galacrosidasc I, 8 0 3 t Bethanechol, for bladder dysfunction, 1052t Betz's cells, 2 2 2 3 Bcxtra. see Valdeeoxib Bifunctional enzyme deficiency, 1817t Bilateral suboccipital craniotomy, for cerebellar infarction, 965 Biliary atresia, 1109 Binasal hemianopias, 7 3 3 , 735 Binswangcr's disease, 331 Bioavailability, 9 1 6 Biofeedback, 1058 for tinnitus, 2 5 5 Biological rhythms, 855 Biopsy brain Creurzfcldt-Jakob disease, 9 8 7 dementia diagnosis by, 9 8 7 herpes simplex virus encephalitis uses, 987 indications for, 9 8 7 infection evaluations, 9 8 7 neoplastic disorders diagnosed by, 987 parasitic infection evaluations, 1559 prion disease evaluations, 1625 risk-ro-benefit considerations for, 4 6 0 tumor evaluations, 1402 vasculitides use, 9 8 7 muscle denervation changes, 2 4 6 4 - 2 4 6 5 , 2465f Duchenne's muscular dystrophy findings, 2 4 7 1 f - 2 4 7 2 f facioscapulohumeral dystrophy findings, 2 4 6 6 , 2467f floppy infant evaluations, 4 0 5 bukuyama type congenital muscular dystrophy findings, 2478f lower m o t o r neuron diseases, 2 2 3 1 mitochondrial disorders evaluated by, 1840-1841 myopathic changes, 2 4 6 5 - 2 4 6 6 myotonic dystrophy type 1 findings, 2485f myotubular myopathy findings, 2500-2501 normal, 2464f
Biopsy {Continued) polymyalgia evaluations, 3 9 2 ragged-red fibers, 1840 skeletal muscle disorders evaluated by, 2463-2467 weakness evaluations, 3 7 7 nerve, 4 0 5 ^ 1 0 6 Biotin, I 8 1 9 t Biotransformation, 9 1 7 Biperidin, 2 1 3 4 t Bitemporal visual field defect, 7 Bithermal caloric testing, 7 3 9 Black w i d o w spider, 1728t, 1 7 2 8 - 1 7 2 9 , 2460 Bladder arcflcxic neck, 1172 autonomic failure a n d , 2 4 1 9 - 2 4 2 0 cystometry evaluations, 7 5 1 - 7 5 3 dysfunction of arteriovenous malformation of the spinal cord, 4 2 7 basal ganglia and, 4 2 4 - 4 2 5 LLUUILI equina damage and, 42^ cortical lesions a n d , 4 2 3 detrusor overactivity, see Detrusor overactivity diabetic neuropathy a n d , 4 2 9 frontal lobe lesions a n d , 423 Guillain-Barre s y n d r o m e a n d , 4 2 9 incontinence, see Urinary incontinence indwelling catheter for, 7 5 8 - 7 5 9 metastatic epidural spinal cord compression, 1447 multiple sclerosis and, 4 2 6 ^ 1 2 7 , 759 multiple system atrophy and, 424—425 myotonic dystrophy and, 4 2 9 nerve r o o t stimulators for, 7 5 9 - 7 6 0 parkinsonism-related symptoms, 424-425 pelvic nerve injury a n d , 4 2 9 pharmacological trearment of, 1052-1053 in spina bifida, 1 0 5 3 spinal cord disorders and, 4 2 6 spinal cord injury and, 4 2 6 , 1 0 5 2 , 1171-1172 surgical management, 7 6 0 , 760t transverse myelitis a n d , 4 2 7 treatment of, 2 4 3 6 filling of, 752 functions of, 4 1 9 , I 171 incomplete emptying of, 7 5 7 - 7 5 8 innervation of, Mi9, 4 2 6 l.-dopa effects, 425 micturition, 4 1 9 neurogenic, 750 neurological control of, 4 1 9 - 4 2 0 physiology of, 1171 positron emission tomography studies of, 4 2 0 , 420f-421f postmicturition residual volume measurements, 7 5 0 , 7 5 I f sacral segmental reflex, 1 1 7 2 storage functions of, 4 1 9 Blastomyces dermatitidis, 1548 Blastomycosis, 1545, 1548 Blcbbing, 843 BI cp ha roc I onus, 7 2 2 Blepharophimosis, 8031
1NDLX Blepharospasm, 2156 central, 229 description of, 229 excessive lid closure caused by, 229 illustration of, 230f Blindness, transient monocular, 178-179, 179t Blindsight, 67 Blink reflex, 514 Blood-brain barrier cerebral blood vessels, 1746-1748 cerebral edema caused by alterations in, 956 characteristics of, 1747t chemoinfusion disruption of, 996 description of, 821 cpendymal cells, 1749 ctoposide penetration through, 1407 functions of, 1401 interstitial fluid, 1746 multiple sclerosis-related disruptions of, 1633 opening of, 1751-1752 pial cells, 1749 superoxide dismutase effects, 1121-1122 traumatic brain injury effects, I 116 vasogenic edema and, 1752 viral infection passage across, 840 Blood-ccrcbrospinal fluid barrier, 1747t Eilood Him carotid artery, 16 cerebral, 1676 brain death criteria, 64 ischemic interruption of, 1201 normal, 1201 regional description of, 667 neuroseiences critical care unit monitoring of, 946 subarachnoid hemorrhage effects on, 1279 transcranial Doppler ultrasonography monitoring of, 945-946 syncope caused by rednctions in, 16 Blood pressure coma evaluations, 48 drugs to increase, 2431-2432 monitoring of, 943 stroke-induced elevation of, 955-956 syncope evaluations, 13 Bobath technique, 1030 Body temperature coma evaluations, 48^(9 hypothalamic regulation of, 852-853, 853f monitoring of, 943 neuroseiences critical care unit monitoring of, 943 Body weight support to treadmill training, for locomotor training, 1056-1057 Bogorad's syndrome, 2412 Bombesin, 851t Bone conduction tests, 743 Bone conduction thresholds, 249 Bone marrow transplantation-related neuroparhies, 2369-2370 Borna virus, 832t Borrelia burgdorferi., 559
Borrcliosis, 1498-1499, 2392. see also Lyme disease Boston Naming Test, 695f Botulinum toxin comitant and noncomitant strabismus treated with, 211 detrusor overactivity treated with, 756 dysphagia caused by, 172 dystonia treated with, 928 focal and segmental dystonia treated with, 2157 migraine treated with, 2086 spasticity treared with, 1055-1056, 1654 Botulism clinical features of, 1508-1509, 2458-2459 diagnosis of, 1509 differential diagnosis, 1509 electromyographic findings, 2459 etiology of, 1508
food-borne, 1509 forms of, 2459 infantile, 404 mortality rates, 1510 nicotinic receptors and, 893t pathogenesis of, 1508 pathophysiology of, 1508 public health issues associated with, 1508 treatment of, 1509-1510, 2459 Bovine spongiform encephalopathy, 1626 Bowel continence in, 420 dysfunction of basal ganglia and, 425 Cauda equina damage and, 428 cortical lesions and, 423-424 lower motor neuron, 1173 metastatic epidural spinal cord compression, 1447 spinal cord injury and, 427, 1172-1174 upper motor neuron, 1173-1174 function of, 420 peristaltic movement, 1173 physiology of, 1172-1173 Brachialgia, 434 Brachial neuritis, 438, 1467 Brachial plexitis, 346 Brachial plexopathy arm pain caused by, 438 in cancer patients, 438 characteristics of, 1456-1457 clinical features of, 2288-2289 diagnosis of, 2289 epidemiology of, 2288 etiology of, 2289 pathophysiology of, 2289 prognosis of, 2289-2290 treatment of, 2289-2290 Brachial plexus disorders anatomical features of, 2282-2283, 2283f clinical features of, 2284 Compound motor action potentials in, 2284
diagnosis of, 2284 electrodiagnostic studies of, 2284-2285 metastatic plexopathy, 2286-2287 neonatal, 2527 neurogenic thoracic outlet syndrome, 2286 neurological examination of, 2284 radiation-induced plexopathy, 2287-2288
xiii
Brachial plexus disorders (Continued) radiological stutlics, 2285 sensory nerve action potentials in, 2284 traumatic plexopathy, 2285-2286 Brachial plexus injuries, 1075 Brachiocephalic artery stenosis, 122If Brachiocephalic trunk, 625-626 Brachytherapy, for brain tumors, 1403 Bradycardia, 2416, 2417r Bradykinesia description of, 300 trearment of, 872 Bradykinins, 85It Bradypbrema, 296 Brain Cajal-Retzius cells, 1773-1774 convolutions of, 1766 extracellular space of, 1746 far embolism to, 1225 gyri of, 1766, 1767f malformations of anciiccphah , I 77r>, I 777i ccphalocele, 1776, 1777t, 1778 cerebellar development, 1786-1788 cerebellar hypoplasia, 1787f, 1787-1788 Chiari, 1786-1787 colpocephaly, 1783 corpus callosum agenesis, 564, 564f, 1777t, 1782-1783 Dandy-Walker malformation, 1786 ectopic gene expression, 1782 encephalocele, 1776 fotebrain, 1779-1783 heniimegalencephaly, 1785-1786 holoprosencephaly, see Holoprosencephaly isolated arrhineticophalv, 1781 Kallmann syndrome, 1781 meningomyelocele, 1776, 1777t, 1778-1779 midline, 1779-1783 Millci-nieker ivndroine. S 11, l"l\", 1777t, 1784-1785 neuroblast migration, 1783-1786 ncurulation stage, 1776-1779, 1777t rachischisis, 1778 rhombomeric deletions, 1782 schizcnccphaly, 567, 568f, 1769, 1785 selective cerebellar hemispheric aplasia, 1786 selective vermal aplasia, 1786 septo-optic-pituitary dysplasia, 1781-1782 spinal bifida, 1778-1779 spinal dysraphism, 1778 subcortical laminar heterotopia, 1785 Walker-Warburg syndrome, 804t, 1768, 1777t, 1785 sulci of, 1766, 1767f Brain abscess actinomycosis and, 1505 in AIDS patients, 1597f antibiotics for, 1487 in children, 1102 clinical features of, 1484 computed tomography of, 1484 corticosteroids for, 1487 diagnosis of, 966, 1484 differential diagnosis, 1485, 1487
Volume 1 pp. 1-1070 • Volume II p. 1071-2546
xiv
INDFX
Brain abscess [Continued] frontal lobe, 1484 hematogenous spread of, 1484 magnetic resonance imaging of, 1484, 1485f-1486f meningitis-related, 1476 neurosurgical treatment of, 966, 966f pathogens associated with, 1484-1485 predisposing causes of, 1484 sites of, 1484 treatment of, 1487 Brain biopsy Crcurzfcldr-Jakob disease, 987 dementia diagnosis by, 987 herpes simplex' virus encephalitis uses, 987 indications for, 987 infection evaluations, 987 neoplastic disorders diagnosed by, 987 parasitic infection evaluations, 1559 prion disease evaluations, 1625 risk-to-benefit considerations for, 460 tumor evaluations, 1402 vasculitides use, 987 Brain cells, 1745 Brain death in children, 1670 criteria for, 63-64, 476, 1669-1670 definition of, 476 diagnosis of, 1669-1670 elecrnencephalography evaluations, 476 survival in, 64 Brain edema computed tomography of, 1753f corticosteroids of, 1756 cytokine's role in, 1752 cytotoxic, 1750-1751, 1752-1755 description of, 1745 etiology of, 1750-1751, 1753 hypertensive encephalopathy and, 1753-1754 inflammation, 1752 intracerebral hemorrhage and, 1753 mechanisms of, 1750-1751, 17Jlf meningiomas and, 543 osmolality changes and, 1754 osmotic therapy for, 1756
stroke and, 1753 Treatment of, 1755-1757 vasogenic, 1751 Brain herniation coma and, 59 computed tomography for, 62 signs of, 58-59 rraumaric brain injury and, 1130
types of, 1131f Brain metastases chemotherapy for, 1446 clinical features of, 534, 536-537, 1372f clinical presentation of, 1442-1443 computed tomography of, 1443 differential diagnosis, 1443 epidemiology of, 1441-1442 headache associated with, 1442 histopathology of, 1442 imaging of, 1443 incidence of, 1441 lung cancer and, 1441-1442 magnetic resonance imaging of, 1372f, 1442f, 1443 management of
Brain metastases [Continued) anticonvulsants, 1443-1444 Karnofsky performance score, 1443, 1443t prophylacric cranial irradiation, 1444-1445 tadiation therapy, 1444 stereotactic radiosurgery, 1445-1446 supportive care, 1443-1444 surgery, 1445 parenchymal, 1441 pathology of, 1442 pathophysiology of, 1442 radiation therapy for, 978, 1444 recurrenr, 1446 signs and symptoms of, 1442-1443 sources of, 1371, 1441 survival rates for, 766 Brain monitoring, in neurosciences crirical care unit cerebral oximerry, 946 electroencephalography, 945 evoked potentials, 945 intracranial pressure, 944-945 jugular bulb oximetry, 945 mean cerebral blood flow, 945-946 microdialysis, 946-947 near-infrared spectroscopy, 946 overview of, 943-944 regional, 945-947 tissue monitoring, 947 transcranial Doppler ultrasonography, 945-946 whole-bra in, 944-945 Brainstem astrocytomas of, 539f-540f, 539-540, 1427t compression of, S3 distributed motor functions, 1045 gait and, 324 glioma of, 1385, I391f gliosis of, 1106 hemorrhage of, 483f, 1129 lesions of brainstem auditory evoked potentials findings, 482 cavernous angiomas, 973 characteristics of, 34It hemiplegia caused by, 340-341 monoplegia caused by, 343 motor deficits caused by, 341t pelvic organ dysfunction caused by, 426 sensory abnormalities caused by, 412-413 malformations of, 1774 motor organization of, 340f, 340-341 myoclonus and, 317 postural righting and, 324
respiration regulation by, 52 sensory pathways, 407 serotonergic neurons in, 898 spinothalamic tracts, 407 transient ischemic attacks of, 239-240 Brainstem auditory evoked potentials acoustic neurinoma, 482, 482f-^183f brainstem lesions, 482 definition of, 481 hearing assessments using, 483-484, 745 multiple sclerosis, 482^183
Brainstem auditory evoked potentials (Continued) neurological diseases, 482^184 normal, 481-482, 482f Brainstem encephalitis, 172 Brainstem reflexes, 64 Brainstem syndromes diencephalic syndrome, 1~" foramen magnum syndrome, 278 ischemic stroke clinical manifestarions of, 279 medullary, 284-285, 2851, 286f midbrain, 280-281, 281f, 282t pontine, 281, 283r-284r, 284f thalamic, 280, 280t ocular motor combined vertical gaze ophthalmoplegia, 273-274, 274t dorsal midbrain syndrome, 274t, 274-275 downga^e paresis, 275 global paralysis of gaze, 276 horizontal gaze paresis, 275-276 internuclear ophthalmoplegia, 275 one-and-a-half syndrome, 276-277, 718 upgaze paresis, 274-275 sixrh cranial nerve nucleus, 277 syringobulbia, 279 tectal deafness, 278 thalamic syndrome, 277-278 third cranial nerve nucleus, 277 Brain tumors acoustic neurinoma, 547, 548f agricultural workers and, 1334-1335 alcohol and, 1337 astrocytomas brainstem, 539f-540f, 539-540 cerebellar, 538 classification systems for, 1330t desmoplastic cerebral astrocytoma of infancy, 1429 diffuse, 1344f high-grade, 1432 low-grade characteristics of, 532 in children, 1430-1431 imaging of, 1330 management of, 1412 magnetic tesonance spectroscopy evaluations, 671f-673f metabolic polymorphisms associated with, 1339t pilocystic, 975, 1385, 1390f, 1412 subependymal giant cell, 541, 1350, 1381, 1413 Toxoplasma gondii and, 1338 biopsy of, 1402 cerebral metastases, 534, 536-537 characterises of, 532, 1350, 1412-1413 in children, 1428 classification of, 1329-1330 clinical evaluation of, 1365 clinical features of cognitive dysfunction, 1364 description of, 1363 endocrine dysfunction, 1364 headaches, 1363-1364, 2056-2057 hypothyroidism, 1364 nausea and vomiting, 1364 plateau waves, 1364—1365
INDEX Brain tumors {Continued) seizures, 1364, 1366 visual symptoms, 1364 colloid cysts characteristics of, 1361 magnetic resonance imaging of, 5 4 3 , 543 f, 1384, 1388f third ventricle, 2 4 - 2 5 , 964f complications of cerebral edema, 1 3 6 6 - 1 3 6 7 deep venous thrombosis, 1 3 6 7 - 1 3 6 8 seizures, 1366 venous thrombosis, 1 3 6 7 - 1 3 6 8 craniopharyngioma characteristics of, 5 4 6 , 547f, 8 6 2 , 1360-1361 in children, 1434 clinical presentation of, 1434 illustration of, 547f, 976f imaging of, 1400f, 1401 management of, 1419, 1 4 3 4 - 1 4 3 5 neurosurgical treatment of, 9 7 5 - 9 7 6 prognosis, 1435 cytomegalovirus a n d , 1338 dysembryoplastic neuroepithelial t u m o r , 5 3 2 - 5 3 3 , 1 3 8 1 , 1429 in elderly, 1 3 3 3 electromagnetic fields a n d , 1334 endovasculat therapy of, 9 9 6 ependymomas anaplastic, 1 3 8 4 - 1 3 8 5 , 1414 characteristics of, 5 3 8 - 5 3 9 , 580f-581f, 5 8 0 - 5 8 1 , 1344f in children, 1 4 3 2 - 1 4 3 3 imaging of, 1 3 8 4 - 1 3 8 5 , 1389f management of, 1414 myxopapillary, 1352 subependymoma, 1352, 1385, 1414-1415 epidemiology of analytic, 1 3 3 3 - 1 3 3 9 cohort studies, 1334 gender, 1331 geographic irends, 1333 incidence, 1 3 3 0 - 1 3 3 1 migrant studies, 1333 mortality factors, 1331 prognostic factors, 1331 race, 1 3 3 1 , 1332f study designs, 1 3 3 3 - 1 3 3 4 temporal trends, 1 3 3 1 , 1 3 3 3 epidermoid cysts, 5 2 7 , 53Of, 5 4 7 , 55Of extta-axial, 5 4 1 - 5 4 7 frontal lobe, 1364 ganglioglioma characteristics of, 5 3 3 , 534f in children, 1429 imaging of, 1381 management of, 1415 gender predilection, 1331 genetic polymorphisms associated with, 1338-1339 genetic syndromes associated with, 1 3 3 8 , 1338t geographic trends, 1333 glioblastoma multiforme characteristics of, 5 3 3 - 5 3 4 , 535f imaging of, 1376, 1379f management of, 1413 prognosis for, 1 4 0 1 , 1 4 1 3
Brain t u m o r s (Continued) gliomatosis cerebri, 1347, 1414 hemangiohlastoma characteristics of, 5 4 0 , 540f, 5 8 1 , 1360 embolization of, 994 histologic findings, 1360 imaging of, 1392, 1394f hemangiopericytoma, 5 4 4 , 545f, 1417-1418 high-grade astrocytomas, 1432 histopathological classification of, 1329-1330 historical descriptions of, 1 3 2 9 - 1 3 3 0 hypothalamic glioma, 5 4 7 incidence of, 7 6 6 , 1 3 2 7 , 1 3 3 0 - 1 3 3 1 infections a n d , 1 3 3 7 - 1 3 3 8 infra tentorial, 5 3 7 - 5 4 0 intracerebral h e m o r r h a g e caused by, 1253, 1255f ionizing radiation a n d , 1 3 3 5 - 1 3 3 6 laboratory investigation!-. tor computed t o m o g r a p h y , 1365 electroencephalography, 1365 imaging modalities, 1365 lumbar puncture, 1 3 6 5 - 1 3 6 6 magnetic resonance imaging, 1365, 1365f low-grade astrocytomas characteristics of, 5 3 2 in children, 1 4 3 0 - 1 4 3 1 imaging of, 1330 management of, 1412 l y m p h o m a , 5 3 4 , 536f management of, 1 4 1 2 - 1 4 1 3 medulloblastoma characteristics of, 5 3 8 , 538f, 1355-1356 imaging of, 1392f-1393f management of, 1416 metastases, 1416 posterior fossa, 1425f meningeal sarcoma, S45 meningioma, 5 4 6 - 5 4 7 , 549f molecular classification of, 1330 morbidity rates, 766 mortality rates for, 7 6 6 , 1331 neurocytoma, 5 4 1 , 542f, 1 3 8 1 , 1383f neurofibroma characteristics of, 5 7 9 , 579f, 1358-1359 management of, 1 4 1 6 - 1 4 1 7 neurosurgical treatment of, 9 7 5 - 9 7 8 N-nitroso c o m p o u n d s a n d , 1 3 3 6 - 1 3 3 7 occupational studies of, 1 3 3 4 - 1 3 3 5 oligodendrogliomas, 5 3 2 , 533f optic chiasm glioma, 5 4 7 , 548f, 1 3 8 1 , 1382f overview of, 1339 pineal, 5 4 1 - 5 4 2 pinealoblastoma, 5 4 2 , 542f pituitary a d e n o m a , 5 4 5 , 546f, 1399f during pregnancy, 2 5 3 6 - 2 5 3 7 prevalence of, 7 6 6 primitive neuroectodermal, 5 3 8 , 1416 characteristics of, 5 3 8 , 1 3 5 4 - 1 3 5 5 management of, 1416 prognosis for, 1331 racial predilection, 1 3 3 1 , 1332f radiation exposure a n d , 1 3 3 5 - 1 3 3 6 smoking a n d , 1337
xv
Brain t u m o r s {Continued) studies of design of, 1 3 3 3 - 1 3 3 4 occupational, 1 3 3 4 - 1 3 3 5 summary of, 1368 survival rates, 1331 tobacco a n d , 1337 t r a u m a a n d , 1336 treatment of alkylating agents, 1 4 0 4 - 1 4 0 5 , 1409 angiogenesis inhibitors, 1409 antifolates, 1405 antimicrotubulc agents, 1 4 0 5 - 1 4 0 6 apoptotic pathways, 1411 blood-brain barrier considerations, 1407 catboplatin, 1406 cell growth targeting, 1408 chemotherapy, 1404, 1 4 0 7 - 1 4 0 8 cisplatin, 1406 cytidine analogs, 1405 cytokines, 1411 cytosine arabinoside, 1405 delivery strategies, 1407, 1409 epidermal growth factor receptor, 1408 gene therapy, see Gene therapy genetically modified neural stem cells, 1411 growth factor receptors, 140R immune-mediated therapies, 1 4 1 0 - 1 4 1 1 intracellular signal transducer targeting, 1408 methotrexate, 1405 neural stem cells, 1411 oncolytic viruses, 1411 overview of, 1 4 0 1 - 1 4 0 2 platelet-derived growth factor receptor, 1408 platinum c o m p o u n d s , 1406 proteasome inhibitors, 1409 protein kinase C inhibition, 1408 radiation therapy brachy therapy, 1403 chcmorhcrapciitic agc-nts used with, 1403 conventional, 1403 description of, 1402 external beam, 1 4 0 2 - 1 4 0 3 hyper fractionation protocols, 1 4 0 3 stereotactic, 1 4 0 3 - 1 4 0 4 target for, 1402 t u m o r cell sensitization to, 1 4 0 3 whole-brain, 1403, 1418 Ras signaling pathway inhibition, 1408-1409 resection, 1402 surgery, 1402 temozolomide, 1 4 0 7 - 1 4 0 8 , 1 4 1 3 topoisomerase inhibitors, 1 4 0 6 - 1 4 0 7 vaccinations, 1 4 1 0 - 1 4 1 1 vascular endothelial growth factor receptors, 1408 vinca alkaloids, 1 4 0 5 - 1 4 0 6 vincristine, 1406 trends in, 1 3 3 1 , 1333 Brain w a r t s , 1 7 6 8 - 1 7 6 9 Branch retinal artery occlusion, 191 Brandt-Daroff exercise, 748 Breath-holding spells cyanosis associated with, 20 loss of consciousness caused by, 20
Volume f p p . 1-1070 > Volume II p. 1071-2546
xvi
INDEX
Breathing apncusdc, 53 ataxic, 53 cluster, 53 k u ^ i r a u l , 5 '•> short-cycle periodic, 52—53 Brightness-mode imaging, 6 4 8 - 6 4 9 Broca's aphasia agrammatism associated with, 1061 causes of, 67 characteristics of, 1 4 4 - 1 4 5 , 145t treatment of, 1061 Broca's area, 142f Brodmann's areas, 66, 142, 7 0 7 Bromism, 2448 Bromocriptine, 8 6 5 - 8 6 6 , 894, 2 0 8 8 , 2134t for neuroleptic malignant syndrome, 854 Bronchopulmonary dysplasia, 1106 Brownian motion, 524 Brown-Sequard syndrome description of, 358 hemiplegia caused by, 3 4 1 - 3 4 2 modified, 3 5 9 - 3 6 0 sensory loss caused by, 4 1 6 spinal cord hemisection as cause of, 358 trauma and, 360 Brucellosis, 1 5 0 2 - 1 5 0 3 , 1 9 4 0 Brtm's nystagmus, 215t Brun's sign, 25 Bruxism, 2037 Buccofacial apraxia, 1922 Buerger's disease, 1220 Bulbar-cervical dissociation pattern, 1154 Bulbar poliomyelitis, 2 4 1 0 Bulbocavernous reflex, 7 5 4 Bulimia nervosa, 855 r>uriy,i\ iridae, 8 Ml Bunyavirus, 1 5 1 6 t - l 5 l 7 t Burning hand syndrome, 1160 Burns, 1744 Burst fracture cervical spine, 586 thoracic spine, 593f C Cabergoline, 2134t Cafe au lait spots, 1874, 1875f Caisson's disease, 1225 Cajal-Reuius cells, 1 7 7 3 - 1 7 7 4 Calcarine artery anatomy of, 637f disorders associated with compromise of, 638t occlusion of, 1208 Calcitonin gene-related peptide, 903t, 9 0 4 Calcium channcl(s) antiepileptic drug effects o n , 913 disorders associated with, 91 It, 9 1 3 L-type, 912 N-rype, 9 1 2 operating cycle of, 913 pharmacology of, 913 physiology of, 913 P-type, 912 structure of, 2 4 8 7 T-typc, 9 1 2 Calcium-channel blockers cluster headaches treated with, 2 0 9 3 migraine treated with, 2085
Calcium-channel blockers (Continued) vasospasm treated with, 9 6 9 , 1009 Calcium disorders, 1094, 1690 California virus, 1 5 3 I t , 1532 Callosal agenesis, 177r, 5 6 4 , 565f, 1782-1783 Caloric-induced nystagmus, 2 1 7 , 7 4 1 Caloric testing of oculocephalic reflex, 5 6 - 5 7 Calpain-3 deficiency, 2475 Calpains, 1239 Calvarial metastases, 1 4 5 5 - 1 4 5 6 c A M P response element-binding protein, 9 0 9 Campylobacteriosis, 1506 ('..i"ijiYli:!i.ii!i-y
it-jn'ii.
i
^i'fi
Canalith theory, 2 3 7 Canavan disease, 1829 Cancer ataxia-telangiectasia a n d , 1886 brachial plcxopathy a n d , 4 3 8 brain metastases, I 44 1 I 4 4 1 in children, 1302 Cancer-associated retinopathy syndrome, 1 8 2 , 1469 Candida albicans, 1548 Capgras* syndrome, 31 Capillary endothelial cells, 8 4 0 - 8 4 1 Capillary hemangiomas, 5 7 5 , 576f Capillary telangiectasia, 5 6 9 , 9 7 0 Capsaicin, 9 3 7 Carba maze pine administration of, 1 9 8 2 - 1 9 8 3 characteristics of, 1 982t metabolism of, 1982 psychotropic effects of, 98t trigeminal neuralgia treated with, 2100 C a r b a m o y l p h o s p h a t c synthase deficiency, 1825t Ca r ho h y d rate-dc fic i c n t glycopro rein syndromes, 1829 Carbohydrate metabolism disorders, 2491-2443 C a r b o n disulfide, 1711 Carbonic anhydrase inhibitors, 1987 C a r b o n m o n o x i d e , 1711 Carbon monoxide poisoning, 2 1 4 4 Carboplatin, 1406 Carboxy hemoglobin, 271 Carcinoid tumors, 868 Carcinoma choriocarcinoma, 9 7 7 , 1 3 6 0 , 2 5 3 7 choroid plexus, 1 3 5 3 , 1415 Cardiac arresr, 1075 Cardiac catheterization, 1 0 7 5 - 1 0 7 6 , 1103 Cardiac cephalalgia, 2071 Cardiac disorders cardiac arrest, 1075 cardiogenic embolism, 1074 congenital heart disease, 1 1 0 1 - 1 1 0 2 description of, 1 0 7 3 - 1 0 7 4 endocarditis, 1 5 0 7 rheumatic fever, 1508 syncope, 1 0 7 4 - 1 0 7 5 venrricular arrhythmias, 1102 Cardiac o u t p u t , 1 4 - 1 5 Cardiac surgery, 1 0 7 5 - 1 0 7 6 Cardiac transplantation in adults, 1 0 7 5 - 1 0 7 6 in children, 1 1 0 3 Cardiofacial syndrome, 2 1 1 4
Cardiogenic embolism acute myocardial infarction a n d , 1211-1212 arrial fibrillation a n d , 1 2 1 2 - 1 2 1 3 atrial m y x o m a s , 1213 characteristics of, 1211 description of, 1074, 1209 dilated cardiomyopathy, 1212 cchoeardiogenic contrast material as source of, 1 2 1 3 investigations of, 1233 left ventricle, 1211 mitral stenosis a n d , 1212 patent foramen ovale, 1 2 1 3 prosthetic heart valves a n d , 1212 sick sinus syndrome, 1213 sources of, 1 2 1 1 , 1 2 l 2 t stroke caused by, 1 2 1 1 - 1 2 1 3 substrates, 1211 Cardiomyopathy, 1813-1814 C a r d i o p u l m o n a r y arrest anoxic coma after, 1 6 6 8 - 1 6 6 9 , 1669t electrocnccphalographic findings, 1670 prognostic assessments, 1671 Carmusrine, 1412 Carnitine, 1812t Carnitine deficiency m y o p a t h y , 2 4 9 4 Carnitine palmitoyl transferase-1, [815t Carnitine palmitoyl transferase-2, I 8 1 5r Carnitine palmitoyl transferase deficiency, 1817r, 2 4 9 3 Carnitine pa Imitoyltransfe rase deficiency, 803t Carnitine translocase deficiency, 1815t Carnitine transporter deficiency, 1 8 I 5 t Carotid arteries aneurysms of, 1277f, 2 1 0 9 atherosclerosis effects, 6 0 5 - 6 0 6 , 2199-1200 bruits, 1199, 1 2 0 3 coils and kinks of, 1225 common a n a t o m y of, 6 2 6 , 6 2 6 f - 6 2 7 f duplex ultrasound of, 6 5 0 left, 6 2 6 right, 6 2 6 dissection computed tomographic angiography of, 617-618 headaches caused by, 2 0 6 5 magnetic resonance angiography of, 610 external a n a t o m y of, 6 2 6 - 6 2 7 branches of, 62#t disorders of, 6 2 7 internal anatomy of, 6 2 9 - 6 3 5 anterior cerebral artery branch. see Anterior cerebral artery carotid siphon, 6 3 0 cavernous portion of, 6 2 9 , 629f cerebral portion of, 6 3 0 - 6 3 1 cervical portion of, 6 2 9 , 629f cisternal segment of, 631 disorders of, 631 dissection of, 6 1 7 - 6 1 8 , 978f Doppler imaging of, 6 4 7 duplex ultrasound of, 6 5 0 Fischer classification segment, 6 3 0 , 6 3 0 t maxillary artery anasromoses with, 6 2 7
INDEX Carotid arteries [Continued) middle cerebral artery branch, see Middle cerebral artery Moyamoya disease, 979-980, 980f, 1217f, 1217-1218 petrous portion of, 629, 629f posterior communicating artery, 630t, 6.31 segments of, 629-631, 630r stenosis of atherosclerotic plaque as cause of, 655 carotid endarterectomy for, 655 description of, 631 illustration of, 999f-1000f transcranial Doppler ultrasonography of, 656 transient ischemic attack caused by, 997 supraclinoid portion of, 630-631 occlusion of, 1213, 2065 stenosis of asymptomatic, 1241 atherosclerotic plaque associated with, 997 carotid endartc recto my for, 1240-1241 computed tomographic angiography of, 616-617, 617f Doppler ultrasound of, 651, 652f cndovascular treatment for, 997-1000 illustration of, 999f-1000f magnetic resonance angiography of, 603, 604f, 605-606 prevalence of, 996-997 stroke caused by, 997-1000, 1199 surgical rreatmenr, 1240-1241 ultrasound flow velocity criteria for, 651t stenting of, 996-1000 thrombosis of, 1209 transient ischemic attacks of, 1202t ultrasound imaging of B-mode, 650-652 color flow imaging, 652 duplex, 650 power Doppler imaging, 652 technical limitations, 653 volume flow rate determinations, 652-653 Carotid artery syndromes, 1203-1205 Carotid blood flow, 16 Carotid-cavernous fistulas, 557, 558f, 613, 614f, 1017-1018, 1019f-1020f, 1878-1879 Carotid endarterectomy carotid arrery stenosis treated with description of, 1240-1241 internal carotid artery, 655, 656f stroke prophylaxis, 997 rranscranial Doppler ultrasonography monitoring during, 663-664, 664f transient ischemic attacks treated with, 979 Carotid Revascularisation Endarterectomy Versus Stent Trial, 998 Carotid sinus hypersensitivity, 2413-2414, 2416 Carotid sinus syncope, 13-14 Carotid siphon, 630
Carpal tunnel syndrome arm pain caused by, 439 causes of, 439,2312-2313 characteristics of, 3441 diagnosis of, 2312 differential diagnosis, 439 hypothyroidism and, 1097 localisation of, 414t monoplegia caused by, 344 nerve conduction studies of, 415, 439, 494^195 physical examination for, 439 predisposing conditions, 2313 during pregnancy, 2534 sensory conduction assessment* u^itir; inching technique, 494, 2313 sensory features of, 414t, 415 symptoms of, 2312 thenar atrophy associated with, 2312f treatment of, 2313 CAS. see Confusion assessment method Case control study, 1333 Caspases, 1123 Casdeman's disease, 1467 Catamenial epilepsy, 1972 Cataplexy characteristics of, 2006, 2014-2015 drop attacks caused by, 26 rreatmenr of, 2046 Cataracts developmental disorders associated with, 78t surgery for, delirium caused by, 37 Catatonia clinical features of, 44, 44t description of, 114-115 Catecholamines epinephrine, see Epinephrine norepinephrine, see Norepinephrine transmission principles for, 897f transporrers, 894 Catechol-O-mcthyl transferase inhibitors, 2134t Car-scratch disease, 1504 Cauda equina anatomy of, 1158 compression of, 967-968 damage to bladder dysfunction caused by, 428 bowel dysfunction caused by, 428 sexual dysfunction caused by, 428 lesions of, 349, 362-363, 363t Cauda equina syndrome, 1158-1160, 1159f, 2212, 2217 Caudal loop, 635 Caudate hemorrhage, 1260r, 1261, 126lf Caudate nucleus, 2126 CausaIgia. see Complex regional pain syndromes Caveolin-3 deficiency, 2475 Cavernous angiomas clinical features of, 972, 973f description of, 569 intracerebral hemorrhage caused by, 1252 magnetic resonance imaging of, 1252f, 1287f natural history of, 973 neurosurgical trcatmenr of, 972-973 seizures associated with, 1252
xvii
Cavernous fisrulas, carotid, 1017-1018, 1019f-1020f Cavernous hemangiomas, 575, 576f Cavernous malformations in children, 1300 description of, 1285 epidemiology of, 1286-1288 signs and symptoms of, 1286-1288 stereotactic radiosurgical therapy for, 1294 treatment of, 1294 Cavernous sinus syndromes, 2109 CCNU, 1404 CCR-5, 817 CD3, 814-815 CD4, 815 CD4+ T cells in adults, 1584 in children, 1606 CDS, 815 CD28, 816 CD45, 811 CD80, 819 CD86, 816, 819 CD95L, 819 Ceftriaxone, syphilis treated with, 1496t Celebrex, see Celecoxib Celecoxib, 93 2t Cell cycle genes, 806t Cell-mediated immunity, 810 Cell membrane excitability of, 1771 polarity of, 1771 Cell protection genes, 806t Central auditory system disorders, 254 ( ciural blepharospasm, 229 Central chromatolysis, 1184 Central cord syndrome, acute, 360-361, 1155-1157, 1156f Central core disease, 2498 Central disruption of fusion, 723 Central herniation, 1131f Central nervous system coccidioidal infection of, 1553-1554 congenital lesions of aqucducral stenosis, 566, 567f Chiari malformation, see Chian malformation corpus callosum agenesis, 177t, 564, 565f, 1782-1783 Dandy-Walker syndrome, 566, 567f descriprion of, 564 hamartomas, 567-568 heterotopias, 567, 568f holoprosencephaly, 564, 564f hydranencephaly, 567, 568f immune system and, 828 schizencephaly, 567, 568f septo-optic dysplasia, 564 syringohydromyelia, 565f cryprococcal infection of, 1553 cysticercosis of, 560, 561f diabetes mcllitus effects, 1098-1099 embryo logical development of, 1763-1764 fetal development of, 1763-1764 fungal infections of, 1546 granulomatous angiitis of, 1255-1256 immune system and, 821 lymphoma
Volume 1 pp. 1-1070 • Volume II p. 1071-2546
xviii
INDEX
Central nervous system {Continued) computed tomography of, 1594, 1595f diagnosis of, 1594 outcome of, 1594 lymphoma of AIDS related, 562f, 563, 1418, 1594 characteristics of, 534, 536f, 562f, 563, 837 epidemiology of, 1333 Fpstein-Rarr virus and, 1359 histologic findings, 1359 imaging of, 1381, 1384f-1385f management of, 1418 methotrexate for, 1405 radiation therapy for, 1418 malformations of, 1764 anencephaly, 1776, 1777t brainstem, 1774 cephalocele, 1776, 1777t, 1778 cerebellar development, 1786-1788 cerebellar hypoplasia, 1787f, 1787-1788 Chiari, 1786-1787 colpocephaly, 1783 corpus callosum agenesis, 564, 564f, 1777t, 1782-1783 Dandy-Walker malformation, 1786 description of, 1773-1775 ectopic gene expression, 1782 e nc eph a loce le, 1776 forebrain, 1779-1783 hemimegalencephaly, 1785-1786 ho I oprosen cep haly. sec Holo prosencephaly isolated arrhinencephaly, 1781 Kallmann syndrome, 1781 meningomyelocele, 1776, 1777t, 1778-1779 midline, 1779-1783 Miller-Dicker syndrome, 8 11, 1767, 1777t, 1784-1785 molecular generic classification of, 1775-1776 neuroblast migration, 1783-1786 neurulation stage, 1776-1779, 1777t rachischisis, 1778 rhombomeric deletions, 1782 schizencephaly, 567, 568f, 1769, 1785 selective cerebellar hemispheric aplasia, 1786 selective vermal aplasia, 1786 septo-optic-pituitary dysplasia, 1781-1782 spinal bifida, 1778-1779 spinal dysraphism, 1778 subcortical laminar heterotopia, 1785 Walker-Warburg syndrome, 804c, 1768, 1777t, 1785 metastases to brain, see Brain metastases Icptomcningcal. see Leptomcningcal metastases radiation therapy effects on, 1437 transplants, immunology of, 828 tuberculosis, 1940 vasculitis of cerebrospinal fluid tests fot, 1324 cerebrovascular amyloid and, 1326 definition of, 1323 description of, 1323
Central nervous system {Continued) diagnostic approach, 1324-1325 graft-versus-hosr disease and, 1326 herpes /.oster infection and, 1325 intravenous drug use and, 1325-1326 isolated, 1323-1324 lymphoma and, 1326 treatment of, 1325 viral infections of antiviral drugs for, 847 arboviruses, see Arboviruses arenaviruses, 1537-1538 diagnosis of antigen detection for, 845 criteria for, 845 immunofluorescenr Techniques, 844 immunological tests, 845 improvements in, 844 molecular techniques for, 845 polymerase chain reaction, 845-846 herpesviruses, see Herpesviruses historical studies of, 844 mumps, 832t, 1520t, 1537 pathogenetic stages of capillary endothelial cell infection, 840 central nervous system invasion, 840-841 entry, 838-839 neural spread, 841-842 neurotropism, 842 polarized infection, 839 receptors, 842, 843t spread, 839 systemic invasion, 839 target cell effects, 842-843 Trojan horse entry, 840-841 viremia, 839-840 rabies, see Rabies rubella, 832t, 835, 1537 supportive therapy for, 847 symptomatic therapy for, 847 symptoms associated with, 845 treatment of, 846-848 vaccines for, 846-847 Central nervous system lymphoma, 534, 536f Central neurocytoma characteristics of, 541, 542f, 1354 in children, 1429-1430 imaging of, 1381, 1383f management of, 1415 Central neurofibromatosis, 568-569 Central neurogenic respiration, 53 Central pattern generators, 324 Central pontine inyelinolysis, 553 Centra] retinal artery occlusion, 191 Central scotoma, 732 Central serous chorioretinopathy, 180 Centra! sulcus arteries, 634 Central tolerance, 819 Central vestibular disorders description of, 244 medical treatment of, 748 surgical treatment of, 748 Central visual field loss, 177-178 Centripetal nystagmus, 219 Ceil I ron uclcar myopathy, }78, 2500-2501 Cephalocele, 1776, 1777t, 1778
Cephalosporins, for bacterial meningitis, l4S()t Cerebellar asrrocytoma, 538 Cerebellar ataxia cognitive function assessments. 290 descriprion of, 287, 1663 features of, 327t gait disturbances in, 288, 327, 327t intention tremor in, 288 limb incoordination in, 288 muscle tone and strength abnormalities in, 289 neurological signs in, 288-290 nystagmus in, 289 oculomotor disturbances in, 289 pursuit disorders in, 289 saccadc disorders in, 289 signs and symptoms of, 329-330 speech function in, 289-290 stance disturbances in, 288 Cerebellar fits, 58 Cerebellar hemorrhage characteristics of, 1260t, 1262, 1262f diagnosis of, 964 headaches associated with, 2064 hydrocephalus caused by, 1759 magnetic resonance imaging of, 1262f, 1266f neurosurgical treatment of, 964-965 prognosis for, 965 signs and symptoms of, 964-965 Cerebellar infarction anterior inferior cerebellar artery syndrome and, 1205 bilateral suboccipital craniotomy for, 965 diagnosis of, 964 hydrocephalus caused by, 1759, 1760f neurosurgical treatment of, 964-965 prognosis fot, 965 signs and symproms of, 965 signs of, 240 vcrrigo and, 240 Cerebellar mutism syndrome, 1425 Cerebellar syndromes ataxia cognitive function assessments, 290 description of, 287 gait disturbances in, 288 intention tremor in, 288 limb incoordination in, 288 muscle tone and strength abnormalities in, 289 neurological signs in, 288-290 nystagmus in, 289 oculomotor disturbances in, 289 pursuit disorders in, 289 saccadc disorders in, 289 signs and symptoms of, 329-330 speech function in, 289-290 stance disturbances in, 288 falls associated with, 25-26 Cerebellar tremors, 2147 Cerebellitis, 1663 Cerebellopontine angle tumors, 240 I .; rvlvllnm degeneration of alcohol-related, 1706 description of, 1463 paraneoplastic, 2I71-2I72
INDEX
Cerebel lu in (C '.on tinned) developmental malformations of cramosynostosis, 17H8 Dandy-Walker malformation, 1786 description of, 1786 focal dysplasia, 1788 selective vermal aplasia, 1786 focal dvsphsia of, I 7NN hypoplasia o/, 1787f, 1 7 8 7 - 1 7 8 8 motor functions, 1045 Cerebral amoebiasis, 1566 Cerebral amyloid angiopathy central nervous system vasculitis a n d , 1326 description of, 1225 familial, 1937 intracerebral hemorrhage caused by, 1253,
Cerebral arteries [Continued) posterior a n a t o m y of, 636f branches of, 6 3 8 t course of, 6 3 7 fetal, 6 3 8 - 6 3 9 fetal origin of, 6 3 7 infarction of, 3 3 9 lesions of, 6 3 8 proximal, 6 3 7 PI segment, 6 3 7 P2 segment, 6 3 7 P3 segment, 6 3 8 Cerebral arteriography aphasia evaluations, 156 indications, 4 5 9
1255 vascular dementia a n d , 1937 Cerebral aneurysms computed tomography angiography of, 619, 621 management of, 9 5 7 Cerebral angiography arteriovenous malformations, 5 6 9 , 569f central nervous system vasculitis evaluations, 1324 headache evaluations, 2 7 0 indications, 5 3 0 - 5 3 1 intracerebral hemorrhage, 1252 leptomeningeal metastases evaluation, 1453 sleep disturbances and disorders evaluation, 2 0 4 2 stroke evaluations, 1234 technique for, 531 Cerebral arteries anterior anatomy of, 631 Al segment, 6 3 1 , 632f A2 segment, 6 3 1 , 632f azygous, 632
risk-to-benefit considerations for, 4 5 9 - 4 6 0 Cerebral arteriopathy with subcortical infarcts and leukoencephaloparhy, 805t Cerebral a u t o s o m a l d o m i n a n t arteriopathy with subcortical infarcts and leukoencephalopathy, 1 2 2 2 - 1 2 2 3 , 1937 Cerebral blood flow, 1676 brain death criteria, 64 ischemic interruption of, 1201 normal, 1201 regional
branches of, 6 3 1 , 632f-633f infarction of, 3 3 9 neurological symptoms, 6 3 2 variants of, 632 middle anatomy of, 636f aneurysms of, 619f, 6 3 5 branches of a n a t o m y of, 632f-633f, 634t variability in, 634 description of, 6 3 2 disorders of, 6351 infarction of, 3 3 8 - 3 3 9 , 570 M l segment anatomy of, 632f, 6 3 4 branches of, 634 course of, 634t M2 segment anatomy of, 632f, 6 3 4 branches of, 6 3 4 course of, 634t M 4 segmenr compromise of, 635t description of, 634t, 6 3 4 - 6 3 5 stenosis of computed tomographic angiography of, 6 1 9 magnetic resonance angiography of, 61 If
description of, 6 6 7 neurosciences critical care unit monitoring of, 9 4 6 subarachnoid h e m o r r h a g e effects o n , 1279 transcranial Doppler ultrasonography monitoring of, 9 4 5 - 9 4 6 Cerebral circulatory arrest, 6 6 2 - 6 6 3 Cerebral contusion, 5 5 4 , 555f, 1116 Cerebral cortex cognition tole of, 6 5 - 6 6 fetal, 1 7 7 3 lesions of, 67 malformations of, 1 7 7 3 - 1 7 7 4 modules of, 65 neuroanatomy of, 6 5 - 6 6 organization of, 6 5 - 6 6 sensory pathways, 4 0 9 visual processing in, 701 voltage potential at, 4 6 6 Cerebral edema acute m o u n t a i n sickness and, 1755 brain t u m o r s a n d , 1 3 6 6 - 1 3 6 7 hypoxia a n d , 1 6 6 7 - 1 6 6 8 management of, 1 3 6 6 - 1 3 6 7 neurosciences critical care unit management of, 9 5 6 - 9 5 7 vasogenic, 1 3 6 6 - 1 3 6 7 Cerebral embolism, 1212 Cerebral embolization, 1102 Cerebral gigantism, 1112 Cerebral infarction acquired immunodeficiency syndrome-related, 1219 description of, 5 7 0 - 5 7 1 , 571f, 1 1 9 7 - 1 1 9 8 infectious causes of, 1219 niliei i r LL! disorders lli.il cause, 1 2 2 3 - 1 2 2 6 lacunar, 1201 in malignancies, 1229 of undetermined cause, 1232 pathologic changes associated with, 1201 stroke caused by, 764
xix
Cerebral ischemia carotid artery syndromes, 1 2 0 3 - 1 2 0 5 crescendo episodes of, 1203 focal, 1666 headaches caused by, 2 0 6 4 - 2 0 6 5 parhophysiology of, 1201 posirron emission tomography evaluations, 670 single-photon emission computed t o m o g r a p h y evaluations, 670 syncope caused by, 1074 transient ischemic attacks, see Transient ischemic attacks Cerebral lesions electroencephalography evaluations, 4 7 2 , 4"li hemiplegia caused by, 3 3 7 - 3 4 0 monoplegia caused by, 3 3 7 sensory abnormalities caused by, 4 1 3 Cerebral mycotic aneurysms, 1077, 1077f Cerebral oximetry, 946 Cerebral oxygenation, 1137 Cerebral palsy diagnosis of, 1791 epidemiology of, 1791 etiology of, 1 7 9 1 - 1 7 9 2 imaging in, 1792 mental retardation a n d , 1794 m o t o r evoked potenrials in, 4 8 7 periventricular leukomalacia, 1791-1792 risk factors for, 179 I treatment of, 1792 Cerebral perfusion pressure, 9 5 5 , 1137 Cerebral salt wasting, S65 Cerebral steal, 1289 Cerebral vasculitides brain biopsy for, 9 8 7 classification of, 1215t Cerebral vasculitis, 1218 Cerebral vasospasm angioplasty for, 9 6 9 , 970f calcium-channel blockers for, 9 6 9 mechanical therapies for, 1 0 0 9 - 1 0 1 1 subarachnoid hemorrhage and description of, 6 6 1 - 6 6 2 , 9 5 7 , 9 6 9 treatment of, 1 0 0 9 - 1 0 1 1 symptoms of, 1009 syncope caused by, 16 Cerebral veins cortical, 6 3 9 deep, 6 3 9 - 6 4 0 Cerebral venous thrombosis anticoagulants for, 2 5 4 3 in children, 1 2 4 4 - 1 2 4 5 description of, 1230, 1 2 4 3 - 1 2 4 4 epidemiology of, 2 5 4 3 pregnancy a n d , 2 5 4 3 signs and symptoms of, 1245 Cerehritis description of, 559 Listeria, 1 4 8 3 - 1 4 8 4 Cerebrospinal fluid absorption of, 1 7 4 9 - 1 7 5 0 , 17501" African trypanosomiasis findings, 1563 amoebic infection findings, 1565 arachnoid granulations, 1 7 4 9 - 1 7 5 0 bacterial meningitis of. see Bacterial meningitis
V o l u m e 1 p p . 1-1070 • V o l u m e II p. 1071-2546
xx
INDEX
Cerebrospinal fluid {Continued) central nervous system vasculitis tests, 1324 central nervous .system viral infections tests, 846 Chiari malformations, 564-566, 565f-566f choroid plexus production of, 1748 coma evaluations, 47 (iivurztrUr-l.ikiib disr.ise findings, 1942 cysticcrcosis findings, 1570-1571 cytomegalovirus encephalitis findings, 1591-1592 drainage of, 1138 drugs that affect production of, 1749 encephalitis findings, 833-834 fistulas, 1128 fungal infection findings, 1550-1551 headache evaluations, 270, 2058-2059 herpes simplex encephalitis findings, 1518 human herpesvirus-rype 6 findings, 1526-1527 human immunodeficiency virus-associated progressive encephalopathy findings, 1609 human immunodeficiency virus-related dementia findings, 1589 in horn errors of mem holism findings, 1812t, 1812-1813 JC virus in, 1539 laboratory studies of, 1745-1746 Lance-Adams syndrome findings, 2162 leak of, 1161, 2058 lepromeningeal metastases evaluation, 1451-1453 Lyme disease findings, 1499 lymphocytosis, 2059-2060 malaria findings, 1561 mitochondrial disorder evaluations, 1839-1840 muckarmine staining of, 155If multiple sclerosis findings, 1650-1651 neuropathy evaluations, 413 neurosyphilis findings, 1497-1498 obstruction of, 20-21, 1746, 2058. see also Hydrocephalus paraneoplastic necrotizing myelopathy findings, 1465 parasitic infection evaluations, 1559 poliovirus findings, 1528 prion disease evaluations, 1624 production of, 1748-1749 protein level, 1452 relapsing fever findings, 1500 rhinorrhea, 856 shunting of, 981 syphilis findings, 1496 syringomyelia and, I 162 tabes dorsalis findings, 2278 tuberculosis meningitis findings, 1491-1492 tumor markers in, 1452, 1452t ventriculoencephalitis findings, 1592 West Nile virus findings, 1530 Cerebrospinal fluid pressure, 1750 Cerehrotendinous xanthomatosis biochemical features of, 1889-1890 clinical features of, 1889t description of, 803t, 1889
Cerebrotendinous xanthomatosis (Continued) neurological features of, 1889 petipheral neuropathy in, 1889 treatment of, 1890 xanthomas, 1889 Cerebrovascular ischemia, syncope caused by, 15-16 Cerebrovascular reactivity, 658 Cerebrum abscess of, 559 blood vessels of, 1746-1748 capillaries of, 1748t glucose metabolism in, 1684 hemorrhage in, 571, 573f, 573t hypoplasia of, 1765f infections of, 558-560 metastases, 534, 536-537 venous system of, 639-643 Ceroid lipofuscinosis, infantile, 803t Ceruloplasmin, 1812t Cervical collar, 1164-1165 Cervical myalgias, 2070 Cervical myelitis, 436 Cervical nerve root lesions, 354t Cervical radiculopathy clinical presentation of, 2205-2206 computed Tomography of, 2206, 2206f description of, 346t diagnosis of, 2206 magnetic resonance imaging of, 2206 symptoms of, 2205-2206 treatment of, 2206-2207 Cervical spine atlantoaxial dissociation/dislocation, 1153 fractures of burst, 586 clay shoveler's, 585 hangman's, 585, 585f Jefferson, 585-586, 586f odontoid, 586-587, 587f headaches and, 269, 2070-2071 intcrfacctal dislocation bilateral, 584 unilateral, 584, 584f osteoarthritis of, 2207 radiographic evaluation of, 1164 rheumatoid arthritis of, 441 stenosis of, 583-584 Cervical spondylosis description of, 2205 lower motor neuron involvement considerations, 986 motor evoked potentials in, 486, 487f motor radiculopathy vs., 986 motor system disease and, 986 neck pain caused by, 436-437 neurosurgical treatment of, 986-987 spinal cord injury caused by, 1152 Cervical spondylotic myelopathy, 2207 Cervicocephalic arterial dissection, 1215, 1216f, 2065 Cervicocephalic fibromuseular dysplasia, 1218, I218f Cervicogcnic headaches, 2071 Ccrvicoiucdullary junction abnormalities, 2194-2196 Cervicomedullary syndrome, 1154-1155, 1155f
C fibers, 426 Chagas' disease, 1564, 2412 Chamberlain's line, 2190f Chance fracture, 592, 592f Ch a myelopathies Andersen's syndrome, 2490 autosomal dominant nocturnal frontal lobe epilepsy, 1848t, 1862 benign familial neonatal convulsions, 1848t, 1862-1863 characterisrics of, 1848t definition of, 2463 description of, 2486 familial episodic ataxias clinical features of, 1859 definition of, 1859 diagnosis of, 1860 forms of, 1859 myokymia associated with, 1859 pathophysiology of, 1859-1860 treatment of, 1 860 familial hemiplcgic migraine clinical features of, 1848t, 1857 description of, 1222, 1305 diagnosis of, 1858-1859 genetic mutations associated with, 1857-1858 pathophysiology of, 1857-1858 treatment of, 1859 generalized epilepsy with febrile seizures, 1863-1864 hereditary hyperekplexia clinical features of, 1848t, 1860 diagnosis of, 1861 genetic mutations associated with, 1860-1861 pathophysiology of, 1860-1861 signs and symptoms of, 1860 treatment of, 186 1 myoclonic epilepsy familial adult-onset, 1864-1865 severe myoclonic epilepsy of infancy, 1864 myotonia congenita clinical features of, 1851t, 1853-1854, 2490-2491 description of, 1848t diagnosis of, 2491 myotonia fluctuans, 2490 paroxysmal dyskinesias, 1864 periodic paralysis Andersen/Tawil syndrome, 1848t, 1852, 1855-1856 hyperkalemic clinical features of, 1851c, 1852, 2489 diagnosis of, 1852 mutations associated with, 1849f pathophysiology of, 1852 secondary, 2490 treatment of, 1853 hypokalemic clinical features of, 1850-1851, 1851t, 2487-2488 description of, 8031 diagnosis of, 1851-1852 genetic mutations associated with, 1851 onset of, 2487 pathophysiology of, 1851 prevalence of, 1850 secondary forms of, 1851-1852, 2488
INDEX Channelopathies (Continued) treatment of, 1852 type 2, 2490 Ch a re ot-M a ne -Tooth disease complex forms of, 2321 diagnostic resting for, 2324-2325 electrophysiological studies of, 2323-2324 genetics of, 783, 794f, 803t history of, 2319 linkage analysis in, 799-800, 800f molecular advances in, 2321-2322 myelin gene mutations in, 2322f, 2322-2323 nerve conduct ion srudies of, 501, 2324 pedigree of, 782f point mutations in, 2324 pregnancy issues, 2535 prevalence of, 2319 treatment of, 2325 type 1, 2319-2320, 2321f type 2, 2320-2321, 2323 type 3, 2321 rypc 4, 2321 weakness associated with, 380-381, 872 x-linkcd, 2321 Chediak-Higashi syndrome, 738 Cheiralgia paresthetica, 2315 Cheiro-oral migraine, 2073 Cheiro-oral syndrome, see Opercular syndrome Chemokincs description of, 815-816 immune response regulation by, 817 Chemosensory systems, 257 Chemotherapy agents for cyrarabine, 1454-1455 tyrosine arabinoside, 1454 methotrexate, 1454 thiotcpa, 1404, 1455 anaplastic astrocytomas treated with, 1413 astrocytomas treated with, 1412 ataxia caused by, 2169-2170 blood-brain barrier passage of, 996 bone marrow suppression caused by, 1438 brain metastases treated with, 1446 hram tumots treated with, 1404, 1407-1408 in children, 1438 epidural spinal cord compression treated with, 1449-1450 esthes in neuroblastoma treated with, 1416 germ cell tumors treated with, 1419 germinomas treated with, 1419 gliomas treated with, 975 hemangiopericytomas treated with, 1417-1418 intrathecal delivery of, 1454 leptomeningeal metastases treated with, 1454-1455 low-grade astrocytomas treated with, 1412 medullohlastoma treared with, 1416 oligodendrogliomas treated with, 1414 peripheral neuropathy caused by, 1438 pineoblastoma treated with, 1415 primitive neuroectodermal tumors treated with, 1425-1426 spinal tuberculosis treated with, 1492
Cheyne-Stokcs brearhing, 2018 Chcyne-Srokcs respiration, 52, 53f Chiari malformations clinical features of, 2192-2193 definition of, 1786 drop attacks associated with, 25 esotropia associated with, 201 history of, 2192 hydrocephalus and, 1162 magnetic resonance imaging of, 564-566, 565f pathogenesis of, 1786-1787 periodic alternating nystagmus caused by, 219 type 1, 564, 565f, 1786, 2192-2193 type II, 565-566, 566f, 1786, 2193 type IV, 2193 Chief complaint, 4 Childhood onset jienenili/ed primary dystonia, 312, 2155-2156 Children, see also Infant; Neonate abducens nerve palsy in, 2112 adrenal gland dysfunction in, 1111 alternating hemiplegia in, 340 attention deficit hyperactivity disorder in clinical features of, 1802-1803 diagnosis of, 1802, 1802r dyslexia and, 1798 etiology of, 1803 evaluation of, 1803 genetic factors, 1803 prevalence of, 1 802 psychostimulants for, 1803, I803t signs of, 1803t Tourctte's syndrome and, 95, 692 treatment of, 1803, 1803t autistic spectrum disorders in clinical fearures of behaviors, interests, and activities, 1796-1797 cognition, 1795 communication disorders, 1796 intelligence, 1795 language, 1796 social dysfunction, 1796 social skills, 1796 developmental language disorders vs., 1794 diagnosis of, 1794-1795 etiology of, 1797 evaluation of, 1797 genetic findings, 1794-1795 hereditary factors, 1794 incidence of, 1794 medications for, 1798t neuropathology associated with, 1797 outcome studies of, 1795 symptoms of, 1795 treatment of, 1797 tuberous sclerosis and, 1797 brain abscess in, 1102 brain death in, 1670 cancer in, 1302 cardiac disorders in acquired heart disease, 1102-1103 aortic stenosis, 1101-1102 congenital heart disease, 1101-1102 diagnostic techniques, 1103 hypoplastic left heart syndrome, 1102 surgical interventions for, 1103
xxi
Children (Continued) ventricular arrhythmias, 1102 cardiac transplantation in, 1103 cavernous malformations in, 1300 chemotherapy effects, 1438
connective tissue diseases Behcet's disease, 1105-1106 Churg-Strauss syndrome, 1104 Cogan's syndrome, 1106 juvenile rheumatoid arthritis, 1104-1105 mixed, 1105 Sjogren's syndrome, 1106 systemic lupus erythematosus, 1105 Takayasu's atteritis, 1104 Wegener's granulomatosis, 1104 diabetes mellitus in, 11 12 dizziness in, 241 gastrointestinal disorders in hepatic encephalopathy, 1109, 1109c Whipple's disease, 1110 go n a dotro p i n - relea si ng h or m on c deficiency i n , 867
headaches in, 2103-2104 hematological disorders in aplastic anemia, 1107 hemolytic disease of the newborn, 1107 hemophilia, 1108 hemorrhagic disease of the newborn, 1108-1109 neonatal polycythemia, 1108 sickle cell disease, 1107-1108, 1300, 1301f thrombocytopenic purpura, 1108 thrombotic thrombocytopenic purpura, 1108 human immunodeficiency virus in CD4+ Tcell count, 1606 clinical approach to, 1605-1606 clinical features of, 1606 diagnosis of, 1605-1606 epidemiology of, 1603-1604 global prevalence of, 1604 highly active antiretroviral therapy for, 1610 incidence of, 1603, 1604f intracerebral hemorrhage, 1609 laboratory monitoring, 1605-1606 neurodevelopmenral abnormalities in, 1603 neurological disorders, 1607 nonhemorrhagic infarctions, 1609 nucleotide reverse transcriptase inhibitors for, 1610 parenterally acquired infection, 1604-1605 perinatal transmission, 1603 plasma viral load determinations, 1605-1606 pregnancy prophylaxis, 1610-1611 prevention of, 1610-1611 prognosis for, 1610 progression of, 1606 progressive encephalopathy, 1607-1609 sexual transmission, 1605 stroke in, 1609-1610 symptom categories for, 1607t treatment of, 1610 trends in, 1603-1604 vertical transmission of, 1604
Volume 1 pp. 1-1070 * Volume II p. 1071-2546
xxii
INDEX
Children {Continued) hydrocephalus in, 1758-1759 hyperthyroidism in, 1110-1111 intracranial hemorrhage i n , 1308 ischemic stroke in, 1211 Leber's congenital amaurosis i n , 737—738 liver transplantation in, 1109-1110 mcdulloblastoma in, 1355 migraines i n , 2103-2104 nervous system tumors in astrocytomas characteristics of, 1426, 1426t juvenile pilocystic, 1426-1428 subependymal giant cell, 1428-1429 atypical teratoid/rhabdoid tumor, 1426 brainstem, 1427t central neurocytoma, 1429-1430 choroid plexus tumors, 1434 colloid cyst of the third ventricle, 1430 craniopharyngioma, 1434-1435 description of, 1423-1424 desmoplastic cerebral astrocytoma of infancy, 1429 dysembryoplastic neuroepithelial rumor, 1429 ependymomas, 1432-1433 ganglioglioma, 1429 germ cell tumors, 1435-1437 high-grade astrocytomas, 1432 optic pathways gliomas, 1381, 1382f, 14.51 1432 pineoblastoma, 1435 primitive neuroectodermal tumors, 1424-1426 subependymal giant cell astrocytomas, 1428-1429 treatment effects, 1437-1438 obstructive sleep apnea syndtome i n , 2037 ocular motor apraxia in, 714 opsoclonus-myoclonus in, 1464 parathyroid disorders i n , 1111 pituitary disorders i n , 1111-1112 radiation therapy effects, 1437-1438 renal failure i n , 1112-1113 respiratory diseases apnea, 1106 bronchopulmonary dysplasia, 1106 cystic fibrosis, I 106 periodic breathing, 1106 sarcoidosis in, 1106-1107 sexual abuse of, 1605 spinal cord injury in, 1163 stroke in, 1211 bleeding disorders risk, 1300 cardiac causes, 1303 clinical presentation of, 1302-1303 congenital heart disease risks, 1300-1301 differential diagnosis, 1305 Down syndrome, 1302 drug-related causes, 1304 epidemiology of, 1299-1302 evaluation of angiography, 1307 cardiac-based, 1308 computed tomography, 1307 electroencephalogram, 1308 history-taking, 1305-1306 imaging studies, 1306-1307
Children {Continued) laboratory tests, 1308 magnetic resonance imaging, 1307 physical examination, 1305-1306, 1306t-1307t extracorporeal membrane oxygenation risks, 1300 future of, 1310 genetic evaluations, 1308 hematological causes, 1303 high-risk subgroups for, 1300-1302 imaging studies, 1306-1307 infectious causes, 1303-1304 metabolic causes of, 1304-1305 migraines, 1304 neonates, 1299 neurofibromatosis, 1302 outcomes, 1309-1310 pregnancy concerns, 1309 premature infants, 1299 prognosis, 1310 seizures associated w i t h , 1302-1303 trau ma-tela ted, 1303, 1304f treatment of acute, 1308-1309 chronic, 1309 ultrasound evaluations, 1306-1307 vascular malformations and, 1304 syncope i n , 12 tension-type headaches in, 2104 thyroid disorders in, 1110-1111 Tourette's syndrome in, 691 vertigo i n , 241 vision loss in, 737t Chin tremor, 2161-2162 Chlamydial diseases, 1506-1507 Chlamydia pneumoniae, 1200, 1219 Chloramphenicol bacterial meningitis treared w i t h , 1480t neuropathy caused by, 2382 Chloride channels in cystic fibrosis, 914 description of, 914 disorders associated w i t h , 9111 Chloroquin phosphate, 1556t, 1566, 2382-2383 Chlorpromazine, for spasticity, 1055t Cholccystokinin characteristics of, 904—905 description of, 85Or disorders associated with, 903t dorsal root ganglion neurons, 904 mutations of, 903t receptors, 904 Cholesterol, 1198-1199 Cholesterol emboli syndrome, 1225 Cholesterol ester storage disease, 1822t Choline magnesium tri sal icy I ate, 932t Cholinesterase inhibitors adverse effecrs of, 2448 description of, 1925-1926 Lambert-Eaton myasthenic syndrome treated w i t h , 2457 myasthenia gravis treated w i t h , 2447-2448, 2448t Cholincstcrases, 890 Chondrosarcoma, 575 Chorda tympani, 263 Chordoma, 574-575, 575f-576f
Chorea age of onset, 308 ballismus, 2153-2154 benign hereditary, 2153 characteristics of, 306-307 dentatorubral-pallidoluysin atrophy, 2152 etiological classification of, 308t examination for, 309 finger-to-nose testing in, 309 gait disturbances in, 308 hereditary, 3081 history-taking clues, 308 I liiiiin,i',inn\ disease, see Huntington's
disease investigative apptoach to, 319-320, 320t onset of, 308 senile, 2154 stereotypics associated w i t h , 307 Sydenham's characteristics of, 2153 diagnostic clues, 308 movements in, 306-307 symptoms of, 307-308 tardive dyskinesia vs., 309 Chorea gravidarum, 2536 Choreic gair, 332 Choreiform movements, 309 Choreoathctosis, 1103 definition of, 307 paroxysmal, 318 Choriocarcinoma, 977, 1360, 2537 Chorionic gonadotropin, 852t Chorioretinitis, 78t Choroidal artery, 637f Choroidal melanoma, 578, 578f Choroidal point, 635 Choroideremia, 80 51 ( l i o m i d plexus anatomy of, 1748-1749 carcinoma, 1353, 1415 cerebrospinal fluid producrion by, 1748 functions of, 1748 papilloma characreristics of, 3 352-1353 in children, 1434 imaging of, 1384, 1387f management of, 1415 Chromatolysis, 2300 Chromosomal aberrations description of, 785-786 D o w n syndrome, 785-786, 786f-787f two-hit phenomenon, 786 Chromosomal translocation, 785 Chromosome jumping, 798 Chromosome I p , 1347 (:hroniosome I 7p, 792 Chromosome 19q, 1347 Chromosome walking, 798 Chronic adhesive arachnoiditis, 2219-2220 Chronic fatigue syndrome, 2034 Chronic idiopathic agonal polyneuropathy. 2308 Chronic idiopathic demye I mating polyradiculoneuropathy, 2235 Chronic inflammatory demye I in a ting polyneuropathy, 825-826, 1593t
INDEX Chronic inflammatory demyelinating polyradiculoneuropathy algorithm for, 2349f azathioprinc for, 2349 clinical features of, 2.145-2346 corticosteroids for, 2347 description of, 2.145 diagnostic criteria, 2346t epidemiology of, 2345 human immunodeficiency virus, 2387 immunoglobulin G for, 2348 laboratory studies, 2346-2347 magnetic tesonance imaging of, 2347f plasma exchange for, 2348 prevalence of, 2345 prognosis for, 2349 treatment of, 2347-2349 variants of, 2345-2346 Chronic obstructive pulmonary disease, 2033 Chronic pain evaluative approach to, 930 neurosurgical Treatment of, 982-983 NMDA receptors and, 925 Chronic progressive encephalopathy, 402 Chronic progressive radiation myelopathy, 1447 Chronic wasting disease, 1618 Churg-Strauss syndrome in adults, 1079-1080 in children, 1104 description of, 2370 Cidofovir, 1525 Ciguatera fish poisoning characteristics of, 1736t cigua toxins, 1736-1737 clinical features of, 1737 description of, 1736 diagnosis of, 1737 history of, 1735 incidence of, 1736 signs and symptoms of, 1737 treatment of, 1737 Ciprofloxacin, salmonellosis treated with, 1506 Circadian rhythms description of, 855, 1999-2000 disorders of, 2024, 2046-2047 Circle of Willis abnormalities that affect, 639 anatomy of, 639 components of, 639, 640t endovascular treatment considerations, 639 transcranial Doppler ultrasonography of, 654 vessels of, 639, 640t Circumscribed astrocytomas, 1349 Cisapride, 2435 Cisplatin, 2383 Cisplatin, 1406 Cisternogram, 981 Cisternography, 1761 Citicoline, 1006 Classical conditioning, 71 Claude's syndrome, 1206, 2108t Claudication, 449r, 4.55, 1078 Clay shovclcr's fracture, 585 Clindamycin, for toxoplasmosis, 1593
Clinical trials design of, 1039-1040 drugs, 915 measures for, 1039-1040 thrombolytic rherapy, 1006-1008 Clinoril. see Sulindac Clobazam, 1982t Clock drawing test, 683-684, 685f Clonazepam, 1654, 1981, 1982t, 2047 Clonic seizures, 18 Clonidine, 1055c, 2426 Cloning, positional, 802 Clopidogrel, 1235 Clopidogrcl hi sulfate, 999 Closed lips, 1769 Closed lip schizencephaly, 567, 56Hf Clostridium bntulinum, 1508, 2459. see also Botulism Clostridium difficile, 953 Clostridium tetani, 1510. see also Tetanus Clozapine, dementia with Lewy bodies treated with, 1926 Clubfoot, 396 Clumsy-hand syndrome, 34It Cluster breathing, 53 Cluster headaches chronic, 2093-2094 classification of, 2090 clinical features of, 2090-2091 description of, 266-268, 2090 diagnosis of, 2092 epidemiology of, 2092 gastrointestinal disturbances and, 2091 laboratory studies of, 2091 onset of, 2091 pain associated with, 2091 pathophysiology of, 2091-2092 periodicity of, 2090 prophylactic therapies, 2093-2094 surgical treatment of, 2094 treatment of, 2092-2094 Cluttering, 1804-1805 Coagulation factor deficiency, 1303 Coarctation of the aorta, 1079 Cobb's syndrome, 1318 Cocaine abuse of, 1722-1723 dependence on, 1722-1723 intracerebral hemorrhage caused by, 1257 left putaminal hemorrhage caused by, 1257f maternal use of, 1304 neuropathy caused by, 2382
seizures caused by, 1722 stroke and, 1304, 1722, 1725 Cocddioides immitis, 1547t, 1548 Coccidioidomycosis, 1545 Cockayne's syndrome, 1897-1898 Cocktail parry syndrome, 1806 Codeine, 934t Coenzyme A, 1696 Coenzyme Qjn, 1834 Coffin-Lowry disease, 805t Cogan's syndrome, 240, 1106, 1220 Cognition anticonvulsant effects on, 695 cerebral cortex's role in, 65-66 description of, 65 neural basis of, 65-68
xxiii
Cognition {Continued) systemic lupus erythematosus effects, IDS;
white-matter lesion effects, 1933 Cognitive dysfunction brain tumors and, 1364 delirium and, 31-32 psychogenic, 1364 Cognitive impairment Alzheimer's disease, 114 dementia-related, 1902 depression, 114 diseases associated with, 1934t drug-induced, 1902 folate deficiency and, 1697 human immunodeficiency virus, 696, 697f Huntington's disease, 690 mild Alzheimer's disease and, 685, 1908 amnestic, 1908 criteria for, 685 heterogeneity of, 685 neuropsychological characteristics of, 684-686 outcome of, 684-685 prevalence of, 684 multiple sclerosis, 692, 1639, 1655-1656, 1945 traumatic brain injury, 697 vascular definition of, 687 neuropsychological findings, 687-688 vascular dementia, 1931-1932, 1935 Cogwheel pursuit, 205 Cohort study, 1334 Coital headache, 2071-2072 Colchicine, 2383 Cold injury, nerve injuries caused by, 1188 Cold-stimulus headache, 2099 Collct-Sicard syndrome, 2120t Colloid cysts characreristies of, 1361 magnetic resonance imaging of, 543, 543f, 1384, 1388f third ventricle, 24-25, 964f, 1430 Coloboma, optic nerve, 190 Colorado rick fever virus, 832t, I531t, 1533 Color flow imaging carotid arteries, 652 description of, 649 vertebral arteries, 65.3 Color vision testing, 730 Colpoccphaly, 1783 Coma abdominal conditions in, 45 adrenal function tests in, 60-61 alpha, 474, 475f, 1670 ,i:i\k-
cardiopulmonary arrest-related, 1668-1669, 1669t delayed deterioration, 1668 description of, 1666-1667 epilepsy after, 1668 managemenr of, 1671-1672 memory acquisition, 1667 movement disorders, 1668 persistent vegetative state, 1667 recovery from, 1667 sequelae of, I66S barbiturate-induced, 957, 957t Volume I pp. 1-1070 • Volume I] p. 1071-2546
xxiv
INDEX
Coma {Continued) behavioral states eon fused with, 44 brain death criteria, 63 brain herniation, 5 8 - 5 9 cardiac arrest, 1075 causes of, 46t cerebrospinal fluid evaluations, 47 clinical approach and tests for description of, 45 electrocardiography, 61 electroencephalography, 62 evoked potentials, 62 general examination, see C o m a , examination for intracranial pressure monitoring, 62 laboratory studies, 6 0 - 6 1 , 611 magnetic resonance imaging, 62 neurological examination, see C o m a , neurological examination neuroradiology imaging, 6 1 - 6 2 prognosis, 62-63 rapid initial examination, 45 decerebrate posturing in, 5 7 - 5 8 decorticate posturing in, 58 deep venous thrombosis risks, 1139 definition of, 43 differential diagnosis, 5 9 - 6 0 emergency therapy of, 4 5 - 4 6 examination for abdominal, 50 blood pressure, 48 body temperature, 4 8 - 4 9 cardiac, .50 eyes, 49 general appearance, 49 head and neck, 49 heart rate, 48 hypertension, 48 integument, 50, 511 lymph nodes, 50 meningismus, 49 neurological, see Coma, neurological examination oral, 50 otoscopic, 49 respiration, 48 temperature, 4 8 - 4 9 Glasgow Coma Scale, 5 2 , 52t, 63 glucose for, 45 hepatic, 1681 hypotension and, 48 hypothermia and, 49 intracranial pressure reductions by, 9 5 7 , 957t lesion localization, 50 lumbar puncture in, 46 medical history evaluations, 47—48 motor system evaluations in, 5 7 - 5 8 muscle tone evaluations description of, 58 toxic-metabolic vs. structural coma, 60 myoclonic jerking in, 58 neurological examination consciousness state, 5 1 - 5 2 description of, 50 ocular motility description of, 55 eye deviation, 5 5 - 5 6 eye movements, 56, 60 resting position of eyes, 55
Coma
(Continued) spontaneous eye movements, 56 pupil si/.e and reactivity, 5 3 - 5 5 , 55f purposes of, 50 respiration, 5 2 - 5 3 nonketotic h y p e r o s m o l a r 1 0 9 8 - 1 0 9 9 , 1685 nystagmus in, 56 opiate overdose-induced, 45 plantar reflex in, 58 postoperative causes of, 46t, 47 posturing in, 58 preceding symptoms, 47 presentation of, 47 prognosis, 6 2 - 6 3 pseudocoma characteristics of, 44t, 45 differential diagnosis, 60 respiratory patterns in, 5 2 - 5 3 , 53f structural, 5 9 - 6 0 toxic-metabolic, 5 9 - 6 0 traumatic, prognosis for, 63 C o m a vigil, 67 Combivir, l.587t Comitant strabismus botulimim toxin for, 2 1 1 description of, 201 Communicating hydrocephalus, 5 7 2 - 5 7 3 Complementary D N A libraries, 7 9 7 Complement system, 8 1 0 Complex absence seizures, 18 Complex partial seizures, 18, 19t Complex regional pain syndromes classification of, 9 2 7 contracture associated with, 928 description of, 4 4 0 H 4 1 diagnostic criteria for, 9 2 7 discovery of, 9 2 7 dystonia assuiinlrd wiifi, 1>1H features of, 9 2 7 natural history of, 928 neuropathic pain associated with, 9 2 7 nonsteroidal anti-inflammatory drugs for, 928 opioid analgesics for, 9 2 8 spinal cord stimulators for, 928 sympathetically maintained pain in, 928 treatment of, 9 2 8 type I, 9 2 7 type II, 9 2 7 - 9 2 8 C o m p o r t m e n t , l()4t C o m p o u n d muscle action potential aging effects, 4 9 6 amplitude of, 4 9 2 , 1189 area of, 4 9 2 axon loss moiioneuropathy findings, 4 9 9 decrcmenr in, 5 1 6 definition of, 491 demyelinative m o n o n c u r o p a t h y findings, 499 duration of, 492 F wave, 5 1 2 Lambert-Eaton myasthenic syndrome findings, 2 4 5 6 Martin-Gruber anastomosis effect on, 496-^97 in neuromuscular junction disorders, 5 1 7 t Compression peripheral nerve trauma caused by, 1186, 1187t
Compression (Continued) spinal cord acute, 9 6 7 animal models of, 1446 epidural (metastatic) bladder dysfunction in, 1447 bowel dysfunction in, 1447 characteristics of, 3 6 3 , 3 6 5 , 4 3 7 , 1374, 1374f, 1446 chemotherapy for, 1 4 4 9 - 1 4 5 0 clinical presentation of, 1447 corticosteroids for, 1449 decompressive laminectomy for, 1449 differential diagnosis, 1447r, 1447-1448 epidemiology of, 1446 imaging ol. 144X 144lJ magnetic resonance imaging of, 1448b, 1 4 4 8 - 1 4 4 9 management of, 1 4 4 9 - 1 4 5 0 niiitoi M stem im ol\ cineiir, I44~ osteoarthritis vs., 1448 pathology of, 1446 parbophysiology of, 1446 radiotherapy for, 1449 sensory loss associated with, 1447 vertebral corpectomy for, 1449 hematoma as cause of, 9 6 7 hemiplegia caused by, 342 metastatic epidural, 3 6 3 , 3 6 5 , 4 3 7 , 1374, 1374f neurosurgical treatment of, 9 6 7 - 9 6 8 pain associated with, 1171 paraplegia secondary t o , 1171 Compression fractures, 2 2 0 1 , 2201f Compulsion, I04t C o m p u t e d tomography clinical uses of acquired immunodeficiency syndrome, 560-563 aphasia, 156 arteriovenous malformations, 1289, 1290f basilar skull fractures, 1 I28f brain abscess, 1484 brain e d e m a , I753f brain metastases, 1443 brain t u m o r s , 1365 cavernous angiomas, 5 6 9 cervical radiculoparhy, 2 2 0 6 , 2206f cervical spine inrerfacetal dislocation, 5 8 4 , 584f-585f cortical infarction, 338 Creutzfeldt-Jakob disease, 5 5 0 - 5 5 1 cysticercosis, 1570f cytomegalovirus, 5 6 2 - 5 6 3 echinococcosis, 1572, 1573f Ehler-Danlos syndrome, 1878f encephalitis, 8 3 4 epidermoid cysts, 5 4 7 epidural abscess, 5 9 6 global developmental delay, 78 headache, 2 7 0 head t r a u m a , 5 5 4 hearing assessments, 746 herpes simplex encephalitis, 1518 hypoxic-ischemic brain injury, 2516f intracerebral hemorrhage, 1 2 5 8 - 1 2 5 9 intracranial aneurysms, 1 2 7 0 - 1 2 7 1 , 127lf
INDEX
Computed tomography (Continued) meningiomas, 543 middle cerebral artery, 1232f movement disorders, 551 multiple sclerosis, 1 6 4 9 - 1 6 5 0 nerve root avulsion, 2 2 7 0 norma I-pressure hydrocephalus, 1761 pituitary lesions, 865 primary central nervous system lymphoma, 1594, I595i progressive multifocal leukoencephalopathy, 5 6 2 seizures, 1 9 7 6 - 1 9 7 7 skull fractures, 11281 spinal cord injury, 1166 spinal stenosis, 451 stroke, 1307 Sturge-Weber syndrome, 1883f subarachnoid hemorrhage, 5 5 6 - 5 5 7 , 1271, 12731 subdural empyema, 1 4 8 7 , 14881 thalamic infarction and hemorrhage, 416 traumatic brain injury, 1135, 1 1 4 1 , 1141t tuberculous spondylitis, 595 uncal herniation, 62 visual agnosia, 1 36 wh ire-matter lesions, 1 9 3 2 - 1 9 3 3 contrast agents used with, 5 2 1 - 5 2 2 principles of, 5 2 1 - 5 2 2 spiral, 5 2 2 Computed tomography angiography advantages of, 6 1 7 applications of acute ischemic stroke, 6 1 8 - 6 1 9 carotid artery stenosis, 6 1 6 - 6 1 7 , 617f carotid dissection, 6 1 7 - 6 1 8 cerebral aneurysms, 6 1 9 , 621 internal carotid artery aneurysms, 620f-621f intracranial circulation, 6 1 8 - 6 2 1 middle cerebral artery stenosis, 619 steno-occlusive disease, 6 1 9 disadvantages of, 6 1 7 methods of, 616 Computcrized electroencephalography, 477-478 Conceptual apraxia in Alzheimer's disease-related dementia, 129 definition l, 123-124 knowledge impairments associated with, 129 pathophysiology of, 1 2 9 - 1 3 0 testing for, 129 Conceptual knowledge, 129 Concussion acceleration, 1116, 1143 athlete susceptibility t o , 1144 causes of, 1 1 4 3 - 1 1 4 4 grading scales for, 1 1 4 4 t - 1 1 4 5 t incidence of, 1 1 4 3 magnetic resonance imaging of, 1144 medical evaluation and management for, 1144 percussion, 1 1 1 5 - 1 1 1 6 postconcussion syndrome, 1 0 1 , 1144-1145 sequelae of, 1 1 4 4 - 1 1 4 5
xxv
Concussion (Continued) signs and symptoms of, 1 1 4 3 spinal cord, 1160 Conduction desynchromzed ski wing of, 4 9 9 focal slowing of, 4 9 9 Conduction aphasia, 149, 149t Conduction apraxia, 1 2 3 , 1 2 7 - 1 2 8 Conduction block axon loss, 5 0 0 , 500f dcmyelinating, 4 9 9 , 500f nerve conduction studies of, 4 l W, i()(!l Conduction velocity, 492-A94 Conductive hearing loss, 2 5 2 , 2531 Conformational diseases, 1616 Confusion, 104t definition of, 30 delirium a n d , 30 Confusional arousals, 2 0 3 5 Confusional states, 1 6 6 5 , 1902, 2 0 4 9 Confusion assessment method, 34 Congenital biliary atresia, 1109 Congenital fiber-type disproportion, 2 5 0 1 ,
Consciousness alterations in description of, 43 electroencephalography evaluations, 4 7 2 brain lesion effects o n , 67 coma assessments, 51—52 definition of, 43 delirium effects, 30 frontal cortex's role in, 67 left hemisphere, 68 loss of
2501 f Congenital heart disease, 1 1 0 1 - 1 1 0 2 , 1303 Congenital muscular dystrophy, 804t Congenital myasthenic syndromes characteristics of, 2455 description of, 1856 with episodic apnea, 2 4 5 5 - 2 4 5 6 quinidine for, 1856 slow-channel, 2 4 5 6 Congenital ocular motor apraxia, 7 1 4 Congenital stationary night blindness, 1848t Congenital vertical ocular m o t o r apraxia,
autonomic dysfunction a n d , 2 4 1 9 in multiple sclerosis, 1641 in Parkinson's disease, 2 9 6 , 4 2 5 in spinal cord disease, 761 Constraint-induced movement therapy, 1057-1058 Constructional praxis, 6 8 7 Contiguous gene deletion syndrome, 786 Continence, 4 2 0 , 1173 Continuous performance test, 52 Continuous perseveration, 121 Continuous-wave Doppler ultrasonography, 646 C o n t t a c t u r e s , 1051 Contralcsional response inhibition, 120 Contrast agents computed t o m o g r a p h y , 5 2 1 - 5 2 2 magnetic resonance imaging, 523 Contrast sensitivity testing, 7 2 9 - 7 3 0 Contusions cortical, 5 5 4 , 555f punctuate, 1129, 1130f signs and symptoms of, 1136 t r a u m a t i c brain injury, 1129, 1130f, 1136, 1136f C o n u s mcdullaris lesions, 3 6 2 - 3 6 3 , 363t C o n n s mcdullaris syndrome, 1 1 5 7 - 1 1 5 8 ,
714 Congestive heart failure, 9 5 2 Conjunctivitis, epidemic, 1529 Connective tissue diseases Behcet's disease in adults, 1 0 8 3 in children, 1 1 0 5 - 1 1 0 6 characteristics of, 1079 in children, 1 1 0 3 - 1 1 0 6 Churg-Strauss s y n d r o m e in adults, 1 0 7 9 - 1 0 8 0 in children, 1104 Cogan's syndrome, 1106 giant cell arteritis, 1080 mixed, 1105 neurological complications of, 1079 neuropathy in, 2 3 7 0 polyarteritis nodosa in adults, 1 0 7 9 - 1 0 8 0 , 1081f in children, 1 1 0 3 - 1 1 0 4 progressive systemic sclerosis, 1083 relapsing polychondritis, 1 0 8 3 - 1 0 8 4 rheumatoid arthritis in adults, 1080, 1082, 1082f juvenile, 1 1 0 4 - 1 1 0 5 Sjogren's syndrome in adults, 1083 in children, 1106 stroke risks, 1302 systemic lupus erythematosus in adults, 1 0 8 2 - 1 0 8 3 in children, 1105 Wegener's granulomatosis, 1080, 1104 Connexin-32, 2323
b re a rh -holding spells, 20 description of, 1 I intracranial pressure increases, 11 malingering considerations, 21 miscellaneous causes of, 20 seizure-re I a ted, see Seizures sleep disorders vs., 21 syncope, see Syncope neural basis for, 6 6 - 6 8 right hemisphere, 68 visual perception, 6 6 - 6 7 Constipation
1159f Convergence insufficiency, 7 2 2 Convergence paralysis, 722 Convergence retraction nystagmus, 215t, 223 Convergent divergent nystagmus, 216 Convulsive disorders description of, 767-7f>8 epilepsy, see Epilepsy seizures, see Seizures Convulsive syncope, 17 Copper metabolism disorders description of, 1827 M e n k e s ' kinky hair syndrome characteristics of, 805t, 1 7 7 3 , 1817t, 1828 clinical features of, 1887 connective tissue abnormalities in, 1887 copper replacement therapy for, 1888 cutaneous features of, 1 8 8 7 Volume I p p . 1-1070 • Volume II p. 1071-2546
xxvi
INDEX
Copper metabolism disorders (Continued) definition of, 1886-1887 genetic studies of, 1888 imaging of, 1888 infantile-onset, 1 S>87r neurological features of, 1887-1888 treatment of, 1888 Wilson's disease clinical features of, 2158 description of, S05t, 1828, 1929-1930 differential diagnosis, 319 dysphagia in, IT]-I 72 d; sionia in, 3 1 3 epidemiology of, 2 158 etiology of, 2158 family history of, 293 Kayser-Heisher rings in, 113, 294, 1930 kinky liair syndrome and, 1888 laboratory investigations for, 319, 320t pathogenesis of, 2158 pathology of, 2158 psychiatric disturbances in, 112 treatment of, 2158-2159 Coproporphyrin oxidase, 804t Cornea damage caused by insufficient eyelid closure, 229 opacity of, 78t Coronary artery bypass grafting description of, 1076 stroke after, 1213, 1214f Coronary heart disease, 1200 Coronaviridae, 84 31 Corpus callosotomy, for epilepsy, 1990 Corpus callosum agenesis of, I77t, 564, 565f, 1782-1783 dysgenetic, 18I7t lesions of, ideomotor apraxia caused by, 126 Cortical lesions bladder dysfunction caused by, 423 bowel dysfunction caused by, 423-424 hemiplegia caused by, 337-339 sexual dysfunction caused by, 454 Cortical reflex myoclonus, 1962 Cortical sign, 338 Corricobasal degeneration, 171, 1928, 2142 Corticobulbar tract, 2224 Cotticospinal tract axonal decussation in, 1155f description of, 337, 2224 dysfunction of, in multiple sclerosis, 1640 wallerian degeneration of, after stroke, 1043, 1043f Corticosteroids adverse effects of, 1076, 1110 bacterial meningitis treated with, 1482 brain abscess treated with, 1487 chronic inflammatory demyelmating polyradiculoneuropathy treated with, 2347 epidural spinal cord compression treated with, 1449 giant cell arteritis treated with, 1080, 2069 Guillain-Barre syndrome treated with, 2344-2345 herpes zoster treated with, 1524 increased intracranial pressure treated with, 1756
Corricosteroids (Cantinued) malaria uses, 1561 myasthenia gravis treated with, 2449-2450 neurological complications of, 1110 pain management using, 937 psychosis caused by, 36 relapsing polychondritis treated with, 1083-1084 sarcoidosis treated wttb, 2375 side effects of, 2449 varicella zoster virus treated with, 1522 West's syndrome treated with, 1966 Corticotropin, 852t Corticotropin-releasing hormone, 85Ot, 9031, 905 Corynebacteriuin diphtbenae, 1511, see also Diphtheria Cosmids, 797 Costimulatory molecules, 815-816 Cost-to-benefit analysis, for laboratory tests, 460 Cotton-wool spots, 191 I .ougll headache. 2(F I Cough syncope, 16 Counseling developmental regression treated with, 82-83 genetic, 802, 805, 874-875 tinnitus treated with, 255 Cover-uncover test, for diplopia, 207 COX-2 inhibitors, 93i Coxsackie virus, 832t, 1528-1529 Cramps definition of, 390 electromyography evaluations of, 391, 5()4t, 507 familial syndromes, 391t muscle weakness evaluations and, 374
neurogenic, 391 treatment for, 3911 Cranial arteritis, 1220-1221 Cranial epidural abscess, 1488, 1489f Cranial irradiation, for brain metastases, 1444-1445 Cranial mononeuropathies, 2362-2363 Cranial neuritis, 1499 Cranial neuropathy, 240 Craniectomy, 1139 Craniocervical junction lesions, 357 Craniofacial pain dental causes of, 2070 temporomandibular joint disorders, 2070 Craniopharyngioma
characteristics of, 546, 547f, S62, 1360-1361 clinical presentation of, 1434 illustration of, 547f, 9761" imaging of, 1400f, 1401 management of, 1419, 1434-1435 neurosurgical treatment of, 975-976
prognosis, 1435 Craniosynostosis, 1788 Craniotomy, 1135 C-tcactivc protein, 810 Creatine kinase muscle discomfort evaluations, 389 muscle weakness evaluations, 376
Creatine kinase {Continued) myoglobinuria findings, 376 racial considerations, 376 CREB, 70 Crcdc maneuver, 1052, 1655 CRUST syndrome, 2374 Cretinism, endemic, 1110 Creutzfeldt-Jakoh disease ataxia, 2171 behavioral disturbances associated with, 1941 brain biopsy for, 987 cerebellar involvement, 1941 cerebrospinal fluid findings, 1942 clinical features of, 1941-1942 computed tomography of, 550-551 definirion of, 194 I description of, 107-108 diagnostic criteria, 1942t differential diagnosis, 1943 duration of, 1941-1942 electroencephalography evaluations, 477, 477f, 1624 epidemiology of, 1614-1615, 1941 familial characteristics of, 1620t clinical features of, 1622-1623 differential diagnosis, 1623 epidemiology of, 1614, 1622-1623 genetics of, 1615 neuropathologic findings, 1619 phenotype, 1615, 1616t Heidenhain variant, 1619, 1943 history of, 1613-1614 iatrogenic characteristics of, 1620t clinical features of, 1622 description of, 1619, 1942 epidemiology of, 1622 imaging of, 1624 incidence of, 1941 laboratory tests, 1942 magnetic resonance imaging of, 527, 529f, 550-551, 1624, 1942, 1943f molecular biology findings, 1943 monitoring of, 1626 new variant amyloid deposits in, 1617, 1619 biopsies for, 1625 characteristics of, 1620t definition of, 108 description of, 1942 incidence of, 1615 neuropathology findings, 1619 psychiatric disturbances associated with, 108t Oppenheimer variant, 1619 peripheral neuropathy in, 2390 prevalence of, I 94 1
prevention of, 1626 psychiatric disturbances associated with, 108, 108t, 1941 scrapie, 1613-1614, 1618 signs and symptoms of, 1941 sporadic amyloid deposits in, 1617, 1619, 1625 characteristics of, 1620t clinical features of, 1621-1622 description of, 107-108
INDEX Creutzfeldr-Jakob disease (Continued) differential diagnosis, 1622 epidemiology of, 1621 14-3-3 protein test for, 1624 memory disorder associated with, 1622 ncuropathologic findings, 1619 signs and symptoms of, 1621-1622 stages of, 1621-1622 Stcrn-Garcia variant, 1619 transmission of, 1618, 1941
treatment of, 1627 Crick, Frances, 65-66 Cri du chat syndrome, 81t Critical illness neuropathy, 1084 Critical illness polyneuropathy, 2380 Crixivaii. see Indinavir Cross-cover test, for diplopia, 208 Crossed aphasia, 143, 154 Cruciate paralysis, 1154, 1156t Crush injuries, 1 1 S~ Cryoglobulinemia, 1088, 2355-2356 Cryoglobulins, 1088, 2355-2356 Cryptic malformation, 1287 Cryptococcal meningitis in AIDS patients, 1590-1591, 1593 description of, 1546 magnetic resonance imaging of, 1590f prognostic factors, 1591 treatment of, 1593t Cryptococcosis, 563, 563f, 1553 Oryptococcus, 1546 Cryptococcus tieoformans, 1547t, 1593t Cryptogenic falls, 26 CTLA4, 819 Cupulolirhiasis, 236 Cushing's disease, S60-861, 866, 1095 Cutaneous nociceptors, 921 CXCR-4, 817, 842 Cyanosis, breath-holding spells and, 20 Cyclical esotropia, 723 Cyclical oculomotor palsy, 723-724 Cyclical vomiting, 2104 Cyclic oculomotor palsy, 224 Cyclizine, for vertigo, 746t Cyclophosphamide, 1404, 1658-1659, 2373, 2450 Cyclosporine, 2450 Cyclovergent nystagmus, 216 Cylert. see Pemoline Cyproheptadine, 2085-2086 spasticity treared with, 1055t Cyst(s) colloid characteristics of, 1361 magnetic resonance imaging of, 543, 543f, 1384, 1388f third ventricle, 24-25, 1430 dermoid, 1361, 1393 epidermoid, 527, 530f, 547, J50f, 1361, 1393 hydatid, 1573f inrramedullary, 589f ovarian, 449t spinal cord, 588-589, 589f Cystarin C, 805t Cysticercosis albendazole for, 1572
cerebrospinal fluid findings, 1570-1571 charaeterisrics of, 560, 561f, 768-769, 1556t
Cysticercosis {Continued) clinical features of, 1569 computed tomography of, 1570f cysticerci, 1568-1569 definition of, 1568 diagnosis of, 1569-1571 encephalitic form, 1569 epilepsy caused by, 1970 global distribution of, 1568 intracranial pressure increases associated with, 1569 neurocysticercosis, 1568-1572 pathogenesis of, 1568-1569 pathologic findings, 1568-1569 prevention of, 1572 radiographic findings, 1570 serological tests for, 1570 signs and symproms of, 1569 transmission of, 1568 treatment of, 1571-1572 C A stic fibrosis chloride channels and, 914 neurological complications of, 1106 Cystic fibrosis gene, 788 Cystinosis, 1822t Cystometry, 751-753 Cytarabine, 1454-1455, 1521t Cytidinc analogs, 1405 Cytochrome P450, 1338 Cytokeratins, 1346 Cytokines bacterial meningitis and, 1482 blood vessel effects, 1752 brain edema and, 1752 brain tumors treated using, 1411 cerebral amyloid and, 1326 fever and, 853 hypothalamic role of, 851 immune response regulation by, 817 multiple sclerosis lesion, 1 634 synthesis of, 849, 851 traumatic brain injury and, 1122 viral infections treated with, 1521t Cytomegalovirus in AIDS patients, 562-563 antiviral therapy for, 1525 brain tumors and, 1338 cerebrospinal fluid findings, 1524-1525 congenital, 1524-1525, 2523 description of, 1524 encephalitis in AIDS, 1591-1592 description of, 1524f, 1525 foscarnet for, 847 ganciclovir for, 847 in immunocompromised patients, ^524-1525 neonatal, 2523 polymerase chain reaction diagnosis of, 1520t polyradiculitis, 836 polyradiculomyelitis, 1599-1600 polyradiculoneuropathy, 2278, 2279f, 2389 treatment of, 1525 viral characteristics of, 832r Cytosine arabinoside, 1405, 1454 Cytotoxic brain edema, 1752-1755 Cytotoxic T cells, 810 Cytotoxins, brain tumors treated using, 1411
xxvii
D Dandy-Walker malformation, 1786 Dandy-Walker syndrome, 566, 567f, 2058 Danon disease, 1822t Dantrolene neuroleptic malignant syndrome Treated with, 854 spasticity treated with, 1055t, 1654 Dapsone, 2383 Dapsouc neuropathy, 1495 Darifenacin, 756 Daroff's sign, 218 Darvon. see Propoxyphene Datura stramonium, see Jimson weed DDAVP, 863, 866, 954, 1819 ddC. see Zalcirahine ddl. see Didanosine DDST-il. see Denver Developmental Screening Test II Deafferentation pain, 925—927 Deafness pure word, 137, 148 tectal, 278 Decerebrate posturing, 57-58 Decision analysis, 460-461, 461f Declarative memory, 68 Decorticate posturing, 58 Deep cerebral veins, 639-640, 642t Deep dyslexia, 152 Deep peroneal nerve, accessory, 497 Deep tendon reflexes, spinal cord disease lesion localization using, ^55 Deep venous thrombosis anticoagulanrs for, 1367 brain tumors and, 1367-1368 characteristics of, 954, 1050-1051 clinical presentation of, 1367 in comatose patients, 1139 management of, 1367-1368 mobilization of patients to prevent, 1140 prophylaxis for, 1139-1140, 1176 spinal cord injury and, 1175-1176 stroke and, 954, 1243 treatment of, 1176, 1367-1368 venography for, 1176 Defecation cortical lesions effect on, 423-424 physiology of, 420, 1173 Defecation syncope, 17 Defective response inhibition definition of, 117, 120 testing for, 120 Defibrinogenaring agents, for stroke, 1238-1239 Deficiency diseases beriberi, 1701-1702 folate clinical features of, 1697-1698 cognitive impairment caused by, 1697 description of, 109, 1697 etiology of, 1698 laboratory studies of, 1698 pathogenesis of, 1698 psychiatric disturbances associated with, 109 treatment of, 1698 pellagra, 1699-1700 Stracban's syndrome, 1706—1707
Volume I pp. 1-1070 • Volume II p. 1071-2546
xxviii
INDEX
Deficiency diseases (Continued) vitamin A, 1707 vitamin B 6 , 1700-1701 vitamin B,2 biochemistry of, 1696 clinical features of, 1694-1695 course of, 1697 description of, 1086, 1694 differential diagnosis, 1697 etiology of, 1696-1697 gastric surgery and, 6 laboratory studies of, 1694-1695 magnetic resonance imaging findings, 1694-1695 myelopathy associated with, 1694f pathogenesis of, 1696-1697 pathologic findings, 1696 pen lie tons anemia associated with, 1696-1697 physiology of, 1695-1696 prognosis for, 1697 psychiatric disturbances associated with, 109 treatmenr of, 1697 vitamin D, 1707 vitamin E, 1698-1699 Degenerative disc disease, 582-583 Dejenne-Sottas disease, 2321 Dcjerinc syndrome, 1207, 2319 Delavirdine, 1587t Delayed-onser muscle soreness, 388 Delayed sleep-phase syndrome, 2024 Delirium anticholinergic agents effects, 32 causes of drug-related, 36-37 endocrine dysfunction, 36 epilepsy, 37 infections, 37 metabolic disturbances, 36, 36t neurological, 37-38
overview of, 36t, 114 postoperative, 37 stroke, 37 characteristics of acute onset with fluctuating course, 30 attention a 1 deficits, 30 behavioral abnormalirics, 32 cognitive deficits, 31-32 consciousness alterations, 30 description of, 29-30, 30t disorganized thinking, 30 emotional abnormalities, 32 hallucinations, 30-31 memory impairment, 31 orientation disturbances, 31 perceptual disturbances, 30-31 psychomoror activity alterations, 31 sleep-wake cycle disturbances, 31 speech disturbances, 143 writing disturbances, 31-32 clinical features of, 39t cotifusional behavior, 33-34 definition of, 29 dementia and. 38, 114 diagnosis of confusion assessment method, 34 criteria for, 30t, 34
Delirium Rating Scale-Reviscd-98, 34
Delirium (Continued) differential, see Delirium, differential diagnosis electroencephalogram, 35f laboratory tests, 35, 35f medical history, 33-34 Memorial Delirium Assessment Scale, 34 mental status examination, 34 physical examination, 35 scales for, 34 steps involved in, 33 Diagnostic and Statistical Manual Mental Disorders criteria, 30t, 34, 43 differential diagnosis, 35-38, 39t dopamine and, 33 drug treatment for, 40 in elderly, 29, H, 40 environmental measures of, 38, 40 historical descriptions of, 29 hyperactive-hyperalert, 3 1 , 35 hypoactive-hypoalert, 31, 35 incidence of, 29 incident, 33 management of, 38, 40 mood changes associated with, 32 neurorransmitrer alterations and, 32-33 partial, 40 pathophysiology of, 12-33 prognosis for, 40 psychiatric disturbances caused by, 114 risk factors for, 33t in schizophrenic individuals, 38 subtypes of, 31 terminology associated with. 29 Wernicke's aphasia and, 38 Delirium Rating Scale-K.evised-98, 34 Delirium tremens, 37 Delta activity, on electroencephalography, 472, 474f Delta-receptor, 924, 1720 Delusions in Alzheimer's disease, 88, 1907 cortical structures associated with, 105t definition of, 104t in vascular dementia, 91 Dementia adrenal disorders and, 1947 AIDS-complex, see also Dementia, human immunodeficiency virus description of, 835 glutamate's role in, 888t alcoholic, 1944 Alzheimer's disease, see Alzheimer's disease American Academy of Neurology guidelines for, 1905 amyotrophic lateral sclerosis, 2251 amyotrophic lateral sclerosisparkinsonism-dementia complex, 2260 behavioral assessmenrs, 1904-1905 brain biopsy evaluations, 987 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephaloparhy, 1937 cerebral vasculitis and, 1938 clinical features of, 39t, 1902-1903 cognitive assessmenrs for, 1904, 1904t cognitive impairment, 1902 collagen disorders and, 1937-1938
Dementia (Continued) cortical, 1903t definition of, 104t delirium and, 38, 114 depression and, 88t, 1907, 1944 description of, 1901 diagnostic approach American Academy of Neurology guidelines, 1905 behavioral assessments, 1904-1905 cognitive assessments, 1904, 1904t criteria, 1902t history-taking, 1903, 1903c imaging studies, 1905 laboratory studies, 1905 ncuropsychiatric assessments, 1904-1905 dialysis, 1093, 1683 drug intoxication and, 1948 electroencephalography evaluations, 476-477, 477f finked potentials for, 4 fron to temporal Alzheimer's disease vs., 689t, 1919 amyotrophic lateral sclerosis and, 688, 1922 anatomic sites of, 1917 apraxia and, 1922
aurosomal dominant, 2261 behavioral symptoms of, 89, 112, 1918 characteristics of, 112 cholinergic deficits in, 1920-1921 classification of, 1920t clinical featutes of, 689t, 1918 clinical presentation of, 688-689 cortical neurons in, 1919 definition of, 1917 depression in, 89-90 description of, 156, 688 diagnostic criteria for, 90c, 1918t differential diagnosis, 1918-1919 epidemiology of, 112, 1918 euphoric symptoms in, 90 extrapyramidal signs associated with, 1919 familial cases of, 156 FITD17 genetic mutation, 1919 genetic findings, 156, 791f, 805t histological types of, 688 history of, 1917 laboratory studies of, 1919 language deterioration associated with, 1918 management of, 1921 Mini-Mental State Examination evaluation of, 688 motor neuron disease and, 1922 neurochemical findings, 1920-1921 neuropsychological characreristics of, 688-689 parkinsonism and, 688 pathology associated with, 1917, 1919-1920 Pick's disease, 1917 primary progressive aphasia associated with, 1921 progressive aphasias associated with, 1921 progressive apraxia and, 1922 psychiatric disturbances in, 89-90
INDEX
Dementia (Continued) self-concept a n d , 67 semantic dementia and, 1 9 2 1 - 1 9 2 2 tau protein, 6 8 8 , 1 9 1 9 - 1 9 2 0 head trauma and, 1945 heavy metal toxicity and, 1 9 4 7 - 1 9 4 8 helminthic infections and, 1 9 4 0 - 1 9 4 1 herpes simplex, 1939 history-taking, 1 9 0 3 human immunodeficiency virus cerebrospinal fluid analysis, 1589 clinical features of, 1588, 1938 delirium associated with, 1938 depression associated with, 92 description of, 8 3 5 , 1585 diagnosis of, 1938 evaluations of, 1588 highly active antiretroviral therapy for, 1590 imaging of, 1589 laboratory investigations for, 1588-1590 magnetic resonance imaging of, 1589f management of, 1590 ncuropathologv associated with, 1590, 1938-1939 neuropsychological tests for, 1 5 8 8 - 1 5 8 9 psychiatric disturbances associated with, 106-107 psychomotor dysfunction associated with, 1588 symptoms of, 1938 treatment of, 1939 hydrocephalus as cause of, 39t, 1929, 1945-1946 hyperthyroidism a n d , 1947 hypoglycemia and, 1947 hypothyroidism and, 1947 inborn errors of merabolism a n d , 1948 with Lewy bodies antipsychotic agents for, 1926 chijlincstcmsc-irihiLiitor drugs tor, 1925-1926 clinical features of, 1 9 2 4 - 1 9 2 5 , 1925t description of, 9 1 , 112, 1 9 2 4 - 1 9 2 5 , 2140 diagnosis of, 1925 dopaminergic rherapy for, 1 9 2 6 - 1 9 2 7 hallucinations in, 92, 112 neuroimaging of, 1925 n euro pathological features of, 1925, 1926f occipital lobe hypoperfusion associated with, 1925 parkinsonism symptoms and, 1909 pharmacological management of, 1925-1927 psychotic symptoms in, 92, 112 liver disease a n d , 1947 Lyme disease a n d , 1940 metabolic causes of, 1 9 4 6 - 1 9 4 8 multi-infarct history of, 1930 magnetic resonance imaging of, 5 4 9 - 5 5 0 , 550f psychiatric disturbances associated with, 106 multiple si lerosis, I 945 neoplasms that cause, 1946, 1948 neuropsychiatry assessments, 1 9 0 4 - 1 9 0 5
Dementia [Continued) neurosurgical treatment of, 981 paraneoplastic limbic encephalitis, 1946 parathyroid disease a n d , 1 9 4 7 parkinsonian cognitive profiles of, 1 9 2 3 - 1 9 2 4 corticobasal degeneration, 1928 degenerative, 1 9 2 3 - 1 9 2 4 differential diagnosis, 1923t motor profiles of, 1 9 2 3 overview of, 1 922 vascular, 1929 Parkinson's disease, 3 0 1 , 6 8 9 , 1924 pituitary disorders a n d , 1947 positron emission tomography evaluations, 669 posttraumatic, 1945 post-traumatic stress disorder a n d , 1948 progressive multifocal leukoencephalopathy, 1939 progressive supranuclear palsy clinical features of, 1927 definition of, 1927 diagnostic criteria for, 1927t pathological features of, 1927 pharmacological treatment of, 1927-1928 semantic, 136, 6 8 9 , 1 9 2 1 - 1 9 2 2 single-photon emission computed tomography evaluations, 6 6 9 Sjogren's syndrome, 1937 subcortical, 1 9 0 2 , 1903t, 1931f thyroid disease and, 1947 treatment of, 8 7 3 - 8 7 4 urinary incontinence in, 4 2 3 vascular anxiety in, 91 aparby in, 91 background of, 1 9 3 0 - 1 9 3 1 behavioral disturbances in, 9 1 , 1936t cerebral amyloid angiopathy in, 1 9 3 7 cognitive impairments associated with, 1 9 3 1 - 1 9 3 2 , 1935 cortical, 1934 depression in, 91 diagnostic crireria for, 1931 epidemiology of, 1 9 3 1 - 1 9 3 2 flu id-attenuated inversion recovery imaging, 1 9 3 3 , 1933f history of, 1 9 3 0 - 1 9 3 1 infarcts associated with, 1935t, 1935-1936 ischemic lesions in, 1 9 3 5 - 1 9 3 6 memory impairment in, 6 8 8 neuropathological studies, 1933 neuropsychological findings, 687—688, 193 6t personality disturbances in, 91 prevalence of, 6 8 7 , 1 9 3 1 - 1 9 3 2 psychosis in, 91 subcortical, 1 9 3 4 - 1 9 3 5 treatment of, 1 9 3 6 - 1 9 3 7 white-matter lesions, 1 9 3 2 - 1 9 3 4 vasculitis a n d , 1938 vitamin Ei|i deficiency a n d , 1946 Whipple's disease, 1940 Dementia pugilistica, 1945 Dementia rating scale, 6 8 2 , 682f Demerol, see Meperidine De Morsier's syndrome, 1111
xxix
Dciuyclinanni; diseases acute disseminated encephalomyelitis characteristics of, 553, 553f, 8 2 5 , 838 clinical features of, 1660 diagnosis of, 1 6 6 1 - 1 6 6 2 differential diagnosis, 1659t history of, 1659 idiopathic, 1660 laboratory features of, 1 6 6 0 - 1 6 6 2 lesions associated with, 1 6 6 1 , 1661f measles-induced, 1660 postvacci nation, 1 6 5 9 - 1 6 6 0 recovery from, 1660 treatment of, 1662 acute hemorrhagic leukoencephalitis, 1662 central and peripheral, 1 6 6 2 - 1 6 6 3 cerebellitis, 1 6 6 3 hemiplegia a n d , 339 multiple sclerosis, see Multiple sclerosis postinfectious, 1 6 6 3 types of, 1632t Demyelinating niononeuropathy, 4 9 9 , 500f i Vimcliiulini; p u b neuropathy description of, 4 0 3 , 404t, 413 nerve conduction studies of, 5 0 1 , 502f Dendrites abnormalities of, 1 7 7 0 - 1 7 7 1 growth of, 1770 traumatic brain injury effects, 1119, 11201 Dengue, 1538 Dc novo automatisms, I 9 5 7 neiHaiorLibral-pallidoluysian atrophy, 7 9 3 , 804r Dentatorubral-pallidoluysin atrophy, 2 1 5 2 Dent's disease, 1848t Denver Developmental Screening Test II, 75 Deoxyhemoglobin, 5 7 1 , 572f, 572t, 6 6 8 Depression Alzheimer's disease, 8 7 , 9 1 , 1 1 1 , 1916 amyotrophic lateral sclerosis a n d , 97 anticpileptic drugs and, 98r clinical feattires of, 39t cognitive impairment associated with, 114 cortical structures associated with, 105t definition of, 104t dementia a n d , 88t, 1907, 1944 epilepsy a n d , 9 8 - 9 9 fronrotcmporal dementia a n d , 8 9 - 9 0 in HIV patients, 92 H u n t i n g t o n ' s disease and, 9 3 - 9 4 , 113 insomnia a n d , 2 0 1 2 multiple sclerosis a n d , 96, 1655 neurological causes of, 107t neurological disorders associated with, 86t pain syndromes and, 929 Parkinson's disease a n d , 9 2 - 9 3 , 112 selective serotonin reuptake inhibitors for, 8 7 , 1916 serotonin a n d , 901t stroke-related, 9 9 - 1 0 0 , 1 0 5 - 1 0 6 , 1065, 1243 systemic lupus erythematosus and, 110 thyrotropin-releasing h o r m o n e for, 908 traumatic brain injury-related, 1 0 1 , 114, 1065 treatment of, 1065 vascular dementia a n d , 91 De Q u e r v a i n ' s tenosynovitis, 4 4 2 - 4 4 3 Drrmatochalasis, 2 2 8
Volume 1 p p . 1-1070 • Volume [I p. 1071-2546
xxx
INDEX
Dermatomes spinal cord lesion localization and, 355 upper extremity, 436f Dermatomyositis blood tests, 2504 characteristics of, 1468-1469 definition of, 2503 description of, 168, 827 diagnosis of, 2503-2504 needle electromyography diagnosis of, 512, 2504 neoplasia and, 2505 treatment of, 2505-2506 Detmoid cysts, 1361, 1393 Dermoid lesions, 575, 577 DeSanctis-Ca cell i one syndrome, 1897 Desmin, 2501 Dcsmoplasia, 1344 Desmoplastic cerebral astrocytoma of infancy, 1429 Desmopressin, for nocturnal enuresis, 756 Detail resolution, 648 Detrol. see Toltcrodine Detrusor areflexia, 1655 Detrusor hypcrreflexia, 427, 1655 Detrusor hyper-reflexia, 751 Detrusor overactivity
incomplete bladder emptying and, 757 treatment of anticholinergics, 756, 758 description of, 756t, 756-757 indwelling cathetet, 758-759 nerve root stimulator, 759-760 sacral nerve stimulator, 759 Detrusor-sphincter dyssynergia, 426 Development milestones of, 76t muscle tone and, 397t theory of mind stages, 1796t Developmental delay global algorithmic approach to, 80f biologic conditions associated with, 77t computed tomogtaphy evaluations, 78 definition of, 75 diagnosis of tests for, 76-81 yield for, 75-76 electroencephalography evaluations, 79 etiology of, 75-76 evaluation of, 75 family history evaluations, 76 genetic testing for, 78 imaging studies for, 78 Internet resources, 831 magnetic resonance imaging evaluations, 78 medical history, 76 mental retardation vs., 75 metabolic testing for, 77-78 ocular findings associated with, 76, 78t physical examination for, 76 risk factors, 76, 77t Internet resources, 831 management goals for, 75 prevalence of, 75 Developmental disabilities attention deficit hyperactivity disorder clinical features of, 1802-1803 diagnosis of, 1802, 1802t
Developmental disabilities [Continued) dyslexia and, 1798 etiology of, 1803 evaluation of, 1803 genetic factors, 1803 prevalence of, 1802 psychostimulants for, 1803, 1803t signs of, 1803t Toutette's syndrome and, 95, 692 treatment of, 1803, 1803t autism, see Autistic spectrum disorders cerebral palsy, see Cerebral palsy dyscalculia, 1802 learning, see Learning disabilities mental retardation, see Mental tctardatiou motor function, 1800-1801 visuosparial disabilities, 1801t, 1801-1802 Developmental language disorders articulation, 1804 autistic spectrum disorders vs., 1794 cluttering, 1804-1805 definition of, 1803 electrophysiology studies, 1807 expressive language, 1805-1806 higher order, 1806 lexical syntactic syndrome, 1806 metabolic imaging, 1SU7, IS()"i neurobiologies] basis of, 1806-1807 outcome of, 1808 phonological programming disorder, 1805 phonological syntactic syndrome, 18051806 receptive language, 1805-1806 remediation for, 1808 risk factors, 1803-1804 semantic pragmatic syndrome, 1806 signs of, 1803, 1 R04t stuttering, 1804-1805 subtypes of, 1804, 1805t verbal auditory agnosia, 1806 verbal dyspraxia, 1805 Developmental regression algorithmic approach to, 82f counseling for, 82-83 description of, 81 evaluative approach to, 81 gtay matter involvement in, 81 management of, 82-83 prognosis for, 83 in Rett'5 syndrome, 82 treatment of, 83-84 Devic's disease, 1651-1652 Dextromethorphan, 2310 Diabetes insipidus, 863-864, 953, 1095 Diabetes mellitus Bell's palsy and, 2362-2363 central nervous system effects, 1098-1099 in children, 1112 complications of, 1112 demyclinating processes in, 2364 entrapment neuropathy and, 2363 hypoglycemia, 1099, 1684-1685 ischemic cerebrovascular disease and, 1198 neurological complications of, 1112 peripheral nervous system effects, 1098, 1112 polyradiculopathy in, 1112 prevalence of, 2357 stroke and, 1198, 1230
Diabetic amyotrophy leg pain associated with, 454 monoplegia and, 347-348 Diabetic ketoacidosis, 1098, 1112, 1685-1686 Diabetic mononeotopathy multiplex, 1098 Diabetic neuropathic cachexia, 2360 Diabetic neuropathy asymmetrical proximal, 2361 autonomic, 2360-2361 bladder dysfunction associated with, 429 classification of, 2359t clinical features of, 2359-2363 diagnosis of, 2357-2358 distal symmetrical polyneuropathy, 2359 erectile dysfunction and, 429 laboratory findings, 2363 pathogenesis of, 2364 pathology of, 2363-2364 sensory abnormalities caused by, 413 sexual dysfunction and, 429 treatment of, 2364-2365 truncal, 2361 Diabetic papillopathy, optic disc edema caused by, 189 Diabetic polyneuropathy, 1098 Diabetic polyradiculoneuropathy, 1098, 2275-2276, 2359 Diacylglycerol, 885, 892, 897 Diagnosis anatomic locations, 3, 7-8 chief complaint, 4 differential, 8-9 examination for general, 7 neurological, 6-7, 7t experienced neurologist's approach to, 9 history of present illness, 4-5 laboratory investigations, 9 mode of onset, 4 neurological interview, 4 patienr-specific information for desctiption of, 5 family histoty, 6 history of previous illnesses, 5-6 review of systems, 5 steps involved in, 3^1, 4f terminology variations, 5 Dialysis disequilibrium syndrome, 1093, 1683 Dialysis encephalopathy, 1947 Dialysis-related neurological complications, 1093 3,4-Diaminopyridine, 1654 Diarrhea, 953 Diarrhetic shellfish poisoning, 1736t, 1740 Diastematomyelia, 2197, 2199f Diazepam administration of, 1981 spasticity treated with, 1055t status cpilcpticus treated with, 1969t for vertigo, 746t, 747 Dich I oro acetate, 1844 Didanosine, 1 587t Dideoxynuclcosides, 2383 Diencephalic pupils, 54 Diencephalic syndrome, 277 Dietary intoxication, 888t Dicthvlcarbama/ine, 1557t
INDEX Differential diagnosis, 8-9 Diffuse astrocytomas, 1344f, 1347-1348 Diffuse axonal injury, 554, 555f, 1129-1130 Diffuse idiopathic skeletal hyperostosis, 2203 Diffuse Lewy body disease, 2.5 Diffusion-weigh ted magnetic resonance imaging abscess evaluations, 527, S2Sf apparent diffusion coefficient, 524 clinical application of, 524-527, 525f-526f Creutzfcldt-Jakob disease evaluations, 527, 529f description of, 524 epidermoid cyst evaluations, 527, 530f physics of, 524 stroke findings, 525f-526f DiflLinisal, 932t Di George's syndrome, Sit Dihydroergotamine, migraines treated with, 2081-2083, 2103 Dihydrofolate reductase, 8031 Dihydrolipoyl trans acylase, 803t Dihydroxy phenylalanine, 892 Dimenhydrinate, for vcttigo, 74 61 Dimercaprol, for arsenie poisoning, 1715 Diphtheria, 1511-1512,2391-2392 Dtpbyllobotbrhtm latum, 1557t Diplopia assessment of convergence, 205 cover-uncover test, 207 ctoss-cover test, 208 duct ions, 205 edrophonium test, 211 fatigability, 208 fixation stability, 204 general inspection, 204 head posture, 204, 206f Hirschherg test, 206-207, 208f history-taking, 202-203 Maddox rod test, 206, 208f muscle balance, 205-208 ocular alignment, 205-208 overview of, 2061 pursuit movements, 204-205 red glass test, 206, 207f rules for, 204t saccades, 205 versions, 204-205, 207f visual function, 204 description of, 201-202 disorders related to, 212-213 monocular, 202, 2051 oscillopsia vs., 202 physiologic, 202 prisms for, 211 signs associated with, 210-211 treatment of, 211-212 vertical causes of, 205t description of, 202 three-step test for, 208-209, 21 Of Dipyridamole, 1235-1236 Directional akinesia, 118-119 Directional preponderance, 741 Disassociation apraxia, 123, 128 Disc herniation eauda equina syndrome caused by, 1159, 1159f
Disc herniation (Continued) cervical, 2273 clinical features of, 2271-2272 description of, 2270-2271 diagnosis of, 2273-2275 L4, 2273 L5, 2273
lumbosacral, 2271-2272 magnetic resonance imaging of, 2211f needle electromyography of, 2274 neurophysiologies! rests, 2274 SI, 2273 trearment of, 2275 Disciris, lumbar spine, 456 Discourse, 142 Disc space infections, 595, 595f Disinhibit ion-dementia-park insoniamamyotrophy complex, 2261 Disopyramide, 2383 Disorientation, in delirium, 31 Dissecting aneurysms, 1274 Disseminated intravascular coagulation, 1089, 1229, 1303 Dissociated sensory loss, 412 Dissociated vertical deviation, 208 Distal sensory polyneuropathy, 1598-1599 Distal symmetrical polyneuropathy, 2359, 2388 Distribution of medicarions, 9 I 7 Disulfiram, 2383 Ditropan. see Oxyburynin Divergence disorders central disruption of fusion, 72.3 insufficiency, 722-723 paralysis, 72.3 Divcrticulation disorders holoprosencephaly, 564, 564f septo-optic dysplasia, 564 Dizziness, see also Vertigo acute peripheral vestibular abnormality and, 234, 235f central neurological causes of, 233-234 cerebellar system examination for, 242-243 in children, 241
differential diagnosis, 244t examination for, 242-243 hearing loss with, 240 history taking, 234, 2 S5I mental status examination for, 242 motor system examination for, 242 neuro-orological examination for, 243 oculat motor examination for, 242 screening tests for, 243 sensory exammarion for, 242 signs and symptoms of, 233-234 treatment of, 746-747 DNA bases of, 789 cleavage of, 796 complementary, libraries of, 797 deletions of, 792 fragments of, 796 insertions of, 792 mutations description of, 790, 79 If single base-pair, 791 types of, 791 f polymorphisms, 790 transcription of, 789
xxxi
DNA viruses, 832t Docetaxel, 2386 Dolichocctasia, 1225 Doll's eye maneuver, 56, 273, 301, 714 DolPs eye phenomenon, 56 Dolobid. see Diflunisal Dolophine. sec Methadone Domoic acid, 1740 Donepezil, 1915-1916 Donnaral, for vertigo, 746t Dopamine basal ganglia storage of, 894 chemistry of, 893-894 clinical role of, 895-896, 896t delirium and, 33
descnprion of, 892 disorders associated with, 882t, 895-896, 896t distribution of, 893-894 neuropeptide colocalization with, 902t neurotransmission by, 894, 895f pharmacology of, 893-894 receptors, 894 release of, 894 storage vesicle transport of, 893 Doppler effect, 646 Doppler ultrasonography continuous-wave, 646 principles of, 646-647 pulsed wave, 646-647 spectral display and analysis, 647-648 transducers for, 646 Dorsal column tracts, 407, 408f Dorsal midbrain syndrome, 274t, 274-275 Dorsal rhizotomy, 907 for pain, 982 Dorsal roor ganglia disorders, 2281-2282 Dorsal root ganglion neurons, 904 Dorsal roor ganglionopathics, 355-356 Dorsal scapular nerve entrapment, 231 It Dorsal simultanagnosia, 133 Dorsolateral circuit characteristics of, 87t description of, 86, 87f disruption of, 87t-S8t Dose-responsive dystonia, 2158 Doubiecartin, 1768, 1785 Double crush syndrome, 2.311 Double elevator palsy, 720 Double-ring sign, 737 Downbeat nystagmus, 215t, 218, 21 fir, 22 Ir, 289 Downgaze paresis, 275 D o w n syndrome
Alzheimer's disease and, 1915 characteristics of, 1793t katyotype of, 786f-787f prevalence of, 78 seizures associated with, 785 stroke risks, 1.302 Doxycycline, brucellosis treated with, 1503 Draw a clock test, 683-684, 685f Dreams, 1998 Drop attacks, see also Falls causes of anterior cerebral artery ischemia, 24 basal ganglia disorders, 25 cataplexy, 26 tliian malformation, 25 Meniere's disease, 26 Volume I pp. 1-1070 • Volume II p. 1071-2546
xxxii
INDEX
Drop attacks {Continued) overview of, 24l
Parkinson's disease, 25 seizures, 24 third ventricle tumors, 24-25 transient ischemic attacks, 23-24, 1203 vertebrobasilar insufficiency, 24, 1203 complex partial sei/.ures and, 18 definition of, 23 medical history evaluations, 23 neurological examination for, 23 Dropped head s; ndroine, 368, 369f Drug(s) autonomic dysfunction caused by, 2406t bioavailability of, 916 biotransformation of, 917 Orcadian variation effects on, 918 clinical trials of, S>I.S cognitive impairment caused by, 1902 delirium caused by, 36-37 developmental factors that affect, 918 distribution of, 917 drug interactions, 918 elimination of, 918 half-life of, 918 hyperprolactincmia induced by, 860 idiopathic intracranial hypertension caused by, I757t loading dose for, 916 metabolism of, 918 muscle discomfort caused by, 390t myoclonus induced by, 2163 neurological disturbances caused by, 6 overdose of, 1691, 1691t parkinsonism induced by, 1928-1929, 2144 pharmaceutical companies, 915 pharmacogenetics of, 917 physiological variation of, 918 preparations, 916 principles of, 914-915 properties of, 916-918 research studies of, 915 smell disturbances caused by, 261t tardive dyskinesia caused by, 310 taste disturbances caused by, 261t, 263 titration rate, 916-917 vertigo caused by, 237, 239, 239t, 241 withdrawal syndromes, 36-37 Drug abuse anticholinergics, 1723 central nervous system vasculiris associated with, 1325-1326 detection times, 1719, 1720t drugs commonly used, 1719 Ectasy, 1723 forms of, 1719 hallucinogens, 1724 inhalants, 1723-1724 ketamine, 1723 marijuana, 1723 MDMA, 1723 neurological complications of anoxia, I 725 desctiption of, 1719, 1720t embolism, 1724 hypotension, 1725 myelopathy, 1725 myopathy, 1725 neuropathy, 1725-1726
Drug abuse {Ctm tinned) plcxopathy, 1725-1726 rhabdomyolysis, 1725 stroke, 1724t, 1724-1725 opioids acute effects of, 1720-1721 addiction to, 933-935 adverse effects of, 936 antagonism of, 1720-1721 classification of, 933 dependence on, 1721 dependency, 933-934 description of, 1720 duration of action, 933 epidural administration of, 936 fentanyl, 936 half-life of, 933 heroin, 1720-1721 intrathecal administration of, 936 intravenous administration of, 935 methadone use, 1721 mild, 933, 934t overdose of, 1720-1721 pain management using, 933—936, 1162-1163 pharmacology of, 1720 reversal of, 1720-1721 selection of, 935 strong, 933, 934t titration of, 935-936 transdermal delivery of, 936 types of, 934t withdrawal from, 1721 phencyclidine, 1723 psychiatric disturbances caused by, 110, lilt psychostimulants, 1722-1723 sedatives and hypnotics, 1721-1722 stroke risks, 1219 urine screening for, 1719, 1720t Drug dependence, 1719 Drug interactions, 918 Drug tolerance, 1719 Drusen, optic disc, 181, 185-186 Dry keratin, 1361 d^T. see Stavudinc Duchenne's muscular dystrophybracing for, 2472 cardiac involvement, 2470 clinical features of, 2470f, 2470-2471 creatine kinase levels, 2471 diagnosis of, 2470-2471 dysphagia in, 168 epidemiology of, 2469-2470 gene therapy for, 2472-2473 genetic counseling for, 2473-2474 genetics of, 792, 7931, 805t, 2469 muscle biopsy findings, 2471f-2472f muscle weakness in, 2472-2473 pharmacological treatment of, 2472 physical therapy for, 2471-2472 surgery for, 2472 treatment of, 2471-2473 Ductions forced, 209-210, 210t testing of, 205, 207f Duplex ultrasound, 649 Duragesic. see Fentanyl
Dural arteriovenous fistulas magnetic resonance imaging of, 1318-1319 spinal, 615, 6l6f 3D time-of-flight magnetic resonance angiography evaluations of, 613, 614f Dural fistula, spinal description of, 984 diagnosis of, 984-985 illustration of, 985f neurosurgical treatment of, 984-985 Dural metastases, I456 Dural sinuses anatomy of, 641-642, 642t stenosis in, 1018 Dural veins, 642t Dura mater, 641 Duret hemorrhage, 1129 Durks nodules, 1560 Dying-back neuropathy, 2300-2301 Dynorphins, 924 Dysarthria apraxia of speech vs., 141 causes of, 141 classification of, 161 definition of, 161 flaccid, 161, 162t hyperkinetic, 162, 162t hypokinetic, 162, 162t spastic, 161-162, 162t spastic-flaccid, 162, 162t speech disturbances in, 144 upper motor neuron, I 62, 1 62l Dysarthria-clumsy hand syndrome, 1205 Dysautonomia, 1051-1052 Dysautonomy cephalalgia, 2099 Dyscalculia, 1802 Dysconjugatc nystagmus, 217 Dysdiadochokinesia, 289 Dysembryoplastic neuroepithelial tumor, 532-533, 1354, 1381, 1429 Dysesthesia, 409 Dysferlin deficiency, 2475 Dysgeusia, 263 Dyskinesia paroxysmal kinesigenic, 2159-2160 paroxysmal nonkinesigenic, 2160 secondary paroxysmal, 2160 tardive description of, 309-310, 2154 dopamine's role in, 896t drug-induced, 310 Huntington's disease vs., 309-310 respiratory irregularities in, 309 Dyslexia attention deficit hyperactivity disorder and, 1798 atypical features of, 1799r deep, 152 diagnosis of, 1798 etiology of, 1798-1799 evaluation of, 1798-1799 letter-by-letter, 152 phonologic, 153 surface, 153 treatment of, 1799 Dyshpidemias, 1826-1827 Dysmetria cerebellar ataxia and, 288
INDEX Dysmetria {Continued) definition of, 288 flutter, 223 ocular, 215t, 223 Dysphagia aspiration secondary to, 169-170, 1049 assessment of, 174f hotulinum toxin and, 172 evaluation of, 173-174 gastroesophageal reflux-re I a ted, 166 L-dopa effects, 171 management of, 1049-1050, 1050t mechanical, 166, 167t neurogenic amyotrophic lateral sclerosis, 172 basal ganglia disorders, 171-172 brainstem processes, 172 cranial neuropathies, 172-173 multiple sclerosis, 170-171 Parkinson's disease, 171 prevalence of, 165 pulmonary infection risks, 1049-1050 stroke, 169-170 Wilson's disease, 171-172 neurological disorders associated with, 1049 neuromuscular causes description of, 166 inflammatory myopathies, 168 mitochondrial disorders, 168 myasthenia gravis, 168-169 myotonic dystrophy, 167-168 oculopharyngeal muscular dystrophy, 166-167 overview of, 167t oropharyngeal, 174 testing for, 173t, 173-174 treatment of, 1049-1050, 1050t Dysphasia aphasia vs., 141 migraine headache and, 2074 Dyspnea, 872 Dyspraxia, verbal, 1805 Dysrhyrhmic breathing, 2018-2019 Dystliytoid orbitopathy, 1096 Dystonia action, 312, 318 adult-onset primary focal and segmental, 2156-2157 hotulinum toxin for, 928 causes of, 310, 311t-312t childhood-onset primary, 312, 2155-2156 in complex regional pain syndromes, 928 definition of, 310 diurnal fluctuation, 332 dopa-responsive, 312, 5 I 8 dose-responsive, 2158 etiologic classification of, 311t-312t examination for, 312-313 hereditary progressive, 2031 hysteria vs., 310, 312 movements associated with, 310 myoclonus, 2158 neurological abnormalities associated with, 313 paroxysmal kinesigenit dyskinesia, 2159-2160 paroxysmal nonkinesigenic dyskinesia, 2160 post-traumatic, 2159
Dystonia (Continued) "pure," 312 rapid-onset dystonia parkinsonism, 2158-2159 symptoms of, 312 tardive, 2159 task-specific, 310, 318 Wilson's disease, see Wilson's disease Wilson's disease and, 313 X-linked, 2157-2158 Dystonic gait, 328, 331-332 Dystonic paraparesis, 329 Dystonic tremors, 2146 or-Dystroglycan, 2469 Dystrophin deficiency of, 2469-2474 definition of, 2469 Dystrophin gene, 792, 793f Dystrophinopathy, 2473 E Eagle's syndrome, 522f Hales' disease, 1225 Early growth response 2 gene, 2323 Early infantile epileptic encephalopathy, 1965 Early onset ataxia wirh retained reflexes, 2176 Ear reflexes, 251 Eastern equine encephalitis virus, S32t, 1531t, 1532 Eating disorders, 855 Ebola virus, 1538-1539 Echinococcosis, 1572-1573 Echinococcus granulosus, 1557t Echinococcus multilocularis, 1557t Echoplanar imaging, 530 Hchopraxia, 120 Echo virus, 8321 Eclampsia, 2541 Eclamptic encephalopathy, 2543-2545 Ectasy, 1723 Ectoparasites, 1578 Ectopic gene expression, 1782 Edema brain computed tomography of, 1753f corticosteroids of, 1756 cytokine's role in, 1752 cytotoxic, 1750-1751, 1752-1755 description of, 1745 etiology of, 1750-1751, 1753 hypertensive encephalopathy and, 1753-1754 inflammation, 1752 intracerebral hemorrhage and, 1753 mechanisms of, 1750-1751, 1751f meningiomas and, 543 osmolality changes and, 1754 osmotic therapy for, 1756 stroke and, 1753 treatment of, 1755-1757 vasogenic, 1751 cerebral acute mountain sickness and, 1755 brain tumors and, 1366-1367 hypoxia and, 1667-1668 management of, 1366-1367
xxxiii
Edema [Continued) nen roseiences critical care unit management of, 956-957 vasogenic, 1366-1367 Edinger-Westphal nucleus, 54 Edrophonium test diplopia assessments, 211 floppy infant evaluations, 406 myasthenia gravis evaluations, 2445-2446 technique for, 232 EEC see Electroencephalography Efavirenz, 1587t Eflornithine, for African trypanosomiasis, 1563 Killers Danlos syndrome arterial dissection in, 1879 carotid-cavernous fistula in, 1878-1879 clinical features of, 1877-1878 computed tomography of, 1878f cutaneous hyperelasticity associated with, 1877f description of, 1224 intracranial aneurysms associated with, 1878, 1878f subtypes of, I 877 type IX, 1887 Ehrlichiosis, 1502 Ejaculation Jesci ipiion of, 42 1-422 failure of, 761 physiology of, I 174 rcrrograde, 1174 spinal cord injury effects, 1174—1175 Elbow epicondylitis of, 442 ulnar nerve entrapment at, 344t, 345, 439-^140 Elderly brain tumors in, 1333 degenerative joint disease in, 325 delirium in, 29, 33, 40 depression in, 1944 electroencephalographs changes in, 476 falls in, 26-27 gait in, 333-335 nervous system tumors in, 1343t sleep in, 1997 spinal cord injury in, 1163 Electrical current injuries, 1742-1743 Electrical injury, nerve injuries caused by, 1188 Electrocardiography coma evaluations, 61 syncope evaluations, 17 Elcctrocochleography, 746 Electroconvulsive therapy, 115 Electrocorticography, 465 Elcctrodiagnostic examination for amyotrophic lateral sclerosis, 2253 for lower motor neuron diseases, 2230-2231 for peripheral nerve disorders, 2306, 2307f Electroencephalography abnormalities commonly found, 466 age-related changes, 476 alpha rhythms, 466, 4f,"I artifacts, 472 auditory nerve monitoring by, 488 clinical uses of Volume I pp. 1-1070 • Volume 11 p. 1071-2546
xxxiv
INDEX
Electroencephalography [Continued) absence seizures, 1962 alpha coma, 4 7 4 , 475f altered levels of consciousness, 4 7 2 Alzheimer's disease, 4 7 7 aphasia, 156 atonic seizures, 1963 bacterial meningitis, 4 7 5 ^ 7 6 brain death, 476 brain monitoring, 945 brain tumors, 1365 coma, 62 Creutzfeldt-Jakob disease, 4 7 7 , 477f, 1624 delirium, 35f dementia, 4 7 6 - 4 7 7 , 477f encephalms, 471f, 4 7 5 - 4 7 6 , 834 epilepsy, 4 6 8 ^ 1 7 2 , 469f-472f focal cerebral lesions, 4 7 2 , 474f generalized ronic-clonic seizures, 1961 glioblastoma, 473f global developmental delay, 79 headache, 2 7 0 head trauma, 4 7 2 herpes simplex encephalitis, 471f, 4 7 5 , 8 3 4 , 1518 hypoxia, 4 7 4 - 4 7 5 , 475f-476f, 1670 infectious diseases, 4 7 5 - 4 7 6 metabolic encephalopathies, 4 7 3 - 4 7 4 , 474f migraine, 4 7 2 neonatal seizures, 2 5 1 3 overview of, 4 6 7 - 4 6 8 partial seizures, 1 9 5 8 - 1 9 5 9 portal systemic encephalopathy, 1091 pseudoseizure, 20 psychogenic seizures, 1 9 7 1 - 1 9 7 2 seizures, 19, 9 8 7 , 1 9 7 5 - 1 9 7 6 stroke, 1308 syncope, 17 ton it seizures, 1962-1963 viral encephalitis, 4 7 5 computerized, 4 7 7 - 4 7 8 delta activity, 4 7 2 , 474f description of, 465 disadvantages of, 4 6 6 electrocorricography vs., 465 electrodes used in, 4 6 6 ^ 1 6 7 epileptiform discharges description of, 4 6 6 in qiilepsY, 46S focal, 4 6 9 , 469f periodic lateraltzed, 471f focal arrhythmic slow activity, 4 6 6 generalized arrhythmic slow activity, 4 6 6 ictal, 1961 interictal, 1 9 6 1 , 1 9 7 5 - 1 9 7 6 intermittent rhythmic slow waves, 4 6 6 interpretation of results, 467—468 intraoperative monitoring uses of, 488 limitations of, 4 6 6 neurosciences critical care unit use of, 945 normal findings, 4 6 6 , 467f physiologic principles of, 4 6 5 - 4 6 6 polymorphic slow activity, 4 6 6 recording techniques, 4 6 6 ^ 1 6 7 , 4 6 8 / , 477^178 signal generation, 4 6 5 video recording with, 4 6 9 , 4 7 2 voltage attenuation, 4 6 6
Electrolyte brain levels of, 1748 imbalances of calcium, 1094 magnesium, 1 0 9 4 - 1 0 9 5 neurosciences critical care unit management of, 9 5 3 - 9 5 4 potassium, 1094 sodium, 1 0 9 3 - 1 0 9 4 uremic encephalopathy and, 1682 Electromagnetic fields, 1334 Electromyography blink reflex, 5 1 4 clinical uses of botulism, 2 4 5 9 cramps, 3 9 1 floppy infant, 4 0 5 low back pain, 4 5 0 lower limb pain, 4 5 0 lumbosacral radiculopathy, 451 movement disorders, 3 2 1 muscle weakness, 3 7 6 myasthenia gravis, 2 4 4 6 - 2 4 4 7 urogenital symptoms, 7 5 3 description of, 4 9 1 E wave, 5 1 2 , 514f H reflex, 5 1 2 , 5 1 4 needle amyotrophic lateral sclerosis, 5 1 1 - 5 1 2 anterior horn cell disorders, 5 1 1 - 5 1 2 disadvantages of, 5 1 2 endplate noise, 5 0 3 , 5 0 4 t cndplatc spikes, 5 0 3 , 5 0 4 t insertional and s p o n t a n e o u s activity abnormal, 5 0 3 - 5 0 7 complex repetitive discharge, 506f, 5 0 7 cramp discharges, 507 decreased, 5 0 ? , 505 fasciculation, 504t fasciculation potentials, 5 0 5 fibrillation potentials, 5 0 5 m y o k y m k discharge, 506f, 5 0 7 myotonic discharges, 5 0 5 - 5 0 7 , 506f neuromyotonic discharges, 5 0 7 normal, 503 prolonged, 5 0 3 , 5 0 5 lower motor neuron lesions, 510f, 510-512 mononcuropathies, 511 motor unit action potential amplitude of, 5 0 7 duration of, 508 firing patterns, 5 0 9 interference pattern, 5 0 9 lower motor neuron lesions, 5 1 0 m o n o n e u r o p a t h y findings, 5 1 1 morphology of, 5 0 7 - 5 0 9 peripheral polyneuropathy findings, 511 phases of, 5 0 8 - 5 0 9 recruitment frequency, 5 0 9 recruitment ratio, 5 0 9 stability of, 5 0 9 , 509f voluntary, 5 0 7 - 5 0 9 myopathic disorders, 5 1 2 , 5 1 3 t peripheral polyneuropathies, 5 1 1 plexopathies, 511 principles of, 502—503 radiculopathies, 5 1 0 - 5 1 1 steps involved in, 5 0 3
Electromyography (Continued) techniques for, 5 0 2 - 5 0 3 upper m o t o r neuron lesions, 5 1 0 , 510f nerve conduction studies, see Nerve conduction studies neurological examination before, 491 single-fiber, 5 1 8 - 5 1 9 sphincter multiple system atrophy diagnosis using, 753-754 urinary retention in w o m e n evaluated by, 7 5 4 urethra] sphincter, 2 4 2 4 Electron ystagmography, 7 2 4 , 7 3 9 , 740f-741f Electro-oculography, 7 2 4 Electroretinogram, 1469 Elliptical pendular nystagmus, 2 1 6 Embolism amniotic fluid, 1 2 2 5 - 1 2 2 6 arteriogenic, 1209 cardiogenic acute myocardial infarction a n d , 1211-1212 arrial fibrillation a n d , 1 2 1 2 - 1 2 1 3 atrial m y x o m a s , 1213 characteristics of, 1211 description of, 1074, 1209 dilated cardiomyopathy, 1212 echocardiogenic contrast material as source of, 1 2 1 3 investigations of, 1 2 3 3 left ventricle, 1211 mitral stenosis a n d , 1212 patent foramen ovale, 1213 prosthetic heart valves a n d , 1212 sick sinus syndrome, 1213 sources of, 1 2 1 1 , 1 2 1 2 t stroke caused by, 1 2 1 1 - 1 2 1 3 substrates, 1211 cerebral, 1212 drug abuse-related, 1724 nucleus pulposus, 1161 paradoxical, 1880 spinal cord ischemia caused by, 1316, 1317f Embolization aneurysms caused by, 1274 for arteriovenous malformations, 974 cerebral, 1102 hemangioblastoma, 994 Embryonal t u m o r s , 1354—1355 Emergency M a n a g e m e n t of Stroke Bridging Trial, 1008 Emerin deficiency, 2 4 7 9 Emcry-Drcifuss muscular dystrophy, 3 7 9 - 3 8 0 , 805t, 2 4 7 9 Emetine, 1566 Emotional incontinence, 100 Emotional lability, 32 Encephalitis brainstem, 172 cerebrospinal fluid pattern in, 8 3 3 - 8 3 4 computed tomography findings, 834 cytomegalovirus in AIDS, 1 5 9 1 - 1 5 9 2 description of, I524f, 1525 description of, 833 epidemics of, 833 epidemiology of, 8 3 3
INDEX
Encephalitis [Continued) herpes simplex acyclovir for, 834, 1518 brain biopsy indications, 987
cerebrospinal fluid findings, 15 IK characteristics of, 1516 clinical features of, 1516-1517 computed tomography of, 1518 description of, 62, 833
diagnosis of, 834, 1517-1518 electroencephalography of, 471 f, 475, 834, 1518 magnetic resonance imaging of, 558-559, 559f, 1518, 1523f Transmission of, 1516 treatment of, 834 human immunodeficiency virus, 562 Japanese, 832t, 1515 manifestations of, 834 measles, 1535-1536, 1660 rabies, 1534 Rasmussen's, 1541, 1959-1960 rubella, 1537 St. Louis, 832t, 1530, 1531t symptoms of, 833-834 toxoplasma, 560-562, 56 If Encephalocele, 1776 Encephalomyelitis acute disseminated characteristics of, 553, 553f, 825, 838 clinical features of, 1660 diagnosis of, 1661-1662
differential diagnosis, 1659t history of, 1659 idiopathic, 1660
laboratory features of, 1660-1662 lesions associated with, 1661, 1661f measles-induced, 1660 post vaccination, 1659-1660 recovery from, 1660 treatment of, 1662 benign myalgic, 1542 description of, 111 paraneoplastic, 1463-1464 post vaccination, 1659-1660, 1662 postvital, 1535 progressive encephalomyelitis with rigidity, 1541-1542 Viliuisk, 1541 Encephalopathy anoxic/ischemic cerebral edema and, 1667 sequelae of, 1668 clinical manifestations of, 1673-1674 dialysis, 1947 early infantile epileptic, 1965 eclamptic, 2543-2545 hepatic ammonia's role in, 1676-1677, 1679 astrocyte findings, 1680 cerebral blood flow evaluations, 1676 clinical features of, 1674-1675 complications of, 1681 description of, 1674 diagnosis of, 1675
electroencephalographs findings, 1675 etiology of, 1674-1675 evoked potentials for, 1675-1676 fatty acids and, 1680 fulminating hepatic failure vs., 1674t
Encephalopathy {Continued) glucose metabolism evaluations, 1676 hyperammonemia and, 1676, 1679 imaging of, 1676 magnetic resonance imaging of, 1676, 1677f magnetic resonance spectroscopy ot, 1676 mcrcaptans and, 1680 neuropathology of, 1680 neuropsychiatric abnormalities associated with, 1675t neuropsychological tests, 1675 neurotransmission abnormalities and, 1679 pathophysiology of, 1676-1680 prognosis for, 1681 treatment of amino acids, 1681 goals, 1680 lactulose, 1680-1681 hypertensive, 1102, 1753-1754, 1754f ischemic, 1775 lead, 1716 radiation, 1741 renal failure and, 1112 shigcllosis-related, 1506 subcorneal arteriosclerotic, 1934-1935 uremic acid-base imbalances and, 1682 calcium metabolism abnormalities in, 1682 complications of, 1682-1683 description of, 1681 electrolyte imbalances and, 1682 epileptic seizures in, 1682 neurotransmitter abnormalities in, 1682 parathyroid hormone metabolism abnormalities in, 1682 pathophysiology of, 1681-1682 renal failure in, 1682-1683 treatment of, 1682-1683 water imbalances and, 1682 Wernicke's alcoholism and, 1702-1703 clinical features of, 1702-1703 coma and, 47 course of, 1704 dialysis and, 1093 epidemiology of, 1703-1704 history-taking, 1702 laboratory studies, 1703 pathologic findings, 1703 physiology of, 1 703 prevenrion of, 45 prognosis for, 1704 treatment of, 1704 Endemic cretinism, 1110 Endocarditis, 1507 infective, 1077-1078 Endo-evoked akinesia, 118 Endolymphatic hydrops, 239 Endoncurium, 1181 or-Endorphin, 852t /i-Endorphin, 850t, 852t Endorphins, 924 Endoscopy, 989 Endostatin, 1409
vxxv
Endothelial cells junctions between, 1747 radiation therapy injury of, 1217 Endotracheal intubation, 947 Endovascular neurosurgery, 990 Kndovascular rhcrapy angiograms before, 993 approaches for, 993 arteriovenous malformations, 1015-1016 considerations for, 993-994 description of, 993 embolic agents, 994 intracranial aneurysms treated with, 969-970, 971f, 1012-1013 tumor embolization indications, 994 palliative uses, 994 principles of, 994-995 transarterial, 994-996 venous occlusive disease, 1018, 1020 Endplate noise, 503, 504t Endplate potential, 515 Endplate spikes, 503, 504t Enkephalins, 85 It, 924 /)-F.nolase deficiency, 2493 i'.iujpbthalmos, 49 Entacaponc, 2134t Entactin, 1747 Entamoeba histolytica, 1555, 1556t, 1566 Enterochromaffin cells, 868 Enteroviruses, 833 acute motor neuron disease, 1529 amyotrophic lateral sclerosis and, 1529 epidemic L-(iri|iinciiviiis caused by, 1529 meningoencephalitis caused by, 1529 viral meningitis caused by, 1528-1529 Entrapment neuropathy characteristics of, 231 It clinical features of, 2311 definition of, 2311 description of, 450 diabetes mellitus and, 2363 double crush syndrome, 2311 ilioinguinal nerve, 2312t, 2317-2318 intercostobrachial nerve, 2316 lateral femoral cutaneous netve, 2317 localized perineuria I hypertrophic mononeuropathy, 2318-2319 median nerve anterior interosseous nerve syndrome, 2313-2314 arm pain caused by, 434 carpal tunnel syndrome arm pain caused by, 439 causes of, 439, 2312-2313 characteristics of, 344t diagnosis of, 2312 differential diagnosis, 439 hypothyroidism and, 1097 localization of, 414t monoplegia caused by, 344 nerve conduction studies ot, 415, 439, 494^195 physical examination for, 439 predisposing conditions, 2313 sensory conduction assessments using inching technique, 494, 2313 sensory features of, 414t, 415 symptoms of, 2312 thenar atrophy associated with, 23l2f
Volume I iip. 1 I Ot'd • Volume II p. 1071 2546
xxxvi
INDEX
Entrapment neuropathy (Continued) Treatment of, 2313 characteristics of, 23lit, 2311-2312 at ligament of Struthers, 2314 pronator teres syndrome, 2314 musculocutaneous nerve, 2315 nerve conduction study localization of, 494 obturator nerve, 2312t, 2318 peroneal nerve, 2316-2317 posterior tibial nerve, 2317 radial tiitvi, 231 It, 2315 sciatic nerve, 2312t, 2316 suprascapular nerve, 2316 sural nerve, 2317 ulnar nerve arm pain caused by, 434 characteristics of, 231 It at elbow, 439^140, 2314 at wrist in the ulnar tunnel, 2314-2315 Enuresis, primary, 2037 Envenomation, 1728 Environmental enrichment, for traumatic brain injury recovery, 1124 Enzyme replacement therapy, for inborn errors of metabolism, 1819t Eos inoph ilia, 1558 Eosinophilic pleocytosis, 1551 Ependymal cells, 1749 Ependymomas anaplastic, 1384-1385, 1414 characteristics of, 538-539, 580f-581f, 580-581, 1344f in children, 1432-1433 fourth ventricle, 1433f imaging of, 1384-1385, 1389f management of, 1414
myxopapillary, 1352 prognosis for, 1433 radiation therapy for, 1433 spinal cord, 1433 subependymoma, 1352, 1385, 1414-1415 Ephaptic transmission, 409 Ephedra, 1219 Epicondylitis, 442 Epidemic conjunctivitis, 1529 Epidemic neuromyasrhema, 1542 Epidemics human immunodeficiency virus, 773 multiple sclerosis, 773, 774f Epidemic typhus, 1500-1501 Epidemiology definition of, 763 population-based rates, 763-764 Epidermal growth factor receptor, 1330, 1347, 1408 Epidermal nevus syndrome cutaneous features of, 1890 definition of, 1890 imaging of, 1891 neurological features of, 1890-1891 ocular abnormalities associated with, 1891 seizures in, 1 890
tumors in, 1891 Epidermoid cysrs, 527, 530f, 547, 550f, 1361, 1393 Epidural abscess characteristics of, 596-597, 967 cranial, 1488, 1489f spinal, 1489-1490, 2213-2214
Epidural hematoma clinical presenration of, 1136 description of, 47 magnetic resonance imaging of, 556, 557f mortality caused by, 1141 prognosis for, 1141 spinal, 594 traumatic brain injury as cause of, 1128-1129, 1129f uncal herniation caused by, 1136 Epidural hemorrhage neonatal, 25261 spinal, 1321 Epidural lipomatosis, 2218-2219 Epidural spinal cord compression bladder dysfunction in, 1447 bowel dysfunction in, 1447 characteristics of, 363, 365, 437, 1374, 1374f, 1446 chemotherapy for, 1449-1450 clinical presentation of, 1447 corticosteroids for, 1449 decompressive laminectomy for, 1449 differential diagnosis, 1447r, 1447-1448 epidemiology of, 1446 imaging of, 1448-1449 magnetic resonance imaging of, 1448h, 1448-1449 management of, 1449-1450 motor system involvement, 1447 osteoarthritis vs., 1448 pathology of, 1446 pathophysiology of, 1446 radiotherapy for, 1449 sensory loss associated with, 1447 vertebral corpectomy for, 1449 Epilepsia partialis continua, 1959 Epilepsy, see also Seizures age-based incidence of, 769, 1954 aggression in, 99 antiepileptic drugs for behavioral effects of, 1980 benzodiazepines, I 98 1-1 982 brain rumor-re la ted seizures treated with, 1366, 1366t calcium channels and, l) I 3 cognitive effects of, 1980 ethosuximide, 1982t, 1983 fclbamate, 1982t, 1983 gabapentin, 1982t, 1983-1984 lamotrigine, 1982t, 1984 levetiracetam, 1982t, 1984 long-term effects of, 695 oxcarbazepine, 1982t, 1984-1985 phenobarbital, 1982t, 1985 phenytoin, 1982r, 1985 primidone, 1982t, 1985 sodium channel binding of, 911-912 nagabine, 1982t, 1985-1986 topiramatc, 1982t, 1986 valproic acid, 1982t, 1986 vigabatrin, 1982t, 1986-1987 zonisamide, 1982t, 1987 antiepileptics for, 695 aura, 1956 autosomal dominant nocturnal frontal lobe, 1848t, 1862, 1975 behavioral disturbances in, 97-99 benign childhood epilepsy with centrotemporal spikes, 1959
Epilepsy (Continued) benign rolandic, 471f, 1959 catamenial, 1972 childhood benign childhood epilepsy with centrotemporal spikes, 1959 with occipital paroxysms, 1959 classification of, 1955t cognitive deficits associated with, 695 delirium caused by, 37 depression in, 98-99 dopamine's role in, 8961 driving issues, 1961 electroencephalography evaluations, 468-472, 469f-472f epidemiology of, 1954 executive functioning deficits, 694-695 falls caused by, 336 focal, 469, 469f iiunml lube autosomal dominant, 2026 executive functioning deficits associated with, 694-695 nocturnal, 2026 generalized with febrile seizures, 1863-1864, 1975 idioparhic, 1864-1865 with generalized tonic-clonic seizures on awakening, 1965 genetics of, 1974-1975 glutamate's role in, 888t head trauma and, 1970 history of, 1953 hormonal effects on, 1972 ictal state, 97t incidence of, 768-769, 1954 intellectual functioning in, 694 interictal state, 97t language disorders associated with, 694 memory dysfunction in, 694 morbidity rates for, 768-769, I960 mortality rates for, 768, 769f muscarinic receptors and, 893t myoclonic description of, 316 electroencephalography findings, 469, 469f familial adult-onset, 1864-1865 with ragged-red fiber myopathy, 1845 severe myoclonic epilepsy of infancy, 1864 with myocIonic-astatic seizures, 1966 neuropsychological characteristics of, 693-695 neurosurgical treatment of, 987-988 pathophysiology of description of, 88It, 1972 epileptogcncsis, 1973-1974 genetics, 1974-1975 glial cells, 1974 ion channels, 1974 mesial temporal sclerosis, 1972-1973, 1973f, 1977 neurotransmitter sysrems, 1973-1974 personality disturbances in, 97-99 perit mal, 469, 470f postanoxic coma and, 1668 postictal state, 97t posttraumatic, 1970 prevalence ot, 115, 1 954
INDEX Epilepsy {Continued) prognosis, 1954 progressive facial hemiatrophy and, 1884 psychiatric disturbances associated with, 113 psychosis in, 99, 113 Rasmussen's encephalitis, 1541, 1959-1960 rolandic, 471 f serotonin's role in, 90If sexual dysfunction in, 424 sleep effects, 2025 sudden unexplained death in, 1960-1961 suicide rate in, 98 surgical treatment of, 695, 696r Temporal lobe definition of, 1957 language disorders associated with, 694 memory dysfunction associated with, 694 positron emission tomography findings, 669f surgical resection for, 695 treatment of anterior temporal lobectomy, 1989 carbonic anhydrase inhibitors, 1987 corpus callosotomy, 1990 corticosteroids, 1987 discontinuation of, 1979 focal cortical resection, 1989 hem isph c rectomy, 1990 initiation of, 1978-1979 ketogenic diet, 1987-1988 lesionccromy, 1989 medications adverse effects of, 1980 anticonvulsants, 1980 antiepilcptic drugs, see Epilepsy, antiepileptic drugs selection of, 1980-1981 multiple subpial transections, 1989-1990 surgery, 1988-1990 systematic approach, 1979 therapeutic drug monitoring, 1979-1980 vagus nerve stimulation, 1990 Epileptic syndromes ahsenee syndromes, 1965 benign familial neonatal convulsions, 1848t, 1862-1863, 1964 benign generalized, 1963-1965 benign myoclonic epilepsy of infancy, 1964 febrile seizures clinical features of, 1963 definition of, 1963 description of, 770 epidemiology of, 1963 generalized epilepsy with, 1863-1864 genetics of, 1963-1964 incidence of, 1863 management of, 1964 prognosis, 1963 juvenile myoclonic epilepsy, 1964—1965 l.afora's disease, 1967 I.andau-Kleffner syndrome, 1967 Lcnnox-Gastaut syndrome, 1966 progressive myoclonic epilepsies, 1967 severe generalized, 1965-1970
Epileptic syndromes (Continued) s rat us epileptic us benzodiazepines for, 1968, 1969t clinical features of, 1967-1968 definition of, 959, 1967 electrical, 1967 electroencephalography monitoring for, 945 epidemiology of, 1968 fosphenytoin for, 1968 generalized convulsive, 945 incidence of, 768, 959, 1968 management of, 1968-1970, 1969t morhidity and mortality of, 1968 neurosciences critical care unit management of, 959-960 phcnobarbital for, 1968, 1969t phenytoin for, 1968 tonic, 1967-1968 treatment of, 870, 1968-1970, I 969t treatment protocol for, 959-960 Unverncbt-I.undhorg disease, 1967 West's syndrome, 1965-1966 Hpileptogenesis, 1973-1974 Epileptogenic / o n e , I 4SSI
Epinephrine chemistry of, 896 description of, 896 disorders associated with, 882t, 899t distribution of, 896 excitatory effects of, 898 receptors, 896-897 Epineurium, 1181, 1193f Episodic anisocoria, 224 Episodic ataxia, 1848t Episodic autonomic hypcrrcflcxia, 1052 Episodic memory, 68 Episodic nystagmus, 220 Epivir. see l.amivudinc Epstcin-Barr virus central nervous system lymphoma and, 1359 cerebrospinal fluid polymerase chain reaction detection of, 1526 characteristics of, 832t diagnosis of, 1525 infection caused by, 1525 intravenous immunoglobulin for, 1525
latent, 1525 myelitis caused by, 835 neurological complications of, 2389 polymerase chain reaction diagnosis of, 1520t Viral Capsid Antigen, 1525 Epworrh Sleepiness scale, 201 Ot Erb's palsy, 347, 1186 Erectile dysfunction amyloid neuropathy and, 429 apomorphine hydrochloride for, 761
description of, 760 diabetic neuropathy and, 429 multiple sclerosis and, 428, 1655 multiple system atrophy and, 425^126 Parkinson's disease and, 425 peripheral neuropathy and, 749 radical prostatectomy and, 429 sildenafil for, 760-761 spinal cord injury and, 1174-1175 temporal lobe damage and, 424
xxxvii
Erecrile dysfunction [Continued) treatment for, 760-761, 1175, 2436 vacuum pump devices for, 761, 1174 Ergotamine tartrate cluster headaches treated with, 2093 migraines treated with, 2081 Erythema migrans, 2392 Erythema nodosum leprosum, 1495 Erythromclalgia, 443 Erythromycin legionellosis treated with, 1507 pertussis treated with, 1507 E-sarcoglycan, 320 Esodeviation, 722 Esotropia causes of, 722t Chiari malformations and, 201
congenital, 201 cyclical, 723 description of, 71 1 differential diagnosis, 722t lateral rectus muscle palsy as cause of, 203f, 207 Essential myoclonus, 2161 Essential thromhocythemia, 1230 Essential ti LiiiiJI--, age at onset, 2145 characteristics of, 307f, 803t, 988 clinical features of, 2144-2145 diagnostic criteria for, 2145t epidemiology of, 2144-2145 etiology of, 2145-2146 stereotactic thalamotomy for, 2146 l real n lent of, 2146 Esrhesioneuroblastoma, 1405, 1415-1416 Ethambutol, 1492t, 2383 Etbosuximide, 98t, 1965, 1982t, 1983 Ethylene oxide, 1711 Erhylnirrosourea, 1336 Eromidate, 1133 Etoposide, 1407, 2383 Euphoria in frontotemporal dementia, 90 in multiple sclerosis, 96-97 in neurological disorders, 86t Evoked potentials brainstem auditory acoustic neurinoma, 482, 482f-483f brainstem lesions, 482 definition of, 481 hearing assessments using, 483-484, 745 multiple sclerosis, 482-483 neurological diseases, 482^184 normal, 481-482, 482f coma evaluations, 62 definition of, 478 dementia evaluations, 477 hepatic encephalopathy, 1675-1676 hypoxia evaluations, 1670-1671 intraoperative monitoring using, 487-488 motor, 486-487 multiple sclerosis evaluations, 1651 pudendal, 754, 755f somatosensory description of, 484 hypoxia, 1670 intraoperative monitoring uses of, 488 median nerve, 484, 484M85f Volume 1 pp. 1-1070 • Volume II p. 1071-2546
xxxviii
INDEX
Evoked potentials [Continued) multiple sclerosis findings, 4 8 6 , 1651 neurological diseases, 486 posterior tibial nerve, 4 8 4 - 4 8 5 , 486f stimulus patterns, 47&-A79 visual a b n o r m a l , 4811 description of, 479 flash, 4 7 9 migraine evaluations, 2 0 7 6 multiple sclerosis findings, 1651 in. i.irrj-opiviil ilisi-iisi1 u s e of, 481] 48 If normal, 4 7 9 - 4 8 0 , 480f pattern reversal, 4 8 0 - 4 8 1 , 481f Ewing's sarcoma, 1354, 1446 Examination general, 7 neurological, 6 - 7 , 7t ocular, 2 2 5 - 2 2 7 syncope, 1 2 - 1 3 Excessive daytime sleepiness causes of, 2 0 0 5 - 2 0 0 7 , 2 0 0 6 t cerebral function effects, 2005 consequences of, 2004r medical disorders associated with, 2 0 0 7 morbidity and mortality risks, 2005 myotonic dystrophy and, 2 0 0 7 , 2 4 8 4 neurological causes of, 2 0 0 6 - 2 0 0 7 obstructive sleep apnea syndrome a n d , 2021 pathological causes of, 2 0 0 6 - 2 0 0 7 performance effects, 2 0 0 4 physiological causes of, 2 0 0 5 - 2 0 0 6 productivity effects, 2 0 0 4 quality of life effects, 2005 sleep disorders associated with, 2 0 0 7 social interacrion effecrs, 2005 Excitatory amino acids, 1239, 1731-1732 Excitatory burst neurons, 704 Excitatory postsynaptic potentials, 8 8 5 , 887, 909 Excitotoxicity, 884 Executive functioning epilepsy effecrs, 6 9 4 - 6 9 5 Parkinson's disease effects, 6 8 9 traumatic brain injury effects, 698t Executive motor system, 1044 Exercise disorders exacerbated by, 3 8 2 - 3 8 3 muscle pain caused by, 388 positional vertigo treated with, 746-747 Exercise-induced syncope, 13 Exercise testing muscle weakness evaluations, 3 7 7 - 3 7 8 syncope evaluations, 17 Exertional headache, 2071 Exo-evoked akinesia, 118 Expanded disability status score, 1 6 4 5 - 1 6 4 6 , 1653 Extensor digitorum brevis, 371f External anal sphincrer, 1173 External carotid artery anatomy of, 6 2 6 - 6 2 7 branches of, 628t disorders of, 6 2 7 Extra-axial posterior fossa syndromes, 2111-2112
Extraocular muscles actions of, 199, 2 0 0 t anatomy of, 200f pulling actions of, 199 weakness of description of, 3 6 8 diagnostic approach t o , 3 7 8 yoked pairs of, 1 9 9 , 200r Extrapyramidal disease, 3 2 4 - 3 2 5 Eye(s} autonomic failure a n d , 2 4 2 0 , 2429-2430 bobbing of, 56 caloric testing of, 5 6 - 5 7 connective tissues of, 201f deviation of, 5 5 - 5 6 dipping of, 56 d o w n w a r d deviation of, 55 examination of, in coma evaluations, 49 Fabry's disease manifestations, 1 8 8 0 , 1881F funduscopic examination of, 49 lateral deviation of, 55 melanoma of, 5 7 8 , 578f muscles of. see Extraocular muscles myasthenia gravis findings, 2 4 4 2 t neuro-ophrhalmological examination contrast sensitivity testing, 7 2 9 - 7 3 0 light brightness comparison, 731 lighr stress test, 7 3 0 pupil examination, 7 3 0 - 7 3 1 visual acuity, 7 2 8 - 7 2 9 visual field testing, 7 3 1 - 7 3 3 nystagmus of, 56 oculocephalic reflex of, 56, 57t peripheral visual field in, 7 2 7 pupil of. see Pupil reflex movements of, 5 6 - 5 7 retina of. see Retina retinoblastoma of, 5 7 8 roving movements of, 56 spontaneous movements of, in comatose patients, 56 Eyelid abnormalities apraxia of lid opening, 2 3 0 - 2 3 1 , 2 3 I f clinical presentation of, 2 2 8 - 2 3 0 elevation lower lid, 2 2 9 paradoxical, 2 1 0 examination of, 2301, 2 3 0 - 2 3 2 hemifacial spasm, 2 3 0 , 230f investigations of, 2 3 2 lid closure examinarion of, 2 3 1 excessive, 229-230 insufficient, 2 2 9 ptosis acquired, 2 2 8 congenital, 228 exrraocuiar muscle weakness a n d , 368 frontalis muscle contraction associated with, 2 3 0 - 2 3 1 levator aponeurosis dehiscence a n d , 2 2 8 lid retraction associated with, 2 2 9 neuropathic causes of, 2 2 8 , 228t retraction description of, 2 2 9 examination for, 2 3 0 - 2 3 1 types of, 2 2 8 t
Eye movements cerebellar lesions that affect, 7 0 9 control of, 7 0 1 - 7 0 3 fixation, 703 generation of, 7 0 1 - 7 0 3 hcterophorias, 2 0 0 heterotropias, 2 0 0 horizontal description of, 7 0 4 physiology of, 7 0 4 - 7 0 8 mechanisms for, 7 0 2 - 7 0 3 pursuit control of, 7 0 7 - 7 0 8 defects of, 7 0 8 - 7 0 9 description of, 703 impairments in, 7 0 8 - 7 0 9 pathways for, 7 0 8 , 708f smooth, 7 0 7 - 7 0 8 tecordings of, 703f, 724 saccades in cerebellar ataxia, 2 8 9 classification of, 7 0 6 - 7 0 7 cortical areas that control, 7 0 7 description of, 703 diplopia assessments, 2 0 5 in d o w n g a z e paresis, 2 7 5 externally triggered, 706 frontal eye field's role in producing, 7 0 7 function of, 703 intentional, 704t, 7 0 6 internally triggered, 706 medial longitudinal fasciculus a n d , 7 1 0 recordings of, 703f reflex, 7 0 3 reflexive, 704r spontaneous, 7041, 7 0 6 - 7 0 7 testing of, 2 0 5 types of, 7 0 4 t in upga/£ paresis, 274 types of, 7 0 4 t vergence, 7 0 3 , 709 vertical, 7 0 6 , 7 0 9 - 7 1 0 F Eab portion, SI I Fabry's disease clinical fearures of, 1 8 8 0 - 1 8 8 1 , 2333-2334 description of, 805t, 1 2 2 4 , 1304, 1880 nerve conduction studies, 2 3 3 3 ocular abnormalities associated with, 1 8 8 0 , 1881f treatment of, 1 8 8 1 , 2 3 3 3 - 2 3 3 4 Facet pain syndrome, 449t, 4 5 5 Facial artery, 62Kt Facial nerve Bell's palsy, 2 1 1 5 - 2 1 1 7 bilateral facial palsy, 2 1 1 5 - 2 1 1 6 congenital disorders of, 2 1 1 4 course of, 2 1 1 2 - 2 1 1 3 , 2113f evaluation of, 2 1 1 4 - 2 1 1 5 hemifacial spasm. I I I " infections of, 2 1 1 7 lesions of, 2 1 1 3 blink reflex for, 5 1 4 M o bins' syndrome, 2 1 1 4 n e u r o a n a t o m y of, 2 1 1 2 - 2 1 1 4 paresis of, in multiple sclerosis, 1640 reflex testing, 2114
INDEX
Facial nerve (Continued) regeneration of, 1184 roots of, 2 1 1 2 sensory root of, 2 1 1 2 toxins effect on, 2 1 1 4 traumatic paralysis of, 2 1 1 4 tumor involvement of, 2116 Facial pain, atypical, 2 0 9 9 Facial paralysis, 2 5 2 6 - 2 5 2 7 Facial weakness description of, .368 lower motor neuron lesions, 2 1 1 4 t upper motor neuron lesions, 2114t Facioscapulohumeral muscular dystrophy characteristics of, 2 4 8 0 clinical features of, 2 4 8 0 description of, 3 6 8 , 2 4 6 6 , 2467f diagnosis of, 3 7 8 - 3 7 9 , 380f, 2480-2481 D N A studies for, 2 4 8 0 , 2481f genetics of, 2 4 8 0 scapular winging associated with, 3 7 0 , 371f, 378 severity of, 2480 treatment of, 2 4 8 0 - 2 4 8 1 Factor VIII deficiency, 1108 Factor V Leiden, 1200, 1227 Fahr's disease, 1930, 2 1 4 3 Failed back syndrome, 938 Faint, common, see also Syncope signs and symptoms of, 15 syncope caused by, 15 Falls, see also Drop attacks causes of cerebellar disorders, 2 5 - 2 6 cerebral disorders, 2 5 - 2 6 diffuse Lewy body disease, 25 epilepsy, 336 loss of consciousness, see Loss of consciousness Meniere's disease, 26 myelopathy, 25 myotonic dysrrophy type 1, 2 4 8 4 neuromuscular disorders, 25 overview of, 24t Parkinson's disease, 2 5 , 3 3 0 progressive supranuclear palsy, 25 vestibular disorders, 26 cryptogenic, 26 in elderly, 2 6 - 2 7 gait disturbances and, 325 in middle-aged w o m e n , 26 neurological examination for, 23 pathologic conditions a n d , 27 spontaneous, 3 2 5 stroke-induced, 1243 traumaric brain injury caused by, 1127 False localizing signs, 8 False paternity, 7 8 4 - 7 8 5 Famciclovir, 8 4 7 , 1521t Familial adulr-onset myoclonic epilepsy, 1864-1865 Familial amyloid polyneuropathy definition of, 2 3 2 9 description of, 4 2 9 D N A diagnosis of, 2331 transthyretin amyloidosis, 2 3 2 9 - 2 3 3 1 , 2330t treatment of, 2331 type I, 2 3 2 9 - 2 3 3 0
Familial amyloid polyneuropathy {Continued) type II, 2 3 2 9 - 2 3 3 0 type III, 2 3 3 0 type IV, 2 3 3 0 - 2 3 3 1 Familial Creutzfcldt-Jakob disease characteristics of, 1620t clinical features of, 1 6 2 2 - 1 6 2 3 differential diagnosis, 1623 epidemiology of, 1 6 1 4 , 1 6 2 2 - 1 6 2 3 genetics of, 1615 neuropathologic findings, 1619 phenotype, 1615, 1616r Familial d y s a u t o n o m y , 804t, 2327t, 2328-2329 Familial episodic ataxias clinical features of, 1859 definition of, 1859 diagnosis of, 1860 forms of, 1859 myokymia associated with, 1 859 pathophysiology of, 1 8 5 9 - 1 8 6 0 treatment of, 1860 Familial hemiplegia migraine clinical features of, 1848t, 1857, 2076-2077 description of, 1 2 2 2 , 1305 diagnosis of, 18.58-1859 genetic mutations associated with, 1857-1858 pathophysiology of, 1 8 5 7 - 1 8 5 8 treatment of, 1859 Familial horizontal gaze palsy, 715 Familial petsistent hypcrinsulinemic hypoglycemia of infancy, 1848t Familial spastic paraplegia, X03r-804r Family history, 6 Fanconi's syndrome, 1 1 0 7 Harbor disease, 1822t Fa rnesy I transferase, 1408 Fascicles, 1181 Fasciculation potentials, 505 Fasciculations muscle weakness evaluations a n d , 374 needle electromyography, 5 0 4 t Fas tigand, 8 1 9 Fast-food maneuver, 375 Fast Fourier transform, 6 4 7 Fast spin-echo sequences, 5 2 3 Fatal familial insomnia characteristics of, 1620t clinical features of, 1 9 4 , 1 6 2 3 , 2 0 2 8 definition of, 2 0 2 8 description of, 1614 generic mutations, 1616t neuroendocrine functions in, 2028 neuropathology associated with, 1619, 2028-2029 Fatigue management of, 1654 multiple sclerosis a n d , 1642, 1654 muscle weakness a n d , 373 Parkinson's disease, 2 1 3 2 Far suppression techniques, for magnetic resonance imaging, 5 2 3 Fatty acids description of, 3 8 2 oxidation defects, I 826 Faucial diphtheria, 1511 Fazio-Londc disease, 2 2 4 0
xxxix
Febrile seizures clinical features of, 1963 definition of, 1963 description of, 7 7 0 epidemiology of, 1 9 6 3 generalized epilepsy with, 1 8 6 3 - 1 8 6 4 , 1975 generics of, 1 9 6 3 - 1 9 6 4 incidence of, 1 863 management of, 1964 ptognosis, 1963 Fecal incontinence description of, 49 dietary control, 1174 management of, 1 7 4 , 7 6 1 - 7 6 2 spinal cord injury a n d , 1053, 1172 Felbamate, 98r, 1982t, 1983 Feldene. see Piroxicam Female sexual response, 4 2 3 Femoral nerve entrapment neuropathy of, 2 3 1 2 t lesions of, 357t motor functions of, 4 4 8 t sensory functions of, 448t Femoral n e u r o p a t h y , 2 2 9 4 clinical features of, 449t diagnosis of, 449r differential diagnosis, 4 4 9 t gait disturbances caused by, 3 3 5 leg pain associated with, 452—453 monoplegia caused by, 3 4 5 Fentanyl, 934t, 936 Festination, 3 2 7 , 3 3 0 Fetal hydantoin syndrome, 2529f Fetal posterior cerebral artery, 6 3 8 - 6 3 9 Fetus brain of Cajal-Retzius cells, 1 7 7 3 - 1 7 7 4 cerebral cortex, 1773 motor cottex, 1773f ischemic encephalopathy in, 1775 Fever Argentine hemorrhagic, 1538 Dengue, 1538 description of, 8 5 3 - 8 5 4 headache with, 268 Lassa, 1538 Q , 1500 rat-bite, 1504 relapsing, 1 4 9 9 - 1 5 0 0 rheumaric, 1508 after traumatic head injury, 1121 yellow, 1538 l!i F-Fluorodeoxyglucose, 6 6 7 Fibrillation potentials, 505 Fibrin, 1006 Fibrinogen abnormalities, 1227 Fibromuscular dysplasia, 1218, 1 2 l 8 f Fibromyalgia, 4 4 1 - 4 4 2 , 2 2 2 0 - 2 2 2 2 , 22211 Fibromyalgia syndrome, 2 0 3 4 Fibronectin, 1 7 4 7 Fibular m o n o n c u r o p a t h y , 2 3 1 6 Fibular nerve, enrrapmenr neuropathy of, 2312t Filamentous bacterial infections actinomycosis, 1 5 0 5 - 1 5 0 6 nocardiosis, 1505 Filovirus, 1517t Filovituses, 1 5 3 8 - 1 5 3 9 Finger-to-nose testing, in c ho tea, 3 0 9 Finklcstcin test, 4 4 2 Volume I p p . 1-1070 • Volume II p. 1071-2546
xl
INDEX
First-order neuron, 53 Fistula carotid-cavernous, 557, 558f, 613, «S 14f, 1017-1018, I019f-I020f, 1878-1879 spinal dural description of, 984 diagnosis of, 984-985 illustration of, 985f neurosurgical treatment of, 984-985 Flaccid dysarthria, 161, 162r Flaviviridac, 832t Fiavi virus characteristics of, 1516r St. Louis encephalitis virus, 832t, 1530 West Nile virus, 832t, 1520t, 1530-1531, 1531t Flocculus, 709 Floppy infant cardinal signs of arthrogryposis congenita multiplex, 396-397, 398t endurance, 399 overview of, 394t postural responses, 399 power, 395 range of movement, 396-397 reflexes, 397-399 sensation, 400 strength, 395, 398t tendon reflexes, 397-399 tone, 393-395, 39Si-396i clinical tests fetal posture, 401 horizontal suspension, 401 traction response, 400^101 vertical suspension, 401 description of, 393 differential diagnosis, 393, 394t laboratory tests for description of, 405 edrophonium test, 406 electromyography, 405 muscle biopsy, 405 nerve hiopsy, 405—406 nerve conduction studies, 405 neuroimaging, 405 maternal assessments, 401, 40It syndromes associated with cerehral disorders, 401^403 characteristics of, 4021 chronic progressive encephalopathy, 402 congenital myotonic dystrophy, 402 high cervical spinal cord, 402 hypotonia, 401-402 infantile polyneuropathy, 403 motor ncuronopathy, 402 myopathy, 404-405 neuromuscular junction disorders, 403^104 Flow cytometry, 1346 Fluconazole, 1547t, 1552-1553 Flucytosine, 1547t, 1552 Fludrocortisone, 2431 Flu id-attenuated inversion recovery imaging, 529-530, 531f Fluid percussion concussion model, of traumatic brain injury, 1115-1116 Fluorescence in situ hybridization, 785
Fluorine magnetic resonance spectroscopy, 668 Fluoroquinolones, bacterial meningitis treated with, 14811 Flutter dysmetna, 223 Focal cerebellar dysplasia, 1788 Focal cerebral ischemia, 1666 Focal localizing signs, 8 l-'ni\-.AljIOUJrune's syndroms. 1317 Foix-Chavany-Marie syndrome. see Opercular syndrome Folate deficiency clinical features of, 1697-1698 cognitive impairment caused by, 1697 description of, 109, 1697 etiology of, 1698 laboratory studies of, 1698 pathogenesis of, 1698 polyneuropathy, 2376 psychiatric disturbances associated with, 109 treatment of, 3698 Folinic acid, 1568, 18l9t Follicle-stimulating hormone characteristics of, 856t tumors that secrete, 861 Footdrop amyotrophic lateral sclerosis and, 2250f causes of, 3281 description of, 324-325 myopathic weakness and, 335 Foramen magnum lesions, 361 Foramen magnum syndrome, 278 Foramen of Monro, 543f, 964, 964f Foramina of I.uschkc, 2058 Foramina of Magcndie, 2058 Forced ductions, 209-210, 210t Forearm testing, for muscle weakness evaluations, 377-378 "Foreign accent syndrome," 163 Foscarnet, 847, 1521t, 1525 Fosphenytoin, 1968 Foster Kennedy syndrome, 187 14-3-3 protein, 1624 Fovea, 727 Foville's syndrome, 341t, 1206, 2120t Fractures axial compression, 592-593, 593f burst, 586 cervical spine, 584-587 Chance, 592, 592f clay shoveler's, 585 hangman's, 585, 585f Jefferson, 585-586, 586f odontoid, 586-587, 587f thoracic spine, 590, 591f thoracolumbar, 590-591 Fragile X premutation, 2147 Fragile X syndrome characteristics of, 1793t clinical features of, 80t description of, 1792 genetic mutation associated with, 78, 787, 793, 805t trinucleotide repent expansion in, 793 Frameless stereotaxis, 989-990 Free nerve ending, 408t Free radicals, 1751, 2247 Free radical scavengers, 1121-1122
Fresh frozen plasma, 954 Fried rich's ataxia characteristics of, 783f, 804t clinical features of, 2173 genetic mutation associated with, 2173-2174 nerve conduction studies, 2173 neuropathy associated with, 2329 pathogenesis of, 2174 point mutations in, 2174 treatment of, 2174-2175 Frontal cortex consciousness and, 67 self-concept and, 67 striatal projections of, 122 Frontal eye field definition of, 702 saceade production and, 707 supplementary eye field and, 707 Frontal lohe abscess of, 1484 arteriovenous malformations of, 1293f ataxia, 327t, 334 dorsolateral, 122-123 inferior parietal lobe connection with, 122 intentional network and, 122 lesions of bladder dysfunction caused by, 423 description of, 68 gait disturbances associated with, 333-334 seizures of, 1957-1958 traumatic brain injury-related damage of, 698 tumors of, 1364 Frontal lobe epilepsy autosomal dominant, 2026 executive functioning deficits associated with, 694-695 nocturnal, 2026 Frontal sinusitis, 2069 I 'ronta I -subcortical circuitry anterior cingulate circuit description of, 86 disruption of, 87t-88t description of, 85-86 dorsolateral circuit characteristics of, 87t description of, 86, 87f disruption of, 87t-88t orhitofrontal circuit characteristics of, 87t description of, S6 disruption of, 87t schematic diagram of, 86 f Froiitotemporal degeneration with parkinsonism linked to chromosome 17, 2142-2143 1*rontotemporal dementia Alzheimer's disease vs., 6K9t, 1919 amvotrophic lateral sclerosis and, 688, 1922 anatomic sites of, 1917 apraxia and, 1922 autosomal dominant, 2261 behavioral symptoms of, 89, 112, 1918 characteristics of, 112 cholinergic deficits in, 1920-1921 classification of, 1920t
INDEX
F ran tote mporal dementia {Continued} clinical features of, 689r, 1918 clinical presentation of, 6 8 8 - 6 8 9 cortical neurons in, 1919 definition of, 1917 depression in, 8 9 - 9 0 description of, 156, 688 diagnostic ctiteria for, 90t, 1918t differential diagnosis, 1 9 1 8 - 1 9 1 9 epidemiology of, 112, 1918 euphoric symptoms in, 90 extrapyramidal signs associated with, 1919 familial cases of, 156 F I P D 1 7 genetic mutation, 1919 genetic findings, 156, 791f, 8 0 5 t histological types of, 688 history of, 1917 lahorarory studies of, 1919 language deterioration associated with, I t tumor suppressor, 806t iLiidcrcxprcssion DI. SU2 Gene carrier, 783 Gene libraries, 797 Gene mutations description of, 790, 791 f single base-pair, 791 types of, 79If Generalized anxiety disorder, in vascular demenria, 91 Generalized lymphadenopathy, 50 Generalized tonic-cIonic seizures arterial blood gas monitoring, 1960 clinical features of, 1960 complications "I. I l'f>0 I 9 b I elearociiccphalographic characteristics of, 1961 epilepsy with, 1965 fractures associated with, 1960 injury rates, 1960 phases of, 1960
Gene therapy bacterial enzymes transfected into tumor cells, 1410 brain tumors treated using, 1409-1410 description of, 1195 Duchenne's muscular dystrophy treated with, 2472-2473 glioma cells transfected with wild type p53, 1410 human telomerase reverse transcriptase promoter, 14 10 mechanism of action, 1409-1410 novel transgeues, 1410 strategies for, 1409-1410 vector systems for, 1410 Genetic counseling, 802, 805, 874-875 Genetic heterogeneity, 783 Genetic markers, 801 Genetics autosomal dominant disorders, 781-783, 782t, 800f autosomal recessive disorders, 782t, 783 chromosomal aberrations, 785-788 DNA bases of, 789 deletions of, 792 insertions of, 792 mutations description of, 790, 791f single base-pair, 791 types of, 79If polymorphisms, 790 transcription of, 789 heterogeneity allelic, 783, 792 nonallelic, 783, 792 predicting of, 801 imprinting, 787 inheritance patterns, 782t mitochondrial inheritance, 782t, 788-789 multifactorial disorders, 789 new mutations, 785 polygenic disorders, 789 polymorphisms repeat, 791 resrriction fragment length, 790, 798f single nucleotide, 790 reseatch tools for chromosome jumping, 798 chromosome walking, 798 cosmids, 797 gene libraries, 797 goals, 802 knockout mutants, 802 linkage analysis chromosome cross over, 799, 799f description of, 798-799 I.OD scores, 799 usefulness of, 799-800, 800t phages, 796-797 plasmids, 796 polymerase chain reaction, 798 positional cloning, 802 restriction en do nucleases, 796 vectors, 796-797 restriction fragmenr length polymorphisms, 790, 798 f single nucleotide polymorphisms, 790 Southern blotting, 796, 797f sporadic cases, 784—785
Genetics {Continued) terminology associated with, 781 trinucleotide repeat expansions, 792-796 x-linked inheritance disorders, 782t, 783-784 Genetic testing confidentiality issues, 462 global developmental delay diagnosed by, 78 I kimingron's disease, 457^458, 2149-2150 multiple sclerosis, 772 muscle weakness evaluations, 377 Geniculate neuralgia, 2101-2102 Geniospasin, hereditary, 2161-2162 Genome, 789, 789t Genotype, 781 Germ cell tumors characteristics of, 541-542, 1359-1360 in children, 1435-1437 clinical presentation of, 1436 management of, 1418-1419, 1436-1437 nongerminomatous,
1435
prognosis, 1437 Gcrminomas characteristics of, 1360, 1360f imaging of, 1381, 1386f management of, 1418-1419 pineal, 541-542, 1386f Gerstmann's syndrome, 1204 anomic aphasia and, 149 causes of, 67 elements of, 149 Gers tma nn- S tra u ss 1 e r-Sc h ei n ker syndrome amyloid deposits in, 1617, 1621 amyloidosis in, 1621 ataxia, 2171 characteristics of, 1620t clinical features of, 1623, 1943 ilrscnpiion or, I ft I 3- I (> I 4
genetic mutations associated with, 1623 neuropathologic findings, 1621 phenotype for, 1615 signs and symptoms of, 1623 treatment of, 1626 Gestational rubella, 1537 Gllli. see /-Hydroxybutyrate Ghrelm, 850t, 854 Giant axonal neuropathy, 805t, 2325-2327 Giant cell arteritis amaurosis fugax, 2066-2067 corticosteroids for, 2069 course of, 2068 definition of, 2065 description of, 1080
epidemiology of, 2068 etiology of, 2068 immunology of, 2068
laborarory studies, 2067 pathogenesis of, 2068 pathology of, 2067-2068, 2068f physical findings of, 2066-2067 physiology of, 2067 polymyalgia rheumatica, 2066
prognosis of, 2068 symptoms of, 2065-2066, 2067t treatment of, 2068-2069 Giant cell astrocytomas, subependymal characteristics of, 541, 1350, 1381, 1413 in children, 1428-1429
INDEX
Giant tell astrocytomas, subependymal {Continued) imaging of, 1381 management of, 1413 in tuberous sclerosis, 1871 Gigantism, 860 Glanders, 1503 Glasgow Coma Scale description of, 52, 52t, 63 traumatic brain injury evaluations, 1134-1135, 1135t Glasgow outcome scale, 103 9r, 10491 for penetrating head trauma, I 142 Glatiramcr acetate, 824, 1658 Glaucoma acute, 227 -U11_;11-1 -c11a^11r"i•, vision hiss caused by, 1 H developmental disorders associated with, 78t norma I-tens ion, 181-182 Srurge-Wcbcr syndrome and, 1881 ( .li.'ll
li'lls
apoptosis of, 1765 necrosis, 1765-1766 Glud-derived neurotrophic factor, 2139 Glial fibrillary acidic protein characteristics of, 1343, 1345 diffuse astrocytomas, 1347 oligodendroglioma, 1351 Glials cells, epilepsy and, 1974 Glioblastoma clinical features of, 1348-1349, 1349f electroencephalography findings, 473f endothelial hyperplasia associated with, 1348 genetic findings, 1349 histologic findings, 1344f-1345f incidence of, 1348 sites of, 1348 survival rates for, 766 variants of, 1348 Glioblastoma multiforme characteristics of, 533-534, 535f imaging of, 1376, 1379f management of, 1413 prognosis for, 1401, 1413
Gliomas angiogenesis simulation by, 1409 antibody-mediated therapy of, 1411 astrocyric, 767 brainstem, 1385, 1 3 9 l f
cell-mediated therapy of, 1411 chemotherapy for, 975 choroidal, 1413 chromosomal alterations in, L331t diffuse, 1347 genetics of, 767, 1330, 1331t hypothalamic, 547 immune response restoration in, 1411 immunosuppression caused by, 1411 insulin-like growth factor and, 1411 metabolic polymorphisms associated with, I339t neurosurgical treatment of, 975 N-nitroso compound exposure and, 1 536-1337 optic chiasm, 547, 548f, 1381, 1382f, 1431-1432 optic nerve, 577 optic pathways, 1381, 1382f, 1431-1432
Gliomas [Continued) pathogenesis of, 1330 prognosis for, 1401 radiotherapy for, 975 Gliomatosis cerebri, 1347, 1414 Glioneuronal tumors, 1353 Gliosis, brainstem, 1106 Global amnesia, transient, 71 Global aphasia, 148-149, 149t Global developmental delay algorithmic approach to, 80f biologic conditions associated with, 77t computed tomography evaluations, 78 definition of, 75 diagnosis of tests for, 76-81 yield for, 75-76 electroencephalography evaluations, 79 etiology of, 75-76 evaluation of, 75 family history evaluations, 76 genetic testing for, 78 imaging studies for, 78 Internet resources, 83t magnetic resonance imaging evaluations, 78 medical history, 76 mental retardation vs., 75 metabolic testing for, 77-78 ocular findings associated with, 76, 7St physical examination for, 76 risk factors, 76, 77t Global paralysis of gaze, 276 Globoid cell leukodystrophy, 2334 Glomus jugulare tumor, 574, 574f, 2121-2122 Glossopharyngeal nerve, 2117 Glossopharyngeal neuralgia, 14, 267, 2101 Glucocerebrosidasc, 8031 Glucocorticoids deficiency of, 1111 description of, 852t Glucose cerebral, 1684 homeostasis of, 1683 metabolism disorders description of, 1683 hyperglycemia, 1685-1687 hypoglycemia, 1099, 1684-1685 monitoring of, in stroke patients, 956 resuscitation of, 1686-1687 GLUT1, 1747 GLUT2, 1747 G i . u n , n--iGLUT5, 1747 Glutamate antagonists, 889, 1121 basal ganglia, 2129 brain concentrations of, 884 chemistry of, 884 description of, 1974 disorders associated with, 882t, 888t distribution of, 884 excitatory postsynaptic potentials and, 885, 887 hyperexcitability, 887-888 neuropeptide colocali/ation with, 902t pain and, 888 retinal, 885 MjbsMIKV P\ ctfl'Ct. 9 0 7
xlh'i
Glutamate receptors AM PA receptors, 885 classification of, 884 clinical role of, 887-889 inotropic agonists of, 886 description of, 884-885 kainatc receptors, 885 merahorropic activation of, 886 description of, 885-886 NOMA receptors, 884-885 pharni:iciiloi>\ [, HSu, SIS-1 regulation of, 885 Glutamic acid decarboxylase antibodies, 458 Glutamic acid dehydrogenase, 879 Glutaminc, 884, 1683 Gluten enteropathy, 1092 Gluten sensitivity, ataxia with, 2172 (llycine cellular metabolism by, 881 chemistry of, 883
description of, 881-883 distribution of, 883 functions of, 88 1 inhibitory potentials, 882 NMDA receptors and, 883 presynaptic vesicle release of, 883 receptors, 883-884 Glycogen storage diseases, 1822t Glycogen storage disorders, 1825-1826 Glycogen synthase kinase 3, 1916 /^-glycoprotein 1, 1227 Glycoprotein llb/llla receptor blockers, 1006 Glycosylation disorders, 1829 G M , ganglioside, 1169, 2350 GM1-gangliosidosis, 1822t G ^-gangliosidosis, 1 822t Gnathostoma spinigerum, 1557t, 1574 Gnathostomiasis, 1574-1575 Golgi's tendon organ, 408t Gonadotropin- re leasing hormone characteristics of, 850t, 866t deficiency of, 867 Gorlin's syndrome, 1338 Gowers' maneuver, 375, 3751, 24~0 Gowers' sign, 335 G protein coupled receptors, 879 G proteins activation of, 878-879 a-adrenergic receptors, 897 description of, 861 disorders associated with, 882t mutations of, 879 ras family of, 879 receptor coupling, 877 structure of, 879, 8801 Gradient-recalled echo sequences, 523-524 Graft-versus-host disease, 1326 Granulomatous amebic encephalitis, 1565 Granulomatous angiitis, 1080, 1255-1256 Graves' disease, 1096 Growth factor receptors, 1408 Growth hormone, 852t Growth hormone release inhibiting hormone, 850t Growth hormone releasing hormone, 850r Guadeloupcan parkinsonism, 2143 Guanidine hydrochloride, 2457 Guanosine triphosphate, 862 Volume 1 pp. 1-1070 • Volume II p. 1071-2546
xliv
INDEX
Guillain-Barre syndrome algorithm for, 2344f
autonomic dysfunction associated with, 959, 2410 bladder dysfunction in, 429 cardiovascular abnormalities associated with, 959, 2342-2343 classification of, 2337t clinical features of, 2337-2338 corticosteroids for, 2344-2345 course of, 2345 description of, 2280 diagnostic criteria for, 2336-2337 differential diagnosis, 2339-2340, 2340t functional vital capacity monitoring in, 9S9 H wave in, 512 gastrointestinal abnormalities associated with, 952 history of, 2336 immune mechanisms of, 2341, 2343f immunoglobulin infusions for, 2343-2344
infections associated with, 2337 laboratory studies of, 2339 magnetic resonance imaging of, 2339 mechanical ventilation indications, 959 neurosciences critical care unit management of, 959 pathogenesis of, 2340-2341 pathologic findings, 825-826, 2340 plasma exchange for, 2343-2344 pregnancy issues, ISJ^S prognosis for, 2345 reflex disorder in, 373 respiratory failure associated with, 872 respiratory monitoring in, 959, 2341 sensory abnormalities associated with, 415 signs and symptoms of, 2337-2338 treatment of, 2341-2345 variants of, 2338-2339 viral infections preceding, 838, 2337 viral capacity in, 4d2 Guillain-Mollarct's triangle, 224 Gulf War syndrome, 1691 Gunn's pupil, 730, 73If Gunshot wounds penetrating head trauma caused by, 1141-1143
peripheral nerve trauma, 1187-1188 Gustatory system functions of, 262 receptor cells of, 262 Guyon's canal, ulnar nerve entrapment at, 344t, 2314-2315 Gymnastic ball, 1031f Gynecomastia, 895-896, 2244 H Haemophilus influenzae, 1476, 1483 Half-life, 918 Hallcrvorden-Spatv: disease, 313, 1930, 2158 Hallucinations Alzheimer's disease, 88, 111, 1907 auditory, 31 cortical structures associated with, I05t definition of, 104t delirium and, 30-31 dementia with Lewy bodies and, 92, 112 olfactory, 261
Hallucinations {Continued) Parkinson's disease and, 112, 2138 schizophrenia and, 38 vascular dementia and, 91 Hallucinogens, 1724 Haloperidol delirium treated with, 40 for vertigo, 7461 Hnlsrcad-Keitan Battery. fiTft. isTdt Hamartomas, 567-568 Hand arthritis of, 443 muscle weakness, 348 Hand position test, 52 Hangman's fracture, 585, 585f Hansen's disease, see Leprosy Haptocorrins, 1695 Hard signs, 7 Harlequin syndrome, 2418 Harris Benedict equation, 953 Hashimoto's encephalopathy, 109 Hashimoto's thyroiditis, 1097 Haw River syndrome, 2152 Headaches in adolescents, 2103-2104 aggravating factors, 268 arachnoid cysts, 2057-2058 arteriovenous malformations and, 1015, 1288, 2062-2063 aura, 267 brain metastases and, 1442 brain tumors and, 1363-1364, 2056-2057 carbon dioxide and, 2096 carotid artery occlusion and dissections, 2065 cerebral ischemia and, 2064-2065 cervical spine and, 2070-2071 ccrvicogcnic, 2071 in children, 2103-2104 classification of, 2056t cluster chronic, 2093-2094 classification of, 2090 clinical features of, 2090-2091 description of, 266-268, 2090 diagnosis of, 2092 epidemiology of, 2092 gastrointestinal disturbances and, 2091 laboratory studies of, 2091 onset of, 2091 pain associated with, 2091 pathophysiology of, 2091-2092 periodicity of, 2090 prophylactic therapies, 2093-2094 surgical treatment of, 2094 treatment of, 2092-2094 coital, 2071-2072 cold-stimulus, 2099 cough, 2071 differential diagnosis, 269 disability caused by, 268 duration of, 266 economic costs of, 2055 epidemiology of, 2055 evolution of, 267 exacerbation of, 1363-1364 examination for carboxy hemoglobin levels, 271 cerebrospinal fluid tests, 270 cervical spine, 269
Headaches {Continued} computed tomography, 270 electroencephalography, 270 magnetic resonance imaging, 270 neuroimaging tests, 270 overview of, 269 exertional, 2071 family history of, 268 fever with, 268 giant cell arteritis amaurosis fugax, 2066-2067 corticosteroids for, 2069 course of, 2068 definition of, 2065 epidemiology of, 2068 etiology of, 2068 immunology of, 2068 laboratory studies, 2067
pathogenesis of, 2068 pathology of, 2067-2068, 2068f physical findings of, 2066-2067 physiology of, 2067 polvm\-.ilii.n rheumatics, 2066 prognosis of, 2068 symptoms of, 2065-2066, 206 71 treatment of, 2068-2069 giant cell arteritis and, 1080 glutamate's role in, 888t head and neck trauma-related, 2098-2099 hemicrania continua, 2095 history-taking, 265-269, 266t hypmc, 266 idiopathic intracranial hypertension and, 2059 incidence of, 2055 indomethacin-rcsponsive, 2094-2096 infections and, 2060-2062 intracranial aneurysms and, 2062 location of, 267 low cerebrospinal fluid pressure, 2058-2059 magnetic resonance imaging of, 2059 meningiomas and, 2057 meningitis and, 2060 metabolic abnormaliries, 2096 migraine abdominal, 2104
in adolescenrs, 2103-2104 basilar, 2075 cheiro-oral, 2073 in children, 2103-2104 classification of, 2072t clinical features of, 2072-2075 complications of, 2075-2076 definition of, 2072 delirium caused by, 37 dysphrenic, 2075 equivalents, 2074-2075 familial hemiplcgic clinical features of, 1848t, 1857, 2076-2077 description of, 1222, 1305 diagnosis of, 1858-1859 genetic mutations associated with, 1857-1858 pathophysiology of, 18.S7-1858 treatment of, 1859 focal electroencephalographic changes in, 472 frequency of, 266
INDEX Headaches (Continued) genesis of, 2077-2078 genetics of, 2076-2077 hemiplegia caused hy, 340 hormonal influences, 2086-2090 infarction caused hy, 1221-1222 laboratory findings, 2076 location of, 267 mechanism of, 2078-2079 menopause-related, 2090 menstrual definition of, 2086 management of, 2086-2087 mechanisms of, 2086 nonsteroidal anti-inflammatory drugs for, 2087-2088 prophylactic therapy for, 2087-2088 monoplegia caused by, 343 neurogenic inflammation in, 2079 ophthalmoplegic, 2075 oral contraceptives and, 2088-2089 peak of, 266 physical findings of, 2076 platelets in, 2078 precipitating factors, 266-267 during pregnancy, 2089-2090, 2532-2533 prophylaxis, 2084 retinal, 2074 serotonin and, 90It serotonin levels, 2078 spreading depression theory of, 2077-2078 stroke and, 1221, 1304 summary of, 2079-2080 teichopsia of, 2073-2074 treatment of /{•adrenergic blockers, 2084 anticonvulsants, 2085 antidepressants, 2084-2085 hotulimini toxin, 2086 calcium-channel blockets, 2085 cyproheptadine, 2085-2086 description of, 2080 dietary changes,.2080 dihydroergorarmne, 2081-2083 ergotamine tartrate, 2081 ergot preparations, 2081t, 2081-2082 mcthysergide, 2085 monoamine oxidase inhibitors, 2084-2085 pharmacotherapy, 2080-2084 prophylactic, 2084 propranolol, 2084
riboflavin, 2086 selective serotonin reuptake inhibitors, 2084 serotonergic agents, 2085-2086 serotonin agonists, 2082t triptans, 2082-2084 triggers for, 2080 without aura, 2072-2074 in women, 1221 migrainous syndrome with CSF pleocytosis, 2059-2060 mitigating factors, 268 nasal causes of, 2069-2070 neck-tongue syndrome, 2099 neuroimaging tests for, 270 occurrence of, 266
Headaches [Continued) ocular causes of, 2069 onset of, 265-266 parenchymal hemorrhage and, 2064 paroxysmal hemicranias, 2094-2095 peak of, 266 precipitating factors, 266-267 premonitory symptoms, 267-268 prevalence of, 2055 primary stabbing, 2095-2096 quality of, 267 review of systems, 5 rheumatoid arthritis and, 2215 severity of, 267 sexual activity-related, 2071-2072 sinus, 2069-2070 sleep disorders and, 2027-2028 subarachnoid hemorrhage and, 2063-2064 subdural hematoma, 2098-2099 SUNCT, 2095 symptoms associated with, 267-268 ten si on-type in adolescents, 2104 in children, 2104
chronic, 2098 course of, 2097 description of, 265-267, 2096 laboratory studies of, 2097 pathogenesis of, 2097 prognosis, 2097 psychological factors, 2047 symptoms of, 2096-2097 treatment of, 2097-2098 thunderclap, 2063, 2063t timing of, 266 types of, 265 Valsalva maneuvers, 20.S6r Head and neck pain caused by malignancies of, 982 tremors of, 303-304 Head trauma, see also Traumatic brain injury brain tumors caused by, 1336 computed tomography of, 554 dementia caused by, 1945 diffuse axonal injury, 554, 555f, 1129-1130 electroencephalography for, 472 epilepsy secondary to, 1970 magnetic resonance imaging of, 554 penetrating assessment of, 1142 computed tomography assessments, 1142 Glasgow outcome scale, 1142 gunshot wounds, 1141-1143 incidence of, 1141-1 142 low-velocity missile wounds, )141-1142 outcome predictions, 1143 resuscirarion for, 1142 sexual dysfunction after, 424 smell disturbances secondary to, 259 taste disturbances associated with, 263 vascular injuries caused by, 557, 558f Hearing audiologicaJ testing abnormal resulrs, 744 acoustic reflex, 744-745
xlv
Hearing {Continued) brainstem auditory evoked potentials, 483-484, 745 central, 742 computed tomography for, 746 definitions, 743 description of, 742-743 el ect rococ h I eogra p h y, 746 elements of, 742-743 evoked potentials, 745-746 middle ear testing, 744 normal results, 743f pure-rone air thresholds, 249, 743f speech reeeprion threshold, 743 speech testing, 743-744 terminology associated with, 743 brainstem auditory evoked potentials for assessing, 483^*84 sensitivity range for, 249f Hearing aids, 252-253 Hearing loss acoustic reflex threshold for, 250-251 audio logic assessments, 249-250 auditory neuropathy description of, 247 diagnostic findings, 247-248 examination for, 248-252 bone conduction thresholds, 249 conductive, 252, 253f degree of, 249f description of, 247 with dizziness, 240 ear reflex assessments, 251 immitance test battery for, 250-252 mixed, 253 neural lesions that cause, 254 otoacoustic emissions, 247, 251-252, 254 pure-tone air thresholds, 249 Rhine test for, 248-249 sensorineural, 247, 252-253 sensory lesions that cause, 254 static compliance for, 250 tympanometry for, 250, 251f Weber test for, 248 Heart murmur coma evaluations, 50 syncope evaluations, 13 1 lean transplantation, sec , 294, 1930 Kearns-Sayre syndrome, 378, 1837, 1842, 2496f, 2497 Kennedy's disease charactetistics of, 373, 384, 793, 805t clinical features of, 2243t, 2244 differential diagnosis, 2245 history of, 2243 laboratory studies, 2244-2245 pathogenesis of, 2243-2244 treatment of, 2245 Keratan sulfate, 1770 Kcrnicterus, 1107 Ketaminc, 1723 Ketogenesis disorders, 1826 Kctolysis disorders, 1826 Ketone bodies, 1826 Ketorolac adverse effects of, 932t half-life of, 932t pain management using, 932t Ki-67, 1346 Kindling epileptogenesis, 888t, 889, 901 Kinky hair syndrome characteristics of, 805t, 1773, 1817t, 1828 clinical features of, 1887 connective tissue abnormalities in, 1887 copper replacement therapy for, 1888 cutaneous features of, 1887 definition of, 1886-1887 genetic studies of, 1888 imaging of, 1888 infantile-onset, 1887t neurological features of, 1887-1888 treatment of, 1888 Kleinc-Levin syndrome, 2028 Klinefelter's syndrome, 785 Klippel-b'eil anomaly, 2190-2191, 2191f Klonopin. see Clonazepam Klumpke's palsy, 347 Kluver-Bucy syndrome, 1936t Knee extension weakness, 324 Knockout mutants, 802 Knowledge conceptual, 129 production, 129 Kochcr-Cushing reflex, 48 Kohlmeicr-Degos disease, 1220 Konzo, 2229 Koplik's spots, 1535 Korsakoff's psychosis, 259 KorsakofPs syndrome, 1704, 1944 Krabbe disease, 1822t Krabbe's disease, 553, 805t
Ivii
Krause's end bulbs, 408t Kugelberg-Welander disease, 2238, 2240 Kuru clinical features of, 1623 description of, 1614 neuropathologic findings, 1621 Kussmaul breathing, 53 Kwashiorkor, 1693 Kyasanur Forest disease, 1533-1534 Kyphosis, juvenile, 2203 L Laboratory tests • computed tomography. see Computed tomography computed tomography angiography. see Computed tomography angiography confidenriality of, 462 cost-to-benefit analysis, 460 decision analysis, 460-461, 46If description of, 9, 457 diagnostic uses of, 457^158 electroencephalography. see Electroen ce p ha lography electromyography, see Electromyography interpretation of results, 458^159 magnetic resonance angiography, see Magnetic resonance angiography magnetic resonance imaging. see Magnetic resonance imaging nerve conduction studies. see Nerve conduction studies neurological disease management role of, 462 prioritization of, 460 quantitative methods, 460 risk-to-benefit analysis, 459-460 serum creatine kinase, see Creatine kinase yield of, 458 Labyrinthine artery, 636 Labyrinthitis, 236 Laceration, 1187 LaCrosse virus, 832t ^-Lactams, bacterial meningitis treated with, 148 It Lactate dehydrogenase deficiency, 2492-2493 Lactic acid, 1838 Lactic acidosis, 1813 Lactulose, 1680-1681 Lacunar infarction, 1201, 1205 Lafora body myoclonic epilepsy, 804r Lafora's disease, 1967 Laing's distal myopathy, 2483 Lambert-Eaton myasthenic syndrome cholinesterase inhibitors for, 2457 clinical features of, 2456 compound motor action potentials in, 517t definition of, 2456 diagnosis of, 2456-2457 drugs that affect, 2458 fluctuating muscle weakness associated with, 382 immune responses, 1468 iiiimurniparhology ol. 2-4^T" muscle weakness associated with, 2456 prognosis for, 2457 Volume I pp. 1-1070 • Volume 11 p. 1071-2546
xlviii
INDEX
Herpes simplex virus (Continued} transmission of, 1516 treatment of, 834 meningitis caused by, 1520, 1522 myelitis caused by, 835-836 neonatal meningoencephalitis, 1519-1520 neuropathy, 2389 receptors for, 8431 trigeminal nerve involvement, 2111 type I, 1516-1517 type 2, 1516-1517, 1519 Herpesviruses characteristics of, I516t cytomegalovirus in AIDS patients, 562-563 antiviral therapy for, 1525 brain tumors and, 1338 cerebrospinal fluid findings, 1524-1525 congenital, 1524-1525 description of, 1524 encephalitis, 1524f, 1525 foscarnet for, 847 ganciclovir for, 847 in immunocompromised patients, 1524-1525 polymerase chain reaction diagnosis of, 1520t polyradiculitis, 836
treatment of, 1525 viral characteristics of, 832t I pMein Hart virus central nervous system lymphoma and, 1359 cerebrospinal fluid polymerase chain reaction detection of, 1526
characteristics of, 832t diagnosis of, 1525 infection caused by, 1525 intravenous immunoglobulin for, 1525
latent, 1525 myelitis caused by, 835 polymerase chain reaction diagnosis of, 1520t Viral Capsid Antigen, 1525 herpes simplex virus, see I lerpes simples virus herpes zoster, see Herpes zoster types of, 1515-1516 varicella zoster virus antiviral treatment of, 1522 characteristics of, 832t, 836-837, 1219, L520t immunoglobulins for, 1522 Herpes zoster central netvous system vasculitis associated w i t h , 1325 clinical learures i>1. 228(1 complications of, 1523-1524 description of, 454-455, 837, 1522-1523, 2279-2280 differential diagnosis, 1523 epidemiology of, 2279-2280 motor weakness associated with, 2280 nerve root effects, 2279-2280 neuropathies associated w i t h , 2389 postherpetic neuralgia caused by, 1523-1524, 2280 Ramsay Hunt syndrome, 236, 317, 1523, 2102, 2279 reactivation of, 1522-1523
Herpes zoster (Continued) signs and symptoms of, 1523 treatment of, 1524, 2280 trigeminal nerve involvement, 2111 variants of, 1523 Heschl's gyrus, 136, 142 I [elero;;eiiei[y allelic, 783, 792 nonallelic, 783, 792 predicting of, 801 Heteromodal association cortices description of, 66 tasks mediated by, 104 Heteroplasmy, 788, 1837 Heterotopias definition of, 200 description of, 567, 568f, 1768 diplopia associated with, 202 subcortical laminar, 1785 I lercrozygore, 781 Hexacarbon solvents, 1711-1712 Hexosaminidase-A deficiency, 2260-2261 Hexosaminidase-A gene, 792 Hexosaminidase B, 792 High-density lipoproteins, I I 99 High-grade astrocytomas, 1432 Highly active antiretroviral therapy, 1585-1586 High-threshold mechanical nociceptors, 921 Highway hallucinosis, 212 H i p dip, 375 I lippocainpLis bilateral damage to, 69 memory functions of, 69, 70f sclerosis of, 99 traumatic brain injury effects, 1117-1118 Hippus, 225 II i rschberg test, for diplopia, 206-207, 208f Histoplasma, 1546, 1548 Histoplasmosis, 1545, 1554 History of present illness, 4-5 History of previous illnesses, 5-6 H i v i d . see Zalcitabine H L A - D R 2 allele, 822 Hockey stick sign, 1624 Hoffmann's sign, 362 Hollenhorst plaque, 1 9 l f Holmes-Adie pupil, 2412 Holmes's tremor, 306 H olo p rosencep h a I y alohar, 1777t, 1780 characteristics of, 564, 564f, 803t-804t, 1777t conditions associated with, 1779-1780 course of, 1780 definition of, 1779 diagnosis of, 1780 endocrine dysfunction associated w i t h , 1781 epidemiology of, 1779 genetic mutations i n , 1779t hydrocephalus associated w i t h , 1780-1781 imaging of, 1780, 17S1f lobar, 1777t, 1780 middle inter hemispheric, 1777t, 1780 semilobar, 1777t, 1780, 17811"
Holo p roscn ce p h a 1 y ((' n tinued) treatment of, 178 1 variants of, 1780 Homer Wright's rosettes, 1343 I lomocysteine arherosclerosis and, 1231 description of, 109, 1200 folate metabolism and, 1697-1698 vitamin Bl 2 deficiency, 1695 Homocystmuna, 1223-1224, 1304, 1820, I824i Homonymous hemianopia anterior choroidal artery infarction and, 281f congruous, 735, 736f left' anatomic localization of symptoms, 8 incongruous, 736f neurological examination findings, 6 right congruous, 736f vision loss caused by, 177f unilateral, 735 Homonymous visual field defects, 735 Homozygous, 783 Homunculus, 337 Horizontal eye movements description of, 704 physiology of, 704-708 Horizontal gaze palsy acquired, 715 family, 715 Horizontal gaze paresis, 275-277 Horizontal suspension test, for floppy infant evaluations, 401 Hormone replacement therapy, 1229-1230 Horner's syndrome brachial plexopathy and, 1456-1457 description of, 54, 224, 2411-2412 examination for, 225-226, 226f laboratory investigations for, 227 localization of, 227 superior cerebellar artery infarction and, 1205 H reflex, 512, 514 5-HT1A receptors, 899 5-HT1B receptors, 899 5-HT1 receptors, 899 5-HT2 receptors, 899-900 5-HT3 receptors, 900 5-HT4 receptors, 900 Human genome, 789, 789t Human herpesvirus polymerase chain reaction diagnosis of, 1520t type 6, 832t, 1526f, 1526-1527 type 7, 1527 type 8, 832t, 1527 Human immunodeficiency virus, see also Acquired immunodeficiency syndrome acute syndrome, 1582-1583 amyotrophic lateral sclerosis and, 1540 antiretroviral therapy for, 1585-1586, 1938 antiviral drugs for, 847-848 anxiety associated w i t h , 92 asymptomatic stage of, 1583-1584, 1584f ataxia caused by, 2171 C D 4 + T cells, 1584
INDEX Human immunodeficiency virus (Continued) in children CD4+ T cell count, 1606 clinical approach to, 1605-1606 clinical features of, 1606 diagnosis of, 1605-1606 epidemiology of, 1603-1604 global prevalence of, 1604 highly active antiretroviral therapy for, 1610 incidence of, 1603, 1604f intracerebral hemorrhage, 1609 laboratory monitoring, 1605-1606 neurodevelopmcntal ah normalities in, 160.3 neurological disorders, 1607 nonhemorrhagic infarctions, 1609 nucleotide reverse transcriptase inhibitors for, 1610 parenterally acquired infection, 1604-1605 perinatal transmission, 1603 plasma viral load determinations. 1605-1606 pregnancy prophylaxis, 1610-1611 prevention of, 1610-1611 prognosis for, 1610 progression of, 1606 progressive encephalopathy, 1607-1609 sexual transmission, 1605 stroke in, 1609-1610 symptom categories for, 1607t treatment of, 1610 trends in, 1603-1604 vertical transmission of, 1604 chronic inflammatory dcmyelinating polyradiculoneuropathy and, 2387 cognitive impairment in, 696, 697f dementia cerebrospinal fluid analysis, 1589 clinical features of, 1588, 1938 delirium associated with, 1938 depression associated with, 92 description of, 775, 835, 1584, 1585, 1588 diagnosis of, 1938 evaluations of, 1588 highly active antiretroviral therapy for, 1590 imaging of, 1589 laboratory investigations for, 1588-1590 magnetic resonance imaging of, 1589f management of, 1590 neuropathology associated with, 1590, 1938-1939 neuropsychological tests for, 1588-1589 psychiatric disturbances associated with, 106-107 psychomotor dysfunction associated with, 1588 symptoms of, 1938 treatment of, 1939 depression associated with, 92 description of, 1540 distal symmetrical polyneuropathy in, 2387 encephalitis associated with, 562 epidemic of, 773
Human immunodeficiency virus (Continued) epidemiology of, 1581 gender distribution of, 1581 global prevalence of, 1581 highly active antiretroviral therapy for, 1585-1586 human herpesvirus 6 and, 1526f latent stage of, 1583-1584, 1584f late-stage complications of, 774 lumbosacral polyradiculoneuropathy in, 2387-2388 monitoring of, 1586 mortality rates, 773 motor neuron disorder associated with, 2262-2263 natural history of, 1582-1585 neonatal, 2524 neurological complications of acute stage, 1583 aseptic HIV meningitis, 1587-1588 astrocyte's role in, 1585 bacteremia, 1598 dementia, see Human immunodeficiency virus, dementia description of, 773-775, 774t, 1582t, 1582-1583, 1586-15S7 JC virus, 1593t meningoencephalitis syndromes, 1592 neurosyphilis, 1591 pathogenesis of, 1585 peripheral neuropathies, 2387t, 2387-2388 stroke, 1598 symptomatic stage, 1584 toxoplasmosis, 1592-1594 treatment of, 1593t vacuolar myelopathy, 1596-1598 white matter changes, 1585 neuromuscular disorders associated with distal sensory polyneuropathy, 1598-1599 inflammatory demyelinating polyradiculoneuropathies, 1599 lumbosacral polyradiculomyditis, 1599-1600 mononeuritis multiplex, 1600 myopathies, 1600 neuropathies, 1598-1600 nucleoside analogue-associated toxic neuropathy, 1599 overview of, 1583t peripheral neuropathies, 1598-1600 neuropsychological characteristics of, 696-697 neurotoxic drugs, 1599 neurotoxins, 1585 peripheral neuropathies associated with, 2387t, 2387-2388 Pneumocystis cannii pneumonia, 1587-1588 polyradiculoneuropathy in, 2278 prevalence of, 773, 1581 RNA burden, 1586 symptomatic stage of, 1584-1585 systemic events in, 1584f transmission of, 1581 treatment of nucleoside analogs, 1521t nucleoside reverse transcriptase inhibitors, 1587t
xlix
Human immunodeficiency virus (Continued) nucleotide reverse transcriptase inhibitors, 1587t trends in, 1581-1582 viral causes of, 832t viral load, 1583 worldwide prevalence of, 773 Human immunodeficiency virus-associated progressive encephalopathy in adolescents, 1608-1609 cerebrospinal fluid findings, 1609 description of, 1607-1608 in infants, 1608 in neonates, 1608 in school-age children, 1608-1609 signs of, 1608 Human leukocyte antigens, 813-814, 815f Human T-cell lymphocytotropic virus myelopathy associated with, 1540, 2227-2228 neuropathy associated with, 2389-2390 Human T-cell lymphocytotropic viruses, 1540 Human telomerase reverse transcriptase promotor, 1410 Human T-lymphocytic virus type 1, 832t, 836, 844 Hunt and Hess scale, 1270t Hunter's syndrome, 8051 Huntington's disease age at onset, 308 aggression in, 94, 951 apathy in, 95 behavioral disturbances in, 93-95, 105, 2149, 2149t caudal nucleus head atrophy in, 320 chromosomal aberrations, 803t clinical features of, 307, 2148-2150 cognitive changes in, 690 definition of, 112 depression in, 93-94, 113 description of, 105 diagnosis of, 690, 2149-2150 epidemiology of, 2148-2150 etiology of, 2150-2151 familial patterns of, 308 genetics of, 457-458, 803t, 874-875 genetic testing, 457-458, 2149-2150 history of, 2148 manifest, 690 memory impairment in, 690
Mini-Mental State Examination findings, 680f motor system impairments in, 691 muscarinic receptors and, 893t muscle wasting and weakness in, 309 neuropsvchological characteristics of, 690-691 obsessive-compulsive traits in, 94 n l l a c m i ; impairments in, 690
pathology of, 2150 personality disturbances in, 93-95, 112-113 probabilistic classification learning impairments in, 71 psychosis in, 94 respirarory irregularities in, 309 signs and symptoms of, 2148t smell impairments in, 690
Volume I pp. 1-1070 • Volume II p. 1071-2546
1
INDEX
[ iuntington's disease {Continued) speech disturbances in, 3 0 7 , 691 suicide ideation in, 94, 94f, 113, 2149 tardive dyskinesia vs., 3 0 9 - 3 1 0 Total Functional Capacity scale, 691 treatment of, 2 1 5 1 - 2 1 5 2 Hurler-Scheie syndrome, 803r Hurler syndrome, 803t Hyaluronic acid, 1746 Hydatid cysts, 1573f Hydatidosis, 1572, 1970 Hydralazine, 2384 Hydrancnccphaly, 5 6 7 , 568f Hydrocephalus adult-onset, 1 7 5 9 - 1 7 6 0 causes of, 1746 in children, 1758-1759 communicating, 5 7 2 - 5 7 3 , 2058 definition of, 17.SH delayed, 9 6 9 dementia caused by, 39t, 1929, 1945-1946 emergency treatment of, 9 6 3 - 9 6 4 fungal infection-related, 1553 gait in, 33 I holoprosencephaly and, 1 7 8 0 - 1 7 8 1 in meningomyeloceles, 1779 neurosurgery of, 9 6 3 - 9 6 4 noncommunicating, 1758 normal-pressure, 5 7 3 , 1 7 6 0 - 1 7 6 2 , 1929f, 1945-1946 obstructive, 5 7 2 , 969 shunt for, 9 6 4 , 9 8 1 , 1 7 5 9 - 1 7 6 0 signs and symptoms of, 1758 subacute, 969 subarachnoid hemorrhage-related, 9 5 8 , 9 6 9 , 1275 surgical treatment of, 9 6 3 - 9 6 4 toxoplasmosis a n d , 1567 trephination for, 9 6 3 - 9 6 4 ventriculomegaly vs., 571—572 X-linked, 805t Hydrocephalus ex vacuo, 1048 Hydrocodonc, 934t Hydromyelia, 2 1 9 3 - 2 1 9 4 y- Hydroxy bury rate, 881 5-Hydroxytryptophan, 898 Hymetmlepis nana, 1557t Hyoscyamine, for bladder dysfunction, 1052t Hyperactive-hyperalert delirium, 3 1 , 35 Hyperalgesia, 387, 2 (03, 2308 Hyperammonemia, 1676, 1 8 2 4 - 1 8 2 5 Hyperammonemia -hypcro rn ith i ncm ia homocitrullinemia syndrome, 1825 Hypercalcemia, 1094, 1111, Id90 Hypercapnia, 1084, 2 5 1 6 Hypercoagulablc disorders antithrombin-IH deficiency, 1226 fibrinogen abnormalities, 1227 primary, I226t, 1 2 2 6 - 1 2 2 8 protein C deficiency, 1 2 2 6 - 1 2 2 7 protein S deficiency, 1 2 2 7 secondary, 1226t, 1 2 2 9 - 1 2 3 2 Hypcrckplexia description of, 3 1 8 , 7 9 2 , 2 1 6 2 hereditary clinical features of, 1848t, I 8 6 0 diagnosis of, 1861
Hyperekplexia (Continued) genetic mutations associated with, 1860-1861 pathophysiology of, 1 8 6 0 - 1 8 6 1 signs and symptoms of, 1860 treatment of, 1861 Hypereosinophilic syndrome, 1225 Hyperesthesia, 4 0 9 Hypcrflexion injuries, 5 9 1 - 5 9 2 Hyperglycemia, 1 6 8 5 - 1 6 8 7 Hypcrhidrosis, 2 3 6 0 - 2 3 6 1 , 2 4 1 8 1 lyperkalciuia, 1094 Hyperkalcmic periodic paralysis clinical features of, 1851t, 1 8 5 2 , 2 4 8 9 diagnosis of, 1852 mutations associated with, 1849f pathophysiology of, 1852 secondary, 2 4 9 0 treatment of, 1853 Hyperkinetic dysarthria, 162, 162t Hypermagnesemia, 1095, 1690 Hypernatremia, 9 5 3 - 9 5 4 , 1093 Hypernychthemeral syndrome, 2 0 2 4 Hyperopia, latent, 2 0 1 Hyperosmia, 2 6 1 Hyperosmolality, 1 6 8 9 - 1 6 9 0 , 1 7 5 4 Hyperparathyroidism, 1 0 9 7 Hyperpathia, 4 0 9 Hyperpipecolic acidemia, 1824t Hypcrprolactinemia, 859t, 8 5 9 - 8 6 0 , 865-866 Hyper re flexia episodic autonomic, 1052 pathological, 2 2 2 5 Hypersomnia, idiopathic, 2 0 1 5 - 2 0 1 7 , 2046 Hypersomnolencc alcohol-related, 2 0 0 7 causes of, 2 0 2 9 post-traumatic, 2 0 2 9 I ly pencils ion arousal alterations caused by, 48 autonomic dysfunction a n d , 2 4 1 5 - 2 4 1 6 coma a n d , 48 criteria for, 1198 definition of, 1198 induced, for cerebral perfusion pressure increases, 1138 intracranial characteristics of, 1 1 3 8 - 1 1 3 9 , I 141, 1265-1267 idiopathic clinical features of, 1 7 5 7 - 1 7 5 8 description of, I " 5 7 diagnosis of, 1 7 5 7 drugs associated with, 1757t headaches caused by, 2 0 5 9 obesity a n d , 1757 treatment of, 1758 intracranial hemorrhage caused by, 1251 management of, 2 4 3 5 obstructive sleep apnea syndrome a n d , 2020 oral contraceprives and, 1229 paroxysmal, 2 4 1 5 - 2 4 1 6 prevalence of, 1198 stroke a n d , 1198 supine, 2 4 3 3 treatment of, 1 198 vascular lesion caused by, 1251
Hypertensive encephalopathy, 1 1 0 2 , 1 7 5 3 - 1 7 5 4 , 1754f Hyperthermia hypothalamic disorders a n d , 8 5 2 long-term effects of, 853 malignant, 805t, 8 5 3 , 1 7 4 3 , 1848t, 1856 malignant hyperthermia syndrome, 1743 neurogenic, 48 prognosis for, 1743 signs a n d symptoms of, 1743 systemic manifestations of, 1743 Hyperthyroidism in adults, 1095-1097 apathetic, 109 in children, 1110-1111 dementia and, 1947 psychiatric disturbances associated with, 109 Hypcrtonicity, 1053 Hypertropia asymptomatic, 2 0 0 description of, 2 0 0 Hyperventilation, 9 5 6 - 9 5 7 absence seizure diagnosis by, 18 syncope induced by, 16 Hyperviscosity, 2516 Hyperviscosity syndrome, 1087 Hypnagogic hallucination, 2 0 1 5 Hypnagogic jactitation, 315 Hypnic headaches, 266 Hypnic headache syndrome, 2 0 2 8 Hypnic jerks, 2 0 3 5 - 2 0 3 6 Hypoactive-hypoalert delirium, 3 1 , 3 5 Hy pobcra lipoprotein em ia, 1826 Hypocalcemia, 1094, 1690 Hypocapnia, 1084 Hypocretin, 851t, 2 0 1 4 , 2 0 1 7 Hypofibrinogenemia, 1227 Hypoglossal nerve, 2 1 2 0 - 2 1 2 1 Hypoglycemia, 1099, 1 6 8 4 - 1 6 8 5 , 1685t, 1947 Hypoglycemia unawareness, 1684 Hypoglycemic a m y o t r o p h y , 2 3 7 9 Hypogonadism, 1111 1 lypokalemia, 1094 Hypokalemic periodic paralysis clinical features of, 1 8 5 0 - 1 8 5 1 , 1851t, 2487-2488 description ot, SO '-i diagnosis of, 1 8 5 1 - 1 8 5 2 genetic mutations associated with, 1851 onset of, 2 4 8 7 pathophysiology of, I 85 1 prevalence of, 1 850 secondary forms of, 1 8 5 1 - 1 8 5 2 , 2 4 8 8 treatment of, I 852 type 2, 2 4 9 0 Hypokinesia, 117, 1 1 9 , 2 9 4 Hypokinetic dysarthria, 162, 162t Hypomagnesemia, 1 0 9 4 - 1 0 9 5 , 1690 Hypomclanosis of Ito, 1 8 9 1 - 1 8 9 2 H y p o m etria, 11 9 Hypomimia, 3 0 0 Hypomyelinating polyneuropathy, 403 H y p o n a t r e m i a , 1094, 1 6 8 7 - 1 6 8 9 Hypo-osmolality, 1 6 8 7 - 1 6 8 9 Hypoparathyroidism, 1097-1098 Hypophysectomy, for pain management, 983 Hypophysitis, 8 6 2
1NDKX
Hypopituitarism, 8 5 8 , 858t, 8 6 7 , 1095 Hypoplasminogenetnia, 1227 Hypoplastic left heart syndrome, 1102 Hypotension cerebral hypoperfusion caused hy, 48 clinical features of, 2 4 1 2 - 2 4 1 4 drug abuse-related, 1725 idiopathic orthostatic, 2 4 0 7 postural description of, 2 4 1 3 , 2413t, 2 4 3 0 - 2 4 3 5 management of, 24.30-2435 spinal cord injury and, 1153 spinal cord ischemia caused by, 131 ft syncope and, 2413-2414 syncope caused by, 15 traumatic brain injury-related, 1 1 2 1 , 1138 vertigo caused by, 2 4 1 Hypothalamic glioma, 5 4 7 Hypothalamus appetite regulation by, 8.54-855 biological rhythms and, 855 development of, 856 ciiiiitiuiis and, 855 fever and, 8 5 3 - 8 5 4 flincrions of, 1110 hisun i -raking, 865 hormones, 849 imaging assessments of, 865
Hypoxia (Continued) syncopal states a n d , 1665 syndromes associated with, 1666t traumatic brain injury effects, 1 1 2 0 , 1137 Hypoxic-ischemic brain injury, neonatal asphyxia, 25 1 ^ brain swelling associated with, 2 5 1 8 clinical features of, 251.5t computed t o m o g r a p h y of, 2516f cortical evoked responses for, 2 5 1 5 - 2 5 1 6 description of, 2 5 1 4 diagnosis of, 2 5 1 4 electroencephalography responses, 2515-2516 management of, description of, 2516-2517 metabolic parameters, 2.516 ncuroimaging of, 2 5 1 6 neuropathologies! patterns, 2 5 1 5 t perfusion maintenance for, 2 5 1 6 prognosis, 2518 ventilation adequacies, 2 5 1 6 Hysteria dystonia vs., 3 1 0 , 3 1 2 visual evoked potentials for evaluating, 481 Hysterical gait disturbances, 33.5
libido and, 855 neurotransmitters, 8 4 9 , 856 physical examination for, 865 pituitary function regulated by, 856 sarcoidosis effects, 1085, 1085f temperature regulation by, 8 5 2 - 8 5 3 , 8.53f Hypothermia coma associated with, 49 compensatory mechanisms for, 1744 intracranial pressure reductions using, 1139 management of, 1744, 2435 nerve damage caused hy, 1744 neuroprotective benefits of, 1006, 1123-1124 traumatic brain injury uses of, 1123—1124, 11
:
;'J
Hypothyroidism acquired, 1110 in adults, 1097 ataxia, 2 1 6 9 brain tumors and, 1364 causes of, 109 congenital, I I 10 dementia and, 1947 psychiatric disturbances associated with, 109 Hypothyroid neuropathy, 2 3 7 9 Hypotonia, 4 0 1 ^ 1 0 2 Hypovolemia, 15 Hypovolemic shock, 1154t 11 y po xa n th i n c-gua n ine phosphoribosy [transferase, 1828 Hypoxia cerebral edema in, 1 6 6 7 - 1 6 6 8 confusional states and, 1665 electroencephalography evaluations, 4 7 4 - 4 7 5 , 475f-476f, 1670 evoked potential studies, 1 6 7 0 - 1 6 7 1 neurological complications of, 1084 in premature infants, 1773 prevention of, 1137
1 Iatrogenic Crcutzfcldt-Jakob disease characteristics of. I 620t clinical features of, 1622 description of, 1 6 1 9 , 1942 epidemiology of, 1622 I bu pro fen adverse effects of, 932t half-life of, 932r pain m a n a g e m e n t using, 9 3 1 , 9 3 2 t Ictal nystagmus, 2 2 0 Ideational apraxia, 1 2 3 , 1 2 8 - 1 2 9 Idcomotor apraxia brain tumor-related, 125 convexity premotor cortex lesions a n d , 127 corpus callosum lesions a n d , 126 definition of, 123 hemispheric lesions associated with, 1 2 5 , 128 inferior parietal lobe lesions a n d , 126 left hemispheric dysfunction a n d , 1 2 1 , 128 pathophysiology of, 125—127 postural i-iTors representative of, 125 righr hemispheric dysfunction and, 128 spatial errors representative of, 125 supplementary motor area lesions a n d , 126-127 testing for, 125 timing errors representative of, 12.5 vascular lesions a n d , 1936t Idiopathic basal ganglia calcification, 1930 Idiopathic brachial plexoparhy clinical features of, 2 2 8 8 - 2 2 8 9 diagnosis of, 2 2 8 9 epidemiology of, 2 2 8 8 etiology of, 2 2 8 9 pathophysiology of, 2 2 8 9 prognosis of, 2 2 8 9 - 2 2 9 0 treatment of, 2 2 8 9 - 2 2 9 0
li
Idiopathic detrusor overactivity, 751 Idiopathic generalized epilepsy, 1864-186.5 Idiopathic hypersomnia, 201.5-2017, 2 0 4 6 Idiopathic insomnia, 2 0 1 2 Idiopathic intracranial hypertension clinical features of, 1 7 5 7 - 1 7 5 8 description of, 1757 diagnosis of, 1757 drugs associated with, 1757t headaches caused by, 2 0 5 9 obesity a n d , 1757 during pregnancy, 2 5 3 7 - 2 5 3 8 trearment of, 1758 Iduronate 2-sulfatase syndrome, 805t Ifosfamide, 1404 1231-isopropyl iodoampheraminc, 6 6 7 Ileus, intestinal, 9.52-953 Ilioinguinal nerve entrapment, 2312t, 2317-2318 Imipramine, 16.5.5 for bladder dysfunction, 1052r Immediate memory, 68 Immune-mediated disorders acute disseminated encephalomyelitis, 5 5 3 , 553f acute inflammatory demyelinating polyneuropathy, 414t, 825 a u t o i m m u n e myasthenia gravis, 826-827 chronic inflammatory demyelinating polyneuropathy, 8 2 5 - 8 2 6 Guillain-Barre syndrome. sec Guillain-Barre syndrome multiple sclerosis, see Multiple sclerosis neuropathies, 82.5-826 Immune response adaptive, 8 1 0 antigen presentation, 8 1 4 chemokinc's role in, 8 1 7 cytokine's role in, 8 1 7 infectious diseases, 827 initiation of, 8 1 4 - 8 1 7 paraneoplastic neurological syndromes . i ii-hi liar degeneration, I 46 ! encephalomyelitis, 1464 necrotizing myelopathy, 1465 opsoclonus-myoclonus, 1464-1465 peripheral nerve hypcrcxcitability, 1467 stiff-man syndrome, 1465 regulation of, 8 1 7 termination of, 8 1 7 - 8 1 9 Immune system activation of, 8 3 7 adaptive, 8 0 9 central nervous system a n d , 821 c o m p o n e n t s of B cells, 8 1 0 - 8 1 1 immunoglobulins, 811 macrophages, 8 1 0 - 8 1 1 monocytes, 8 1 0 - 8 1 1 natural killer cells, 8 1 0 - 8 1 1 overview of, 8 0 9 - 8 1 0 Tcell(s), 810-811 T-ccll receptors, 8 1 1 , 812f disorders of, 81 Ot divisions of, 8 0 9 functions of, 8 0 9 , 810t Volume I p p . 1-1070 • Volume II p. 1071-2546
hi
INDEX
Immune system {Continued] generics of antigen receptor gene rearrangements, 812-813 h u m a n leukocyte antigens, 8 1 3 - 8 1 4 , KIM major histocompatibility system, 810, 813-814 hormones that modulate, 851-8.52, H52t innate, 8 0 9 - 8 1 0 prion diseases and, 1618 stress modulation of, 8 4 9 tumor response, 8 2 7 - 8 2 8 viral infections and, 8 3 7 - 8 3 8 Immunocompetent cells, 852, 852t Immunoglobulin G, for toxoplasmosis diagnosis, 1567 Immunoglobulins, 8 1 0 - 8 1 1 for varicella zoster virus, 1522 Immnnoreceptor tyrosine-based activation motif, 814 Immunosuppressants, 2 4 5 0 - 2 4 5 1 Immunosuppression for myasthenia gravis, 827, 2 4 5 0 - 2 4 5 1 viral infections a n d , 8 3 7 Impersistence, motor, 117, 1 1 9 - 1 2 0 Impingement sign, 4 4 2 Implicit memory, 71 Impotence, 2 4 2 0 Imprinting, 7 8 7 Inborn errors of metabolism ahetalipoproteinemia, 1826 in adolescents, 1 8 2 0 - 1 8 2 1 amino acid metabolism disorders, 1823-1825 animal models of, 1830 brain development malformations a n d , 1816, 1 8 l 6 t Canavan disease, 1829 cardiomyopathy associated with, 1813-1814 classification of, 1811 clinical findings associated with, 1813t cofactors used in management of, 1819t copper metabolism disorders, 1827 course of, 1811 dementia and, 1948 diagnosis of carnitine profile, 1813t, 1814 cerebrospinal fluid, 1812t, 1 8 1 2 - 1 8 1 3 delays in, 1814 histological examination, 1815 imminent death prior t o , 1816 magnetic resonance imaging, 1814-1815 magnetic resonance spectroscopy, 1815 mutation analysis. [815 ophthalmologic examination, 1813, I S IM tandem mass spectrometry, 1814, 1814r tests, 1812t dietary considerations, 1817 dyslipidemias, 1 8 2 6 - 1 8 2 7 energy metabolism disorders, 1 8 2 5 - 1 8 2 6 enzyme replacemenr rherapy for, 1819t fatty acid oxidation defects, 1826 Gaucher disease, 1818, 1822t genetic transmission of, 1 8 1 9 - 1 8 2 0 gluconeogene.sis disorders, 1826
Inborn errors of metabolism [Continued) glycogen storage disorders, 1 8 2 5 - 1 8 2 6 glycosylation disorders, 1829 history of, 1811 h y p e r a m m o n e m i a , 1824—1825 uypobetalipoprotcineinia, 1 Xl(t incidence of, 1824t inheritance of, 1 8 1 1 - 1 8 1 2 ketogenesis disorders, 1826 ketolysis disorders, 1826 Lcsch-Nyhan syndrome, 3 1 3 , 805t, 1828 leukotriene synthesis defects, 1830 lysosomal disorders classification of, 1 822t clinical features of, 1821 diagnostic findings, 1 !s I.! hepatosplenomegaly associated with, 1813 history of, 1821 management of, 1 8 1 6 - 1 8 2 0 multidisciplinary team-based a p p r o a c h to, 1820 neurological deterioration associated with, 1813t neurotransmitter defects, 1 8 2 9 - 1 8 3 0 ophthalmologic findings associated with, 1813t organic acid metabolism disorders, 1823-1825 organ transplantation for, 1819t peroxismal disorders, 1 8 2 3 , 1824t porphyrias, 1 8 2 8 - 1 8 2 9 pregnancy issues, 1820 purine metabolism disorders, 1827 pyrimidine metabolism disorders, 1 8 2 7 substrate replenishment for, 1818 sulfite oxidase deficiency, 1827 Tangier disease, 1 8 2 6 - 1 8 2 7 resrs for, 1812t tetrahydrobiopterin for, 1 8 1 8 - 1 8 1 9 toxic metabolite excretion methods, 1817-1818 treatment of, 1 8 1 6 - 1 8 2 0 urea cycle disorders, 1825t Incidence, 763 Inclusion body myopathy, 3 8 4 Inclusion body myositis, 3 8 1 , 8 2 7 , 2506-2507 Incontinence fecal description of, 49 dietary control, 1174 management of, 174, 7 6 1 - 7 6 2 spinal cord injury a n d , 1 0 5 3 , 1172 frontal lobe lesions a n d , 4 2 3 gait disturbances a n d , 3 2 5 - 3 2 6 management of, 757f after stroke, 4 2 3 urinary dementia a n d , 4 2 3 , 5 9 2 7 description of, 49 external devices for, 759 multiple system a t r o p h y and, 7 5 3 radical prostatectomy a n d , 4 2 9 after stroke, 4 2 3 , 1052 surgical m a n a g e m e n t of, 7 6 0 , 7 6 0 t treatment of, 1 9 2 7 Incremental bicycle ergometry, for muscle weakness evaluations, 378 Inderal, see Propranolol
Indinavir, 1587t Indocin. see Indomerhacin Indomethacin adverse efleets of, 9321 half-life of, 932t pain management using, 9 3 1 - 9 3 2 , 9 3 2 t Indomethacin-rcsponsivc headaches, 2094-2096 Indwelling catheter, for bladder disorders, 758-759 Infant, see aha Children; Neonate beriberi in, 1702 botulism in, 4 0 4 , 1509 ceroid lipofuscinosis, 803t cytomegalovirus in, 1 5 2 4 - 1 5 2 5 degenerative syndromes in, 82t developmental milestones for, 76t esotropia in, 7 1 1 h u m a n immunodeficiency virus-associated progressive encephalopathy in, 1608 metabolic syndromes in, 82t muscle rone in, 395f posterior fossa t u m o r s in, 1424 severe myoclonic epilepsy, 1864 sleep patterns in, 1 9 9 6 - 1 9 9 7 stroke in, 1299. see also Stroke, in children Infanrile nemaline myopathy, 4 0 4 Infantile neuronal ceroid lipofuscinosis, 1822r Infantile-onset olivopontocerebellar atrophy, 2176 Infantile polyneuropathy, 4 0 3 , 404r Infantile refusum, 1817t Infantile spinal muscular a t r o p h y differenrial diagnosis, 2 2 4 0 epidemiology of, 2 2 3 7 etiology of, 2 2 3 7 - 2 2 3 8 genetic counseling, 2 2 4 1 genetics, 2 2 3 7 - 2 2 3 8 laboratory studies, 2 2 4 0 prenatal diagnosis, 2241 prevalence of, 2 2 3 7 treatment of, 2 2 4 0 - 2 2 4 1 type 1, 2 2 3 8 type 2 , 2 2 3 8 , 2 2 3 9 f type 3 , 2 2 3 8 , 2 2 4 0 Infarction anterior cerebral artery, 3 3 9 , 1204f cerebellar anterior inferior cerebellar artery s y n d r o m e a n d , 1205 bilateral suboccipital craniotomy for, 965 diagnosis of, 9 6 4 hydrocephalus caused by, 1759, 1760f neurosurgical treatment of, 964—965 prognosis for, 9 6 5 signs and s y m p t o m s of, 9 6 5 signs of, 2 4 0 vertigo a n d , 2 4 0 cerebral acquired immunodeficiency syndrome-re I a ted, 1219 description of, 5 7 0 - 5 7 1 , 571f, 1197-1198 infectious causes of, 1219 inherited disorders that cause, 1223-1226
INDEX Infarction {Continued) lacunar, 1201 in malignancies, 1229 of undetermined cause, 1232 pathologic changes associated with, 1201 stroke caused by, 7 6 4 cerebral venous, 1245 cortical, 338 hemorrhagic, 1258, 1258t lacunar, 1 2 0 1 , 1205 lenticulostriate arteries, 339 middle cerebral artery, 3 3 8 - 3 3 9 , 1204 migrainous, 1 2 2 1 - 1 2 2 2 monoplegia caused by, 343 oculomotor nerve, 2 1 0 9 parietooccipital, 1209 pontine, 1209, 12101 posterior cerebral artery, 3 3 9 , 1206, 1208 spinal cord, 3 4 2 , 1079 superior cerebellar artery, 1205, 12061 thalamic localization of, 4 1 4 t sensory features of, 4 1 4 t tlialamopcrforare arteries, 3 3 9 watershed infarcts, 1209, 1666 Infections abscess brain, see Bacterial infections, brain abscess cranial epidural, 1488, 1489f spinal epidural, 1 4 8 9 - 1 4 9 0 aneurysms caused by, 1273 antimicrobial agents for, 1 4 7 3 ataxia caused by, 2 1 7 0 - 2 1 7 1 brain abscess antibiotics for, 1487 in children, 1102 clinical features of, 1484 computed tomography of, 1484 corticosteroids for, 1487 diagnosis of, 9 6 6 , 1484 differential diagnosis, 1485, 1487 frontal lobe, 1484 hemarogenous spread of, 1484 magnetic resonance imaging of, 1484, 1485f-1486f meningitis-re I a ted, 1476 neurosurgical treatment of, 9 6 6 , 966t pathogens associated with, 1 4 8 4 - 1 4 8 5 predisposing causes of, 1484 sites of, 1484 treatment of, 1487 brain tumors and, 1 3 3 7 - 1 3 3 8 campylobacreriosis, 1506 cerebral, 5 5 8 - 5 6 0 , 1219 chlamydial infections, 1 5 0 6 - 1 5 0 7 cranial epidural abscess, 1488 delirium caused by, 37 description of, 1 4 7 3 ehrlichiosis, 1502 electroencephalography evaluations, 475-476 endocarditis, 1507 epidemic typhus, 1 5 0 0 - 1 5 0 1 facial nerve, 2 1 1 7 fi lam euro us actinomycosis, 1 5 0 5 - 1 5 0 6 nocardiosis, 1505
Infections [Ctmt'mued) funga! acquired immunodeficiency syndrome a n d , 154.5-1546 antifungal agents for, 1552 blastomycosis, 1 5 4 5 , 1548 central nervous system description of, 1546 treatment of, 1547t cerebrospinal fluid findings, 1 5 5 0 - 1 5 5 1 coccidioidomycosis, 1545, 1553—1554 cryptococcal, 1553 description of, 1545 diagnosis of, 1 5 4 9 - 1 5 5 2 epidemiology of, 1 5 4 5 - 1 5 4 6 histoplasmosis, 1545, 1554 hydrocephalus associated with, 1553 imaging of, 1 5 4 9 - 1 5 5 0 incidence of, 1546 magnetic resonance imaging of, 1549-1550 mucormycosis, 1 5 4 5 , 1554 Paracoccidioides, 1548 pathogenesis of, 1546 pathogens Aspeygittus, 1 5 4 8 - 1 5 4 9 , 1551 Blastomyces dermatitidis, 1548 Candida albicans., 1548 Coccidioides immitis, 1547t, 1548 Cryptacoccus, 1546 Histoplasma, 1546, 1548 Zygomycetes, 1549 serologic tests, 1551 sporotrichosis, 1549 treatment of, 1547t pharmacologic, 1 5 5 1 - 1 5 5 2 surgery, 1552 trends in, 1 5 4 5 - 1 5 4 6 headaches caused by, 2 0 6 0 - 2 0 6 2 hematogenous, 1476 immune response t o , 8 2 7 lcgioncllosis, 1 5 0 7 leprosy borderline, 1495 clinical features of, 1 4 9 4 - 1 4 9 5 complications of, 1 4 9 5 - 1 4 9 6 diagnosis of, 1495 differential diagnosis, 1495 epidemiology of, 1 4 9 3 - 1 4 9 4 eryrhema n o d o s u m leprosum, 1495 incidence of, 1493 lepromatous, 1494 Mycobacterium leprae, 1495 prevention of, 1496 signs and symptoms of, 1494—1495 rransmission of, 1494 trea Tine nt of, 1495 tuberculoid, 1 4 9 4 - 1 4 9 5 Lyme disease clinical features of, 1 4 9 8 - 1 4 9 9 description of, 5 5 9 , 1498 diagnosis of, 1499 neurological complications of, 1498-1499 treatment of, 1499 multiple sclerosis caused by, 1636 mycoplasma syndromes, 1507 nosocomial, 1475, 1484 parasitic characteristics of, 1 5 5 6 t - 1 5 5 7 t
liii
Infections {Continued) diagnostic approach brain biopsy, 1559 cerebrospinal fluid analysis, 1559 geographic history, 1558 imaging studies, 1559 immune status, 1558 laboratory investigations, 1 5 5 8 - 1 5 5 9 meningeal biopsy, 1559 travel history, 1558 Entamoeba histolytica, 1555, I556t, ! 566 helminthic cestodes, 1 5 6 8 - 1 5 7 2 cysticercosis. see Cyst ice rcosis echinococcosis, 1 5 7 2 - 1 5 7 3 nematodes angiostrongyliasis, 1 5 7 3 - 1 5 7 4 gnathostomiasis, 1 5 7 4 - 1 5 7 5 strongyloidiasis, 1 5 7 5 - 1 5 7 6 toxocariasis, 1576 trichinosis, 1575 protozoan African trypanosomiasis, sec African trypanosomiasis American trypanosomiasis, 1564 amoebic infections, 1 5 6 4 - 1 5 6 6 cerebral amoebiasis, 1566 characteristics of, 1556t description of, 1555 malaria, see Malaria Plasmodium falciparum, 1555, 1556t, 1559 toxoplasmosis, see Toxoplasmosis types of, 15.55 trematodes ectoparasites, 1578 paragonimiasis, 1.577-1578 schistosomiasis, 1 5 7 6 - 1 5 7 7 pathogenic organisms that cause, 1476 pathways for, 1475 pertussis, 1 5 0 7 pyogenic, 595, 595f relapsing fever, 1 4 9 9 - 1 5 0 0 rheumatic fever, 1508 Rocky M o u n t a i n spotted fever, 1500-1501 salmonellosis, 1506 septic venous sinus thrombosis, 14SS 1489 shigellosis, 1.506 shunt, 1490, 149 If spinal, 595 spinal cord injury secondary to, 1170-1171 spirochetes, 1496 stroke caused by, 1 3 0 3 - 1 3 0 4 subdural empyema clinical features of, 1 4 8 7 - 1 4 8 8 computed tomography of, 1487, 1488f definition of, 1 4 8 7 diagnosis of, 1488 treatment of, 1488 syphilis algorithm for, 1496t antibiotics for, 1498 clinical features of, 1 4 9 6 - 1 4 9 7 congenital presentation of, 1497 diagnosis of, 1496t, 1 4 9 7 - 1 4 9 8 etiology of, 1496
Volume I p p . 1-1070 • Volume II p. 1071-2546
liv
INDEX
Infections (Continued) follow-up visits For, 1498 general paresis caused by, 1497 Jarisch-Hcrxhc inter reactions, 1498 meningitis, 1497 neurosyphilis, 1497 secondary, 1496 tabes dorsalis, 1497 tertiary, 1496-1497 treatment of, 1496t, 1498 Treponema pallidum, 149(5 visual system effects, 1497 toxic shock syndrome, 1504 tropical pyomyositis, 1504-1505 rropism of, 1473 tuberculosis epidemiology of, 1491 global prevalence of, 1491 meningitis, 1491-1492, 1494f pathogenesis of, 1491 pathogens that cause, 1490-1491 spinal, 1492-1493 tuberculomas, 1492 vaccination, 1493 viral adenovirus, 1541 central nervous system antiviral drugs for, 847 arboviruses, see Arboviruses arenaviruses, 1537-1538 causes of, 1516t-1517t description of, 1515 diagnosis of antigen detection for, 845 criteria for, 845 i mm uno flu orescent techniques, 844 immunological tests, 845 improvements in, 844 molecular techniques for, 845 polymerase chain reaction, 845-846 differential diagnosis, I5l9t herpesviruses, see Herpesviruses historical studies of, 844 measles, see Measles mucous membrane findings associated with, 1517t mumps, 832t, 1520t, 1537 nonpolio enteroviruses, 1528 pathogenetic stages of capillary endothelial cell infection, 840 central nervous system invasion, 840-841 entry, 838-839 neural spread, 841-842 neurotropism, 842 polarized infection, 839 receptors, 842, 8431 spread, 839 systemic invasion, 839 target cell effects, 842-843 Trojan horse entry, 840-841 vircmia, 839-840 poliovirus, 1527-1528 polymerase chain reaction diagnosis of, 1520t rabies, see Rabies rubella, 832t, 835, 1537 skin findings associated with, I517t
Infections {{]uniinued) supportive therapy for, 847 symptomatic therapy for, 847 symptoms associated with, 845 treatment of, 846-848 vaccines for, 846-847 encephalitis brainstem, 172 cerebrospinal fluid pattern in, 833834 computed tomography findings, 834 description of, 833 epidemics of, 833 epidemiology of, 833 herpes simplex description of, 62, 833 diagnosis of, 834 clcci ^encephalography evaluations, 47If, 475, 834 magnetic resonance imaging of, 558-559, 559f treatment of, 834 human immunodeficiency virus, 562 manifestations of, 834 symptoms of, 833-834 toxoplasma, 560-562, 561f L'liccphalniiiydilis acute disseminated, 553, 553f, 825, 838 description of, 111 paraneoplastic, 1463-1464 postviral, 1535 progressive encephalomyelitis with rigidity, 1541-1542 Viliuisk, 1541 ganglionitis, 836 Guillain-Barre syndrome and, 838 hemorrhagic fever dengue, 1538 filoviruses, 1538-1539 yellow fever, 1538 hepatitis viruses, 1541 immune system and, 837-838 influenza, 832t, 1540-1541 meningitis acute, 833 characteristics of, 832t clinical features of, 833 course of, 833 description of, 831 diagnosis of, 832-833 recurrence of, 833 multiple sclerosis caused by, 1636, 1645-1646 myelitis epidemiology of, 835 herpes simplex virus, 835-836 incidence of, 835 syphilitic, 416 viral, 835-836 myositis, 837 papova viruses, 1539 parvovirus B-19, 1520t, 1541 polyneuropathy, 836-837 polyradiculitis, 836 Whipple's disease, 1506 zoonotic anthrax, 1503 brucellosis, 1502-1503 cat-scratch disease, 1504
Infections {Continued} glanders, 1503 melioidosis, 1504 paste urcllosis, 1503 plague, 1503 rat-bite fever, 1504 tularemia, 1503 Infective endocarditis, 1077-1078 Inferior oblique muscle, 199, 2(Jdt Inferior parietal lobe ideomotor apraxia caused by lesions of, 126 language role of, 142 phoneme processing by, 142 Inferior rectus muscle, 199, 200t Inferior sagittal sinus, 641 Inflammation bactetial meningitis and, 1477, 1752 traumatic brain injury-related, 1122 Inflammatory demyeiinating polyneuropathy acute, 414t, 825 chronic, 825-826, 1593t Inflammatory demyeiinating polyradiculoneuropathy acute, 414t, 415, 1593t see also Guillain-Biirre syndrome HIV-associated, 1599 Inflammatory muscle diseases, 827 Inflammatory myopathics, 168 Inflammatory response syndrome, systemic, 1084 Inflammatoryspondyloarthropathies, 2216-2218 Influenza, 832t, 1540-1541 Infrarentorial tumors, 537-540 Inhalants, 1723-1724 Inheritance patterns description of, 782t genetic disorders, 803t-805t Inhibitory postsynaptic potentials, 880 Innominate artery description of, 625-626 occlusive disease of, 1202 Insomnia altitude, 2013 anxiety disorders and, 2012 causes of, 2011-2012 chronic causes of, 201 It, 2011-2012 sleep disorders associated with, 2012-2013 clinical manifestations of, 2010-2011 depression and, 2012 description of, 2010 fatal familial characteristics of, 1620t clinical features of, 194, 1623 definition of, 2028 description of, 1614 genetic mutations, 1616t neuroendocrine functions in, 2028 neuropathology associated with, 1619 idiopathic, 2012 medical causes of, 2012t neurological disorders that cause, 2012t prevalence of, 2010 psychophysiological, 2012-2013 short-term, 2011, 2011 r sporadic familial, 1619-1621, 1620t, 1623
INDEX Insomnia [Continued) transient, 2011, 201lt treatment of, 2048-2049 Inspiratory gasp, 2019 Institutional review hoard, 461^162 Insufficient sleep syndrome, 2013 Insulin, S.SOt galanin effects, 905 Insulin hypoglycemia, 866r Insulin-like growth factor, 858, 1411 Integument examination, for coma evaluations, 50, 5 It Intellect, 65 Intentional network frontal lobe's role in, 122 inrrahemispheric networks' role in, 121-123 right hemisphere's role, 121 Intentional (when) disorders akinesia assessing for, 118-119 crossed response task assessments, 118 definition of, 117 diagnosis of, 117-118 directional, 118-119 endo-evoked, 118-119 exo-evoked, 118 hemispatial, 119 spatial, 118 testing for, 118-119 types of, 118 causes of, 123 defective response inhibition definition of, 117, 120 testing for, 120 description of, 117 hypokinesia, 117, 119 hypometria, 119 motor extinction, 119 motor impersistence, 117, 119-120 motor perseveration, 117, 121 parhologic causes of, 123 pathophysiology of intra hemispheric networks, 121-123 right-left hemisphere asymmetries, 121 Intention tremor, 288 Inrercclhilar adhesion molecule 1, 815, 841 Intercosrobrachial nerve syndrome, 2316 Intcrfacctal dislocation of cervical spine bilateral, 584 unilateral, 584, 584f Interferons, 817, 818t, 1411, 152It, 2452 Interferon-^, 817, 818t, 824, 1411 Interferon-^-lB, 96, 1657 Interferon-j/, 817, 818t, 1411 lnterleukin-1, 81Kt Interlcukin-2, 818t, 820, 1411 Interlcukin-3, 818t lnterleukin-4, 818t Interleukin-6, 818t Intcrlcukin-10, 818t Inrerleukin-12, 818t Intermittent explosive disorder, 99 Intermittent positive pressure ventilation, 2045 Internal anal sphincter, 1173 Internal capsule lesions of, 338t sensory abnormalities, 410t
Internal carotid artery anatomy of, 629-635 aneurysm of, 620f-621f anterior cerebral artery branch. see Anterior cerebral artery carotid siphon, 630 cavernous portion of aneurysms, 1020 description of, 629, 629f cerebral portion of, 630-631 cervical portion of, 629, 629f cisternal segment of, 631 disorders of, 631 dissection of, 617-618, 978f Doppler imaging of, 647 Fischer classification segment, 630, 630t maxillary artery anastomoses with, 627 middle cerebral artery branch, see Middle cerebral artery Moyamoya disease, 979-980, 980f, 1217f, 1217-1218 occlusion of, 1201 perrons portion of aberrant course for, 1020 aneurysms of, 1020 description of, 629, 629f posterior communicating artery, 630t, 631 segments of, 629-631, 630t stenosis of angiographic findings, l l l l f atherosclerotic plaque as cause of, 655 carorid cndartcrcctomy for, 655 description of, 631 illustration of, 999f-1000f, 1 2 l 0 f - l 2 l l f transcranial Doppler ultrasonography of, 656 transient ischemic attack caused by, 997 supraclinoid portion of, 630-631 ultrasound imaging of B-mode, 650-651 duplex, 650 vasospasm of, 10l0f Internal mammary artery, 626f Internal inaxillarj artery, ^2Si Internationa! Statistical Classification of Diseases, 764 Interneurons, 2229 Internuclear ophthalmoplegia bilateral, 718 causes of, 718, 718r description of, 275 multiple sclerosis and, 1640 pseudo-, 718 Interstitial fluid, 1746 Intervertebral disk herniation, 1167 Interview neurological, 4 neuropsychology, 676 Intestinal ileus, 952-953 Intimal hyperplasia, 1229 Intra-arterial digital subtraction angiography arteriovenous malformations evaluated using, 612-613 intracranial aneurysms evaluated using, 610 Intracellular adhesion molecules, 1239 Inrraccrcbral abscess, 559 Inrra cerebral hemaroma, 557 Intracerebral hemorrhage brain edema and, 1753
Iv
Intracerebral hemorrhage (Continued) caudate hemorrhage, 1260r, 1261, 1261f causes of amphetamines, 1256-1257 anticoagulants, 1253-1254 bleeding disorders, 1253-1255 brain tumors, 1253, 1255f cavernous angiomas, 1252 cerebral amyloid angiopathy, 1253, 1255 cocaine use, 1257 granulomatous angiitis, 1255-1256 hemophilia, 1253 hemorrhagic infarction, 1258 hypertension, 1251 immune-mediated thrombocytopenia, 1253 intracranial tumors, 1253, 1255f polyarteritis nodosa, 1256 sympathomimetic agents, 1256-1258 thrombolytic agents, 1254-1255 trauma, 1258 vascular malformations, 1252-1253 cerebellar hemorrhage, 1260t, 1262, 1262f cerebral angiography of, 1252 characteristics of, 571, 573f, 573t, 956 clinical features of, 1258-1259 computed tomography of, 1258-1259 conservative treatment of, 965 emergency treatment of, 965-966 evacuarion of, 965 hemorrhagic infarction vs., 1258, 1258t in HIV-infected children, 1609 hydrocephalus management, 1267 incidence of, 1015 intracranial pressure measures for controlling, 1265 treatment of, 1265-1267 intraventricular hemorrhage, 1260t, 1264 leukemia and, 1087 lobar hemorrhage, 1260t, 1261-1262, 1266 magnetic resonance imaging of, 1259t management of initial evaluation, 1264-1265 laboratory tests, 1265 medullary hemorrhage, 1260t, 1263 mesencephalic hemorrhage, 1260t, 1263, 1264f neurosurgical treatment of, 965-966 patient-specific trearmenr plans for, 966 pontine hemorrhage, 1260t, 1263, 1263f putaminal hemorrhage, 1257f, 1259-1261, 1260r, 1261f seizures associated with, 1265 stereotactic drainage of, 1266 thalamic hemorrhage. I260t. [261, 1262f tissue plasminogen activator and, 1254 treatment of, 1264-1267 Intracranial aneurysms causes of, 1271-1274 clinical manifesrations of, 1269-1270 computed tomographic angiography of, 621 computed tomography of, 1270-1271, I271f diagnostic studies for, 101 It dissecring, 1274 in Khler-Danlos syndrome, 1878, 1878f
Volume I pp. 1-1070 • Volume II p. 1071-2546
Ivi
INDtX
Intracranial aneurysms (Continued) endovascular treatment of, 9 6 9 - 9 7 0 , 971f, 1012-1013 epidemiology of, 1274 familial occurrence of, 1 2 7 1 - 1 2 7 4 fusiform, 1274 headaches caused by, 2 0 6 2 incidence of, 1011 laboratory studies, 1 2 7 0 - 1 2 7 1 magnetic resonance imaging of, 1271 microsurgical clipping of, 970 natural history of, 1 0 1 1 - 1 0 1 2 neurosurgical treatment of, 9 6 9 - 9 7 0 pathogenesis of, 1 2 7 1 - 1 2 7 4 physical findings of, 1270 prevalence of, 1011 ruptured, 1014, 1269 saccular, 1 2 7 1 - 1 2 7 4 signs and symptoms of, 1269 surgical classification of, 1273t surgical treatment of, 1012, 1012t 3D contrast-enhanced magnetic resonance angiography evaluations of, 611 3D time-of-flight magnetic resonance angiography evaluations, 6 1 0 treatment of, 1275, 1 2 7 9 - 1 2 8 1 unruptured, 1 0 1 1 - 1 0 1 4 , 1 2 8 0 - 1 2 8 1 Intracranial arterial stenosis atherosclerosis as cause of, 1002 distribution of, 1001 extracranial-intracranial bypass surgery for, 1002 middle cerebral artery computed tomographic angiography of, 619 magnetic resonance angiography of, 611f stroke caused by, 656, 1001 transcranial Dopplcr ultrasonography of, 6 5 6 , 657f percutaneous transluminal angioplasty for, 1002 srenting indications, 1 0 0 2 - 1 0 0 4 , 1003f-1005f stroke caused hy, 1 0 0 0 - 1 0 0 1 treatment modalities for, 1001-1002 Intracranial hemorrhage anticoagulant therapy a n d , 1089 arteriovenous malformations and, 1290 in children, 1308, 2 S 2 4 - 2 5 2 5 description of, 958 neonatal, 2 5 2 4 - 2 5 2 5 during pregnancy, 2 5 4 0 - 2 5 4 1 septic arteritis and, 1077 stroke caused by, 1251 rhromholysis-related, 1238 Intracranial hypertension characteristics of, 1 1 3 8 - 1 1 3 9 , 1 1 4 1 , 1265-1267 idiopathic clinical features of, 1 7 5 7 - 1 7 5 8 description of, 1757 diagnosis of, 1757 drugs associated with, 1757r obesity and, 1757 during pregnancy, 2 5 3 7 - 2 5 3 8 treatment of, 1758
Intracranial pressure craniectomy for, 1138 diuretics to lower, 1138 i increased in bacrerial meningitis, 1482 barbiturate coma for, 9 5 7 , 957t causes of, 2 0 - 2 1 , 1746t corticosteroids for, 1756 in cysricercosis, 1569 gastric stress ulcers secondary t o , 9 5 2 hydrocephalus a n d , 1759 hyperventilation management, 9 5 6 - 9 5 7 loss of consciousness secondary t o , 1 1 , 20-21 management of, 9 5 6 - 9 5 7 mannitol for, 9 5 7 ncuroscicnces critical care unit management of, 9 5 6 - 9 5 7 lowering of, 1138 monitoring of cerebral perfusion pressure, 1 1 3 7 coma evaluations using, 62 devices for, 9 4 4 - 9 4 5 in ncuroscicnces critical care units, 944-945 in traumatic brain injury, 1137 ventriculostomy technique for, 1137 waveforms, 9 4 4 , 944f normal, 9 4 4 , 956 transcranial Dopplcr ultrasonography of, 6 6 2 - 6 6 3 , 663f traumatic brain injury considerations, 1137-1138 Intramedullary cord hemorrhage, 5 8 7 , 1321 Intramedullary cysts, 589f Intramedullary spinal cord metastases, 1450 Intraoperative neurosonography, 5 3 1 - 5 3 2 Intravascular lymphomatosis, 2 3 6 9 Intravenous immunoglobulin for derm a to myositis, 2 5 0 6 for Hpstcin-Barr virus, 1525 for Guillain-Rarre syndrome, 2 3 4 3 - 2 3 4 4 for myasthenia gravis, 2 4 5 1 - 2 4 5 2 Intraventricular h e m o r r h a g e description of, 1260t, 1264 neonatal, 2 5 2 1 - 2 5 2 2 Intubation pre procedural considerations, I 133 rapid sequence, 1 134, 1134t traumatic brain injury indications, 1133 Inverse ratio ventilation, 9 4 9 Inversion of the radial reflex, 355 Invirasc. see Saquinavir Ion channels definition of, 1S47 epilepsy pathophysiology a n d , 1974 ligand-gated, 1847 voltage-gated action potential duration a n d , 9 0 9 calcium channels antiepileptic drug effects on, 913 disorders associated with, 91 I t , 913 L-type, 912 IM-rype, 9 1 2 operating cycle of, 913 pharmacology oi, 9 I ! physiology of, 9 13 P-rype, 9 1 2 structure of, 1849, 2 4 8 6 - 2 4 8 7 T-type, 9 1 2
[on
channels (Continued) chloride channels in cystic fibrosis, 9 1 4 description of, 9 1 4 disorders associated with, 9 l 1 t description of, 909 distribution of, 1 8 4 7 - 1 8 4 8 potassium channels calcium-dependent, 9 1 4 depolarization of, 914 disorders associated with, 911r hippocampal pyramidal neurons a n d , 914 structural features of, 9 1 3 , 1 8 4 8 - 1 8 4 9 , 1849f s u b m i t s of, 9 1 3 sodium channels anticonvulsant drug effects on, 912 antiepileptic drug binding ro, 911-912 disorders associated with, 9 ! 0 , 91 It extracellular loop, 910 function of, 9 1 0 - 9 1 2 intracellular loop, 9 1 0 pharmacology of, 910—912 sequences in, 910 structure of, 9 1 0 , 1 8 4 9 , 2 4 8 7 retrodotoxin-resistant, 9 1 2 Ionizing radiation, see also Radiation; Radiation rhei , ap\ description of, 1 3 3 5 - 1 3 3 6 encephalopathy caused by, 1741 myelopathy caused by, 1 7 4 1 - 1 7 4 2 Ipsilcsional response inhibition, 120 Irinotecan, 1406 Ins degeneration of, 2 2 3 transillumination defects, 2 2 7 Ischemia cerebral carotid artery syndromes, 1 2 0 3 - 1 2 0 5 crescendo episodes of, 1203 focal, 1666 headaches caused by, 2 0 6 4 - 2 0 6 5 pathophysiology of, 1201 positron emission t o m o g r a p h y evaluations, 6 7 0 single-photon emission computed tomography evaluations, 670 syncope caused by, 1074 transient ischemic attacks, see Transient ischemic attacks spinal cotd aortic hemodynamic compromise as cause of, 1315 atherosclerotic plaques a n d , 1316 causes of, 1 3 1 5 - 1 3 1 7 clinical presentation of, 1315 course of, 1315 fibrocartilaginous emboli a n d , 1 3 1 6 , I317f historical description of, 1 3 1 4 - 1 3 1 5 hypotension and, 1316 imaging of, 1315, 1316f magnetic resonance imaging of, 1315, 1316f pain associated with, 1315 sensory loss assoeiared with, 1315 signs and symptoms of, 1315 thromboembolism and, 1316
INDEX Hemorrhage {Continued) description of, 958 neonatal, 2.524-2525 during pregnancy, 2540-2541 septic arreriris and, 1077 stroke caused by, 1251 thrombolysis-re I a ted, 1238 intramedullary cord, 587 intraventricular description of, 1260t, 1264 neonaral, 2521-2522 lobar, 1260t, 1261-1262, 1266 medullary, 1260t, 1263 mesencephalic, 1260t, 1263, 1264f optic disc, 187 pcrimesencephalic, 1282 periventricular-intraventricular clinical fearures of, 2519 computed tomography of, 2519, 2520f diagnosis of, 2518-2519 epidemiology of, 2518 management of, 2519-2521, 2520t pathogenesis of, 2519-2521, 2520t prognosis, 2521 pontine, 1260t, 1263, 1263f putaminal, 1257f, 1259-1261, 1260t, 1261 f spinal subdural, 1321 subarachnoid aneurysmal, 661-662, 1014 cardiac abnormalities in, 1276 cerebral blood flow effects, 1279 cognitive dysfunction after, 1275 complications of, 1275-1276 course of, 1274-1275 delayed ischemic deterioration after, 1279 description of, 661-662, 1014 epidemiology of, 1274 familial history of, 1274 hyponatremia associated with, 1276 ischemic complications, 1280 neuropsychological deficits secondary to, 1275 pathogenesis of, 1271-1274 physical findings of, 1270 pulmonary edema caused by, 1275 rebleeding after, 1276-1279 recurrence prevention, 1276-1279 seizures associated with, 1275 treatment of, 1275 vasospasm associated with, 1279-1280 angiography of, 1271 computed tomography of, 556-557, 1271, 1273f conditions associated with, 958 grading systems for, 968-969 hydrocephalus associated with, 958, 969 laboratory studies, 1271 neurosciences critical care unit management of, 957-958 neurosurgical considerations for, 964 neurosurgical treatment of angiography for, 968 considerations for, 964 description of, 968 diagnosis of, 968
Hemorrhage {Continued) grading systems for, 968-969 hydrocephalus comorbidity, 969 intracranial aneurysms, 969-970 vasospasm, 969, 970f of unknown cause, 1282 penmesencephalic hemorrhage, 1282 physical findings associared with, 1270 in pregnancy, 1281-1282 traumatic, 1129, 1141 vasospasm in, 661-662, 957 description of, 661-662, 957 treatment of, 1009-1011 subdural, 1321 thalamic, 1260r, 1261, 1262f Hemorrhagic diseases antiphospholipid antibody syndromes, 1089-1090, 1090f disseminated intravascular coagulation, 1089 hemophilia, 1088-1089 iatrogenic, 1089 of the newborn, 1108-1109 thrombocyropenia, 1089 thrombotic thrombocytopenic purpura, 1089 Hemorrhagic fever viruses dengue, 1538 filoviruscs, 1538-1539 yellow fever, 1538 Hemorrhagic metastases, 537f Hemorrhagic strokes, 158 Hemosiderosis, superficial, 2220, 222If Hendra virus, 832t, 1535 Heparin deep venous thrombosis prophylaxis using, 1 139, 1176, 1367 stroke treated with, 1236-1237 unfracrionated, 1236-1237 Hepa rin-induced thrombocytopenia, 1230-1231 Hepatic coma, 1681 Hepatic encephalopathy, 1109, 1109t ammonia's role in, 1676-1677, 1679 astrocyte findings, 1680 cerebral blood flow evaluations, 1676 clinical fearures of, 1674-1675 complications of, 1681 description of, 1674 diagnosis of, 1675 electroencephalographs findings, 1675 etiology of, 1674-1675 evoked potentials for, 1675-1676 fatty acids and, 1680 fulminating hepatic failure vs., 1674t glucose metabolism evaluations, 1676 hyperammonemia and, 1676, 1679 imaging of, 1676 magnetic resonance imaging of, 1676, 1677f magnetic resonance spectroscopy of, 1676 mtrcaptans and, 1 680 ne tiro pathology of, 1680 neuropsychiatry abnormalities associated with, 1675t neuropsychological tests, 1675 neurotransmission abnormalities and, 1679 pathophysiology of, 1676-1680
xlvii
Hepatic encephalopathy {Continued) prognosis for, 1681 treatment oi amino acids, 1681 goals, 1680 lactulose, 1680-1681 Hepatitis viruses, 1541, 2389 Hepatocerebral degeneration, 1091, 1947 Hepatolenticular degeneration, see Wilson's disease Hereditary geiiiospasm, 2161-2162 Hereditary hemorrhagic telangiectasia, 1224 Hereditary hyperekplexia . clinical features of, 1 848r, 1860 diagnosis of, 1861 genetic mutations associated with, 1860-1861 pathophysiology of, 1860-1861 signs and symptoms of, 1860 treatment of, 1861 Hereditary motor and sensory neuropathy, 804t Hereditary neuropathy, 344 Hereditary periodic paralysis, 1848t Hereditary progressive dysronia, 2031 Hereditary sensory and autonomic neuropathy definition of, 2327 subtypes of, 2327t
trearment of, 2329 type 1, 2327t, 2327-2328 type II, 2327t, 2328 type III, 2327t, 2328-2329 type IV, 2327t, 2329 Hereditary sensory neuropathy, H04t Hereditary spastic paraplegia, 2227 Henng's law of dual innervation, 199 Hermansky-Pudlak syndrome, 738 Herniated disk cauda equina syndrome caused by, 1159, 1159f magnetic resonance imaging of, 221 If Herniation brain coma and, 59
computed romography for, 62 signs of, 58-59 traumatic brain injury and, 1 130 types of, 113If after lumbar puncture, 46, 964 Heroin, 1720-1721, 2384 Herpes B virus, 1527 1 lerpes sinlpU-s. vim*. characteristics of, 832t congenital, 2524 dementia, 1939 encephalitis caused In acyclovir for, 834, 1518 brain biopsy indications, 987 cerebrospinal fluid findings, 1518 characteristics of, 1516 clinical features of, 1516-1517 computed tomography of, 1518 description of, 62, 833 diagnosis of, 834, 1517-1518 electroencephalography of, 47If, 475, 834, 1518 magnetic resonance imaging of, 55S-559, 559f, 1518, 15231
Volume I pp. 1-1070 • Volume II p. 1071-2546
Ivui
INDEX
Lambert-Eaton myasthenic syndrome (Continued) repetitive nerve stimulation in, 5 I 7 t , 518f symptoms of, 1467-1468 treatment of, 1468, 2457 Lamina termhialis, 1779 Lamimn a 1 deficiency, 2476-2477 tf2-Laniinin gene, 404 1 annviidiriL', 1 iS~i Lamorrigine epilepsy treated w i t h , 1982c, 1984 neuropathic pain treated w i t h , 98t, 2310 psychotropic effects of, 98t Lance-Adams syndrome, 2162 Landau Klcfrner syndrome, 1967 Langer-Giedion syndrome, 81t Language bedside examination of aphasia evaluations, 156-158 description of, 143-144 processes involved i n , 142 speech vs., 141 Language disorileis aphasia, see Aphasia bedside examination, 143-144 dementing diseases and, 155-156 description of, 141 developmental articulation, 1804 autistic spectrum disorders vs., 1794 cluttering, 1804-1805 definition of, 1803 electro physiology studies, 1807 expressive language, 1805-1806 higher order, 1806 lexical syntactic syndrome, 1806 metabolic imaging, 1807, 1807t neurobiological basis of, 1806-1807 outcome of, 1808 phonological programming disorder, 1 sinphonological syntactic syndrome, 1805-1806 receptive language, 1805-1806 remediation for, 1808 risk factors, 1803-1804 semantic pragmatic syndrome, 1806 signs of, 1803, 1804t stuttering, 1804-1805 subtypes of, 1804, 1805t verbal auditory agnosia, 1806 verbal dyspraxia, 1805 differential diagnosis, 143 epilepsy and, 694 right hemisphere disorders and, 154-155 stroke-induced, 1932 symptoms of, 143 traumatic brain injury and, 698t treatment of, 872 Large dense core vesicles, 902-903 Laryngeal mask airway, 1133 Lassa fever, 1538 Latency intensity study, 483 Latent hyperopia, 201 Latent nystagmus, 215 Lateral epicondylitis, 442 Lateral femoral cutaneous nerve entrapment of, 2312t, 2317 motor functions of, 44St sensory functions of, 448t
Lateral geniculate body, 727 Lateral geniculate nucleus, 701 Lateral medullary syndrome description of, 285 etiology of, 1207 postural reflexes in, 326-327 sensory abnormalities i n , 412 Lateral pontomedullary syndrome, 1207 Lateral rectus muscle characteristics of, 199, 200t diplopia caused by weakness of, 203
palsy of clinical examination findings, 206f esotropia caused hy, 203f, 207 Laterodorsal tegmental nuclei, 1499 Lateropulsion, saccadic, 716 Lathyrism, 1731, 2228 Laurence-Moon-Biedl syndrome, 1111-1112 i -dopa akinetic-rigid gait treated w i t h , 330, 3 3 I t bladder function and, 425 dysphagia and, 171 Parkinson's disease treated w i t h , 2134t, 2135 pituitary function testing, H66t psychosis and, 93 side effects of, 2136t transport of, 1747-1748 tyrosine hydroxylase effects, 893 Lead exposure dementia and, 1947-1948 description of, 1716 testing for, 79 Learning disabilities dyslexia attention deficit hyperactivity disorder and, 1798 atypical features of, 1799t diagnosis of, 1798 etiology of, 1798-1799 evaluation of, 1798-1799 treatment of, 1799 nonverbal, 1799-1800 prevalence of, 1797 signs of, 1798t types of, 1797 Leber's congenital amaurosis, 737-738 Leber's hereditary optic neuropathy, 181, 187-188, 1639, 1834, 1843-1844 Left hemisphere consciousness of, 68 ideomotor apraxia and, 121 tumors of, aphasia caused by, 158 Left temporal lobectomy, parrial memory loss secondary to, 7 0 - 7 1 Leg(s) muscle mass, 371 shortening of, 336 Legionellosis, 1507 Leigh's disease, 551 Leigh's syndrome, 1843 Lennox-Gastaut syndrome, 1966 Lennox-Gastain syndrome, 469, 470f Lens dislocation, 78t Lenticular nucleus, 2126 Lenticulostriate arteries infarction, 339, 1204 Lepromin reagent, for leprosy diagnosis, 1495 Leprosy borderline, 1495 clinical features of, 1494—1495
Leprosy (Continued) complications of, 1495-1496 diagnosis of, 1495 differential diagnosis, 1495 epidemiology of, 1493-1494 erythema nodosum leprosum, 1495 incidence of, 1493 lepromatous, 1494 Mycobacterium leprae, 1493 neuropathy associated w i t h , 2390-2391 prevention of, 1496 signs and symptoms of, 1494-1495 transmission of, 1494 treatment of, 1495 tuberculoid, 1494-1495 Lcptomeningeal carcinomatosis, 2277f l.eptomeningeal metastases acute lymphoblastic leukemia and, 1450 adenocarcinoma, 1450 cerebral symptoms of, 1451 clinical features of, 1451 description of, 1371, 1373f, 1374, 1450 diagnosis of, 1453 diagnostic tests for cerebral angiography, 1453 cerebrospinal fluid examination, 1451-1453 description of, 1451t imaging, 1453 lumbar puncture, 145 lr magnetic resonance imaging, 1453 differential diagnosis, 1453t epidemiology of, 1450 non-Hodgkin's lymphoma, 1450 pathogenesis of, 1450-1451 prognosis for, 1455 survival rates, 1453 systemic relapse and, 1453 treatment of chemotherapy, 1454-1455 description of, 1453 goals, 1453-1454 hormonal therapy, 1455 radiation therapy, 1454 regimens, 1454t tumor cells, 1450-1451 Leptospira interrogans, 1500 Lcsch-Nyhan syndrome, 313, 805t, 1828 Lesionectomy, 1989 Lesions, see also specific lesion anatomic localization of, 7-8 differential diagnosis of, 8 multifocal, 8 Lethargy, 43 Leucocyte differentiation molecule, 1560 Leukemia, 1086-1087 Leukoariosis, 1932-1934 Leukocyte function antigen 3, 815 Leukodystrophies adrenomyeloneuropathy, 2334-2335 globoid cell, 2334 Krabbc's disease, 553 metachromatic, 2334 Leukoencephalitis, acute hemorrhagic, 1662 Leukocuccphalopathy, progressive multifocal, see also JC virus in AIDS patients, 1594, 1596 dementia associated w i t h , 1939 description of, 562, 563f, 1539
INDEX Leu k oen ce ph a lo pa thy, progressive multifocal (Continued) diagnosis of, 1.539 hemiplegia and, 333-340 herpes simplex encephalitis and, 834 highly active antiretroviral therapy for, 1596 magnetic tesonancc imaging of, 1539f, 1.596f onset of, 1539 survival tates, 1596 symptoms of, 834 treatment of, 834, 1596 Leukotriene synthesis defects, 1830 Level of consciousness airway integrity based on, 948 electroencephalography and, 472 Lcvctiracctam, 1366, 1982t, 1984 psychotropic effects of, 98t [.evo-Dromoran. see Levorphanol Levorphanol, 934t Lewy bodies, dementia with antipsychotic agents for, 1926 cholinesterase-inhibiior drugs for, 1925-1926 clinical features of, 1924-1925, 1925t description of, 91, 112, 1924-192.5, 2140 diagnosis of, 1925 dopaminergic therapy for, 1926-1927 hallucinations in, 92, 112 ncuroimaging of, 1925 neuropathology I features of, 1925, 1926f occipiral lobe hypoperfusion associated with, 1925 parkinsonism symptoms and, 1909 pharmacological management of, 1925-1927 psychotic symptoms in, 92, I I 2 lexical syntactic syndrome, 1806 Lhermitte-Duclos' disease, 1393, 1395f Lhermitte's phenomenon, 1641 Libido, 421, 855, 1174 Liddlc syndrome, 1848t Lid nystagmus, 220 Lifetime prevalence rate, 763 Li-Frauincni's syndrome, 1338 Ligament of Struthers, compression at, 344t, 2314 Ligainenttim flavum ossification, 2203-2204, 2204f Ligand-gared ion channels activation of, 1849-1850 description of, 1847, 1974 I.igand-gated receptors j'-aminobutyric acid, see y-Aminobutyric acid description of, 877-878 inotropic, 877 metabotropic, 877 structure of, 878f Light chain, 811 Light-near dissociation, 224, 227 Lightning injuries, 1742-1743 Light stress test, 730 Limb akinesia, right hemispheric dysfunction and, 121 Limb ataxia, 287 Limb-girdle dystrophies 1A,2474 IK, 2474-2475
Limb-girdle dystrophies (Cuntinued) 1C, 2475 2A, 2475 2B, 247.5 2C, 2475 2D, 2475 2E, 2475 2r', 2475 2G, 2476 2H, 2476 21, 2476 autosomal dominant, 2474-2476 description of, 2474 Limb girdle muscular dystrophy, 803t, 805t Limbic encephalitis, 1946 Limbic striatum, 2127 Limb impersistence, 120 Limb-kinetic apraxia definition of, 123 pathophysiology of, 124 testing for, 124 types of, 124 Limb mononeuropathy, 2361 Limit-setring sleep disorders, 2037 Linear accelerator, 1402 Lingual artery, 628t Lingua! nerve injury, 263 Linguistic elements, 142 Linkage analysis chromosome cross over, 799, 799f description of, 798-799 LOD scores, 799 usefulness of, 799-800, 800t Lipid metabolism disorders, 2493-2495 Lipofuscinosis, infantile ceroid, 803t-804t Lipomas, 1361 fi-Lipotropic hormone, 8.50t Lisch nodules, 1874, 1876f Lissencephaty, 805t, 1767, 1768, 1777t, 1783-1785, 1784f Listeria monocytogenes, 1483—1484 Lithium carbonate, 6 Little's disease, 328 Liver disease acute heparic failure, 1090, 1090f chronic non-Wilsonian hepatocerebral degeneration, 1091 portal systemic encephalopathy, 1090-1091 renal failure, 1093 Liver transplantation in adults, 1091 in children, 1109-1110 Loading dose, 916 Loa toa, 1557t Lobar hemorrhage, 1260t, 1261-1262, 1266 Lobar holoprosencephaly, 1777t, 1780 Localized perineuria! hypertrophic mononeuropathy, 2318-2319 Locked-in syndrome, 44, 44t, 1207 Lockjaw, 1510 Locomoror training, 1056-1057 Locus of Kiesselbach, 627 Long QT syndrome, 14, 1848t Long-term memory, 68, 1907 Long-term potentiation, 1044-1045 Lophoroxin, 890 Lorazcpam, 1982t status epilepticus treated with, 1969t l.ortab. see Hydrocodonc
lix
Loss of balance, 325 Loss of consciousness breath-holding spells, 20 description of, 11 falls caused by, 23 intracranial pressure increases, 11 malingering considerations, 21 miscellaneous C.ILJM'S of, .\0
seizure-related, sec Seizures sleep disorders vs., 21 syncope, see Syncope Louping ill virus, 1533 Low back pain anatomy of, 445 bone scan evaluations, 450 causes of, 445 classification of, 448t diagnostic approach to, 445-446 differential diagnosis description of, 448t^l49t evaluation, 447, 450-45 1 guidelines for, 446^447 tests, 450t, 450-451 economic costs of, 44.5 electromyography evaluations, 450 history-taking, 445^146 lumbar discitis and, 4.56 lumbar spine compression and, 456 lumbar spine osteomyelitis and, 45.5-456 magnetic resonance imaging evaluations, 450 mechanical, 455 nerve conduction study evaluations, 450 non-neurological causes of, 445, 447 physical examination for, 446 spinal stenosis and, 45 I treatment of, 2212 without leg pain, 455^156 Lowet limbs distal, 369 pain of anatomic considerations, 445 bone scan evaluations, 451 classification of, 448t diagnosis of, 445-446 differential diagnosis, 445 description of, 448t-449t evaluation, 447, 450-451 guidelines for, 446—447 tests, 450t, 450-451 electromyography evaluations, 450 femoral neuropathy and, 452^153 herpes zoster and, 454^155 history-taking, 445-446 lumbar puncture, 450 myelography, 450 nerve conduction study, 450 peroneal neuropathy and, 453^154 physical examination for, 446 polyneuropathy, 454 radiography evaluations, 451 sciatic neuropathy and, 453 without lower back pain, 452^154 proximal, 369 Lower motor neuron (s) inremeurons, 2229 neuroanatomy of, 2229 weakness amyotrophic lateral sclerosis and, 379 foramen magnum lesions and, 361
Volume 1 pp. 1-1070 • Volume II p. 1071-2546
Ix
INDEX
Lower motor neuron(s) {Continued) spondylosis with spinal cord compression as cause of, 342 Lower motor neuron diseases amyotrophic lateral sclerosis age of onset, 2247 atypical features of, 2251-2252 behavioral disturbances in, 97 blood tests for, 2253 characteristics of, 172 chromosomal aberrations, 803t classification of, 2252t dementia in, 2251 depression in, 97 diagnosis of, 383-384, 2253-2254 differential diagnosis, 2254 dysphagia in, 172 electrodiagnostic examination for, 2253 enteroviruses and, 1529 epidemiology of, 2247 etiology of, 2247 familial autosomal dominant, 2258-2259 clinical features of, 2259 description of, 2247, 2258 genetics of, 2258 juvenile, 2259-2260 pathogenesis of, 2258-2259 fascicularions in, 2251 footdrop in, 2250f frontotemporal dementia and, 688, 1922 glu tarn ate excitotoxiciry and, 2247 history of, 2246-2247 human immunodeficiency virus and, 1540 immunological abnormalities associated wirh, 2248 inclusion body myopathy vs., 384 inflammatory abnormalities associated with, 2248, 2249f laboratory studies of, 2252-2253 lower motor neuron-type weakness, 379 magnetic resonance imaging of, 2253 muscle weakness associated with, 383-384, 2249-2250 natural history of, 2252 needle electrode examination for, 2253 needle electromyography diagnosis of, 511-512 nerve conduction studies for, 512 neurofilament dysfunction in, 2248-2249 paraneoplastic, 2262 personality disturbances in, 97 prognosis for, 2252 pseudobulbar palsy associated with, 2250 radiculopathies that simulate, 2282 rehabilitation for, 871 signs and symptoms of, 8 sleep disorders and, 2031 spastic-flaccid dysarthria in, 162 sporadic clinical features of, 2249-2251 etiology of, 2247 pathogenesis of, 2247-2249 susceptibility genes, 2249 symptomatic treatment of, 869-870 tongue atrophy in, 380f
Lower motor neuron diseases (Continued) treatment of ethical and legal issues, 2256 guidelines for, 2254t, 2256t home care, 2258 hospice care, 2258 initial, 2254-2255 multidisciplinary team approach, 2256 neurotrophic factors, 2255 nutritional care, 2257 percutaneous endoscopic gastroscopy, 2257 pharmacological, 2255 physical rehabilitation, 2256-2257 respiratory care, 2257-2258 speech and communication management, 2257 variants of, 2247 benign focal amyotrophy clinical features of, 2236 differential diagnosis, 2237 etiology of, 2236 laboratory studies, 2236-2237 pathogenesis of, 2236 treatment of, 2237 Kennedy's disease clinical features of, 2243t, 2244 differential diagnosis, 2245 history of, 2243 laboratory studies, 2244-2245 pathogenesis of, 2243-2244 treatment of, 2245 laboratory studies electrodiagnostic examination, 2230-2231 magnetic resonance imaging, 2231 muscle biopsy, 2231 needle electromyography, 51 Of, 510-512 multifocal motor neuropathy chronic idiopathic demyelinating polyradiculoneuropathy vs., 2235 clinical features of, 2234, 2234t differential diagnosis, 2235 etiology of, 2234 history of, 2234 laboratory studies, 2234-2235 treatment of, 2235-2236 poliomyelitis clinical features of, 2231 description of, 2231 differential diagnosis, 2232 laboratory features of, 2231-2232 treatment of, 2232 vaccination, 2232 postirradiation syndrome, 2246, 2282 progressive muscular atrophy, 2245-2246 progressive postpoliomyelitis muscular atrophy amyotrophic lateral sclerosis vs., 2234 clinical features of, 2233 diagnosis of, 2233 epidemiology of, 2232 etiology of, 2232-2233 laboratory features of, 2233 prevalence of, 2232 treatment of, 2233-2234 signs and symptoms of fascicular!ons, 2230
Lower moror neuron diseases (Continued) loss of muscle strength, 2229-2230 muscle cramps, 2230 muscle hypotonicity, 2230 spinal muscular atrophy adult-onset clinical features of, 2241, 22411 differential diagnosis, 2241-2242 epidemiology of, 2240 generic abnormalities associated with, 2240-2241 inheritance of, 2240-2241 laboratory features of, 2241 treatment of, 2242 infantile and juvenile differential diagnosis, 2240 epidemiology of, 2237 etiology of, 2237-2238 genetic counseling, 2241 genetics, 2237-2238 laboratory studies, 2240 prenatal diagnosis, 2241 prevalence of, 2237 treatment of, 2240-2241 type 1, 2238 type 2, 2238, 2239f type 3, 2238, 2240 subacute motor nctironopathy, 2246 Lowe's oculocerebral renal syndrome, 805t Low-grade astrocytomas characteristics of, 532 in children, 1430-1431 imaging of, 1330 management of, 1412 Low-velocity missile wounds, 1141-1142 Lubag dystonia parkinsonism, 805t Lubag's syndrome, 2157-2158 Lumbar canal stenosis, 2212-2213 Lumbar plexitis, 346 Lumbar puncture hrain tumor evaluations, 1365—1366 in coma, 46
computed tomography before, 46 herniation risks, 46, 964 low back pain evaluations, 450 lower limb pain evaluations, 450 risk-ro-benefit considerations for, 459 Lumbar radiculopathy, 346t, 2210 Lumbar spine compression of, 456 discitis of, 456 herniated disks of, 582-583 osteomyelitis of, 455—456 Lumbosacral nerve root lesions, 354t Lumbosacral plexitis, 454 Lumbosacral plexus anatomy of, 447f disorders of anatomical features of, 2290, 2290f clinical features of, 2290-2291 differential diagnosis, 2291-2292 electrodi agnostic studies, 2291 nerve conduction studies of, 2291 neuroimaging of, 2291 neurological examination of, 2290-2291 plexopathy
aneurysms and, 2293 hematoma and, 2292-2293 hemorrhagic, 2293f
INDLX Lumbosacral plexus {Continued) idiopathic, 2295 neoplasia a n d , 2 2 9 4 - 2 2 9 5 nonstructural, 2 2 9 5 pregnancy a n d , 2 2 9 4 psoas abscess and, 2 2 9 3 radiation, 2295 trauma a n d , 2 2 9 3 - 2 2 9 4 neoplasms of, 4 5 2 plexopathy of, 1457 Lumbosacral po ly ra d icu lomyc I itis, 1599-1600 Lu mbosacral pol y rati icu Jo ne u ropa th y, 2388-2389 Lumbosacral radiculopathy, 4 5 I t , 4 5 1 - 4 5 2 Lumbosacral radiailoplexopathy, 2361 Lung canter, 1 4 4 1 - 1 4 4 2 Lupus anticoagulants, J 2 2 7 L u n a ' s test of alternating sequences, 68f, 73f Luteinizing hormone, 856t Lyme disease, 559 clinical features of, 1 4 9 8 - 1 4 9 9 dementia and, 1940 description of, 5 5 9 , 1498 diagnosis of, 1499 neurological complications of, 1 4 9 8 - 1 4 9 9 peripheral nfuropathv nssociarrd with, 2392 treatment of, 1499 Lyme ra d icu lone u ropa thy, 2 2 7 8 - 2 2 7 9 Lymphangioma, 5 7 5 Lymphocyte function-associated antigen, 841 Lymphocytic choriomeningitis virus, 832t, 1537-1538 Lymphoma brain, 5 3 4 , 536f central nervous system AIDS-related, 562f, 5 6 3 , 1418, 1594, 1595f characteristics of, 5 3 4 , 536f, 562f, 5 6 3 , 8 3 7 , 1359 computed tomography of, 1594, 1595f diagnosis of, 1594 qiidetniology of, I 333 Epstein-Barr virus a n d , 1359 histologic findings, 1359 imaging of, 1 3 8 1 , 1384f-1385f management of, 1418 methotrexate for, 1405 outcome of, 1594 radiation therapy for, 1418 description of, 1088 neurological complications of, 2 3 6 9 non-Hodgkin's, 1450 toxoplasma encephalitis vs., 5 6 2 vasculitis of central nervous system associated with, 1326 Lymphotoxin, 81 8t Lyonization, 784 Lysinuric protein intolerance, 1825 Lysosomal associated membrane protein 2, 1821 Lysosomal disorders classification of, 1822t clinical features of, 1821 diagnostic findings, 1813 hepatosplenomegaly associated with, 1813 history of, 1821 Lysosomes, 1 8 2 1 , 18211
M Ma, 458 Machado-Joseph disease, 6, 2178f, 2 2 6 0 M a c r o a d e n o m a , 5 4 5 , 546f Macrocephaly, 1892 Macrophages, 8 1 0 - 8 1 1 M a c r o s q u a r e wave jerks, see Square w a v e pulses M a c u l a r cherry-red spot, 78t M a d d o x rod rest, for diplopia, 2 0 6 , 208f Magnesium imbalances, 1 0 9 4 - 1 0 9 5 , 1690 Magnesium sulfate, 2 5 4 4 Magnetic coil stimulation, 4 8 6 - 4 8 7 Magnetic resonance angiography clinical uses of arteriovenous malformations, 6 1 3 , 1 2 8 9 , 1291f carotid arteries, 6 0 3 carotid-cavernous fistula, 5 5 7 , 558f dural arteriovenous fistulas, 1320f extracranial circulation, 6 0 3 headache, 2 7 0 intracranial circulation, 607-612 intracranial veins, 611-612 spinal vascular malformations, 1318-1319 spine, 6 1 5 - 6 1 6 stroke, 1234, 1 3 0 7 venous malformations, 6 1 3 - 6 1 5 venous sinuses, 6 1 1 - 6 1 2 vertebral arteries, 603 description of, 4 5 9 - 4 6 0 , 5 3 2 gadolinium, 6 0 2 - 6 0 3 , 9 9 6 maximum intensity projection, 6 0 2 , 602f phase contrast anticipated m a x i m u m blood flow velocity considerations, 6 0 0 data acquisition methods, 6 0 0 definition of, 5 3 2 description of, 599 illustration of, 600f mechanism of, 6 0 0 3D Fourier methods used with, 602 2D Fourier methods used with, 6 0 2 principles of, 5 9 9 - 6 0 2 techniques for, 5 3 2 3D contrast-enhanced applications of, 6 0 5 - 6 0 7 arteriovenous malformations evaluated using, 613 carotid stenosis evaluations, 604f, 605-606 description of, 6 0 2 - 6 0 3 intracranial aneurysms evaluated by, 611 intracranial arteries, 6 0 9 spinal circulation assessments, 6 1 5 vertebral arteries, 6 0 6 , 6 0 7 f - 6 0 8 f 3 D Fourier transformation description of, 5 3 2 disadvantages of, 6 0 0 illustration of, 6 0 I f rime-of- flight applications of, 6 0 3 , 6 0 5 data acquisition mi'thuds, M)0 definition of, 5 3 2 description of, 5 9 9 familial aneurysmal disease screenings, 610 intracranial veins, 6 1 2
Ixi
Magnetic resonance angiography (Continued} mechanism of, 5 9 9 - 6 0 0 '-11 cerebral aneurysms evaluated using, 619 description of, 6 0 0 , 61)If dural arteriovenous fistulas evaluated using, 6 1 3 , 614f 2 D , descriprion of, 6 0 0 , 601f venous sinuses, 6 1 2 traditional methods of, 5 9 9 - 6 0 2 2D Fourier transformation description of, 5 3 2 , 6 0 0 disadvantages of, 600 illustration of, 601 f Magnetic resonance imaging clinical uses of acoustic neurinoma, 547, 548f acquired immunodeficiency syndrome, 560-563 actinomycosis, 1505f acute disseminated encephalomyelitis, 5 5 3 , 553f adrenoleukodystrophy, 5 5 4 Alzheimer's disease, 5 4 9 , 1910, 191 If amyotrophic lateral sclerosis, 2 2 5 3 aqueduetal stenosis, 5 6 6 , 567f arteriovenous malformations, 569f, 5 6 9 - 5 7 0 , 1289, 1291f astrocytomas anaplastic, 1 3 7 6 , 1377f-1378f brain, 5 3 2 diffuse, 1375f juvenile pilocystic, 13901 pilocysttc, 13901 spinal, 5 8 0 ataxia, 2 9 2 t atrophy, 5 4 8 - 5 4 9 a u t o s o m a l d o m i n a n t ataxias, 2 1 7 9 , 21801" basilar impression, 2191f brain abscess, 1 4 8 4 , 1485f-1486f brain hemorrhage, 5 7 1 , 572f brain metastases, 1372f, 1442f, 1443 brainstem astrocytomas, 539f-540f, 539-540 brainstem glioma, 1391f brain tumors, 1365, 1365f capillary telangiectasia, 5 6 9 cavernous angiomas, 5 6 9 , 1287f central neurocytoma, 5 4 1 , 542f, 1383f central pontine myelinolysis, 5 5 3 cerebellar astrocytoma, 5 3 8 cerebellar hemorrhage, 1262f cerebral infarction, 5 7 0 - 5 7 1 , 571f cerebral infections, 5 5 8 - 5 6 0 cerebral metastases, 5 3 4 , 5 3 6 - 5 3 7 cercbritis, 5 5 9 cervical radiculopathy, 2 2 0 6 , 2206f Chiari malformations, 5 6 4 - 5 6 6 , 565f-566f chondrosarcoma, 575 choroid plexus papilloma, 1387f chronic inflammatory demyelinating polyradiculoneuropathy, 2347f colloid cyst, 1388f coma, 62 concussions, 1144 corpus callosurn agenesis, 5 6 4 , 565f Volume 1 p p . 1-1070 • Volume II p. 1071-2546
Ixii
INDEX
Magnetic resonance imaging [Continued) cortical contusion, 554, 555f cortical infarction, 338 craniopharyngioma, 546, 547f, 1400f Creutzfcldt-jakob disease, 527, 529f, 5 5 0 - 5 5 1 , 1624, 1942, 1943f cryptococcal meningitis, 1590f cryptococcosis, 563, 563f cystieercosis, 560, 5 6 I f Dandy-Walker syndrome, 566, 567f degenerative disc disease, 582-583 dermoid lesions, 575, 577 diffuse axonal injury, 554, 555f disc space infections, 595, 595t ependymomas, 538-539, 580f-5Rlf, 5 8 0 - 5 8 1 , 1384-1385, 1389f epidermoid Cysts, 547, 55Of epidural abscess, 596-597 epidural hematoma, 556, 557f floppy infant, 405 fungal infections, 1549-1550 ganglioglioma, 533, 534f glioblastoma multiforme, 533-534, 535f glioma, 360f, 1391f global developmental delay, 78 glomus jugularc tumor, 574, 574f (I u il I .i i n- ]>;i r 10 syndrome, 2339 hamartomas, 567-568 headache, 270 headaches, 2059 head trauma, 554 hemangioblastoma, 540, 540f, 5 8 1 , 1394f hemangiomas, 575, 576f hemangiopericytoma, 544, 545f hemorrhage, 5 7 1 , 572f hepatic encephalopathy, 1676, 1677f herpes simplex encephalitis, 558-559, 559f, 1518 heicrntopias, 567, 5681 holoprnseiKvphaly, 564, S64( human immunodeficiency virus-related dementia, 1589f hydranencephaly, 567, 568f hydrocephalus, 571-573 hypcrflcxion injuries, 591-592 inborn errors of metabolism, 1814-1815 infra tentorial tumors, 537-540 intracerebral abscess, 559 intracerebral hematoma, 557 intracerebral hemorrhage, 1259t intracranial aneurysms, 1271 leptomeningeal metastases, 1453 leukodystrophies, 553-554 low back pain, 450 lower limb pain, 450 lower motor neuron diseases, 2231 low-grade astrocytoma, 532 1,5-Sl disc herniation, 355f lumbar disc herniation, 221 If lumbosacral radiculopathy, 451 Lyme disease, 559 lymphangioma, 575 lymphoma, 534, 536 medulloblastoma, 538, 538f, 1392f-1393f meningeal sarcoma, 545 meningioma, 543, 544f meningitis, 559-560
Magneric resonance imaging (Continued) metachromatic leukodystrophy, 554, 554f metastatic epidural spinal cord compression, 1448b, 1448-1449 mitochondrial encephalopathies, 551 movement disorders, 320-321 multi-infarct dementia, 549-550, 550f multiple sclerosis, 551-553, 552f, 1643t, 1647-1649 nasopharyngeal carcinoma, 573, 573f neurocutaneous melanosis, 1893, l894f neurofibromatosis, 548 f, 568-569 normal-pressure hydrocephalus, 1761 object recognition studies, 135 ocular lesions, 578 ocular melanoma, 578, 578f oligodendrogliomas, 532, 533f olivopontocerebellar atrophy, 551, 5521 optic chiasm glioma, 547, 548f optic nerve glioma, 577 optic nerve meningioma, 577f, 577-578 orbital pseudotumor, 577 orbital tumors, 575-578 parasitic infections, 1559 Parkinson's disease, 551 pendular nystagmus, 216 petrous apex lesions, 573-574 Pick's disease, 550, 1919f pineal tumors, 5 4 1 - 5 4 2 , 976, 976f pituitary adenoma, 545, 546f, 1096f, 1399f pleomorphic xanthoastrocytoma, 532 primitive neuroectodermal tumors, 538, 1424, 1425f progressive multifocal leukocnccphalopathy, 562, 563f, 1539f, 1596f radiation necrosis, 554 radiculopathy, 415-416 retinoblastoma, 578 schizencephaly, 567, 568f seizures, 19, 1977, 1977f sensory loss of spinal origin, 411-412 septo-opric dysplasia, 564 Shy-Dragcr syndrome, 5 5 1 , 551f skull base lesions, 573-575 spinal arteriovenous malformations, 570 spinal cord cysts, 588-589, 589f spinal cord injury, 1166-1167 spinal cord ischemia, 1315, 1316f spinal cord trauma, 587-588 spinal epidural abscess, 1490, 1490f spinal epidural hemorrhage, 1321-1322 spinal stenosis, 4 5 1 , 583-584 spinal subdural hemorrhage, 1321-1322 spinal trauma, 584-597 spinal vascular malformations, 1318-1320, 1 3 1 9 M 3 2 0 f Sturge-Weber syndrome, 1883f, 1883-1884 subacute combined degeneration, 16961 subdural hematoma, 554, 556, 556f subependymal giant cell astrocytoma, 541 superior oblique myokymia, 224 supra tentorial tumors, 532-537 thoracic spine fractures, 590, 591f thoracolumbar fractures, 590-591 toxoplasma encephalitis, 561f, 562 toxoplasmosis, 1594f
Magnetic resonance imaging {Continued) tuberculosis meningitis, 1494f tuberculous meningitis, ihi). 5(i0f tuberous sclerosis, 5 4 1 , 542f, 567-568, 1871, 1871f-1872f vascular injuries, 557, 558f venous angioma, 569-570 verrehral body fractures, 1167 vestibular schwannoma, 1396f visual agnosia, 136 vitamin B|^ deficiency, 1694-1695 Wernicke's aphasia, 146f-148f white matter disease, 551-554 white-matter lesions, 1932-1933 contrast agents, 523 diffusion-weighted abscess evaluations, 527, 52SI apparent diffusion coefficient, 524 clinical application of, 524-527, 525f-526f Creutzfeldt-Jakob disease evaluations, 527, 5291 description of, 524 epidermoid cyst evaluations, 527, 530f physics of, 524 stroke findings, 525f-526f fast spin-echo sequences, 523 fat suppression techniques, 523 functional, 668 gradient-recalled echo sequences, 523-524 pcrfusion-weightcd clinical applications of, 527, 529 description of, 527 physics of, 527 tumor imaging, 529 principles of, 523 repetition time, 523 Tl-weighted images, 523, 1166, 1167t T2-weighted images, 523, 1166, 1167t Magnetic resonance imaging neurography, 1190 Magnetic resonance specrroscopy astrocyroma evaluations, 671f-673f description of, 668 fluorine, 668 hepatic encephalopathy evaluations, 1676 inborn errors of meraholism evaluations, 1815 lithium, 668 movement disorders evaluation, 321 phosphorus, 668 seizure evaluations, 1977-1978 upper motor neuron disease evaluations, 2225-2226 Magnetization transfer contrast imaging, 524 Magnetoencephalography, 478, 668-669, 1976 Magnocellular layers, 727 Maintenance of wakefulness test, 2041 Major histocompatibility complex antigens, 810, 813-814, 821 Malabsorption syndromes, 1091, 2378 Malaria anemia associated w i t h , 1561 cerebral symproms associated with, 1560 cerebrospinal fluid findings, 1561 clinical features of, 1560 complications of, 1561 corticosteroids for, 1561 diagnosis of, 1560-1561
INDEX Malaria (Continued) epidemiology of, 1559 Incubation period, 1560 manifestations of, 1560 mortality rate of, 1560-1561 pathogenesis of, 1559-1560 pathologic findings, 1560 Plasmodium falciparum, 1559 postmalarial neurological syndrome, 1560
prevention of, 1561, 1562t quinine dihydrochloride for, 1561 transmission of, 1559 treatment of, 1561 Male sexual response, 422-423 Malignancies autonomic dysfunction in, 2411 cerebral infarction in, I ll'> livpircon amiability associated with, ]11^ neurological disease and, 7 peripheral neuropathy in, 2365-2367 spinal cord injury secondary to, 1171 Malignant hypertension, optic disc edema caused by, 189 Malignant hyperthermia, 805t, 853, 1743, 1848t, 1856 Malignant inflammatory sensory po I ygang I i onopathy clinical features of, 2367-2368 differential diagnosis, 2368 history of, 2367 laboratory features of, 2368 prognosis, 2368-2369 sensorimotor polyneuropathy, 2368-2369 Malignant melanoma, ocular, 578 Malignant peripheral nerve sheath tumor, 1417 Malingering definition of, 929 visual evoked potentials lor evaluating, 481 Malnutrition effects of, 1693 protein-calorie, 1708 traumatic brain injury-related, 1139 Manganese poisoning, 1690, 1716-1717 Mania definition of, 104t after stroke, 106 Manifest latent nystagmus, 215 Mannitol, 957, 1265 uf-Mannosidosis, 1822t /(- Ma n n osido sis, 1822t Maple syrup urine disease, 803t, 1824 Marasmus, 1693 Marburg virus, 1538-1539 Marchiafava-Bignami disease, 1706 Marcus Gunn's pupil, 730, 731f, 1639 Marfan's syndrome, 1224 Marginal glioneuronal heterotopia, 1768-1769 Marijuana, 1723 Marine toxins characteristics of, 1735-1736 ciguatera fish poisoning characteristics of, 1736t ciguatoxins, 1736-1737 clinical features of, 1737 description of, 1 7 i(i diagnosis of, 1737 history of, 1735
Marine toxins {Continued) incidence of, 1736 signs and symptoms of, 1737 treatment of, 1737 description of, 1735 historical descriptions of, 1735 pufferfish poisoning, 1736t, 1737-1738 Marinol, spasticity treated with, 1055r Markesbery-Griggs-Udd myopathy, 2483 Marshy cord syndrome, 1162 Martin-Gruber anastomosis, 496-497 Masking, for tinnitus, 255 Mass lesions, 2056 Matrix metalloproteinascs, SI5, 1409 Maxillary artery, 627 Maximum intensity projection computed tomographic angiography, 618f magnetic resonance angiography, 602, 602f McArdle's disease, 804t, 2492 McLcod's syndrome, 2152 MDAS. see Memorial Delirium Assessment Scale MDMA, 1723 Mean arterial pressure, 944 Measles acute encephalitis caused by, 1535 characteristics of, 832t, 835, 1520t, 1535 encephalomyelitis caused by, 1535, 1660 subacute sclerosing panencephalitis caused by, 1536-1537 Measles inclusion body encephalitis, 1535-1536 Mcaslcs-muinps-rubclla \accinc. 1536 Mebendazole, I557t Mechanical low back pain, 455 Mechanical ventilation aspiration pneumonia prophylaxis, 950 assist-control mode ventilation, 949 chest physiotherapy during, 950 chronic, 951 for Guillain-Barre syndrome, 959 indications for, 948-949, 949t medical management during, 950 modes of, 949 myasthenia gravis crisis managed by, 95S-959, 2454 rapid sequence intubation, 949 rapid shallow breathing index, 950 ventilators, 949-950 weaning from, 950 Mechanothermal nociceptors, 92 I Meckel-Gruher syndrome, 1 'St Meclizine, for vertigo, 746t Meclomen. see Mefenamic acid Medial epicondylitis, 442 Medial lenticulostriate arteries, 631 Medial longitudinal fasciculus, 705 Medial medullary stroke, 284-285, 285t, 286f Medial medullary syndrome, 3411, 412^413, 1207, 2120-2121 Medial rectus muscle characterises of, 199, 200t diplopia caused In weakness "t, 203 Median longitudinal fasciculus, 275 Median nerve entrapment of anterior interosseous nerve syndrome, 2313-2314
Ixiii
Median nerve (Continued) arm pain caused by, 434 characteristics of, 231 It, 2311-2312 at ligament of Struthcrs, 2314 pronator teres syndrome, 2314 at wrist, see Carpal tunnel syndtome lesions of, 348, 356t somatosensory evoked potentials, 484, 484f-485f Medical Outcome Study 36 Item Short Form Survey, 1038-1039 Medications, see also Drug(s); specific medication bioavailability of, 916 biotransformation of, 917 circadian variation effects on, 918 clinical trials of, 915 developmental factors that affect, 918 distribution of, 917
drug interactions, 918 elimination of, 918 half-life of, 918 loading dose for, 916 metabolism of, 918 neurological disturbances caused by, 6 pharmaceutical companies, 915 pharmacogenetics of, 917 physiological variation of, 918 preparations, 916 principles of, 914-915 properties of, 916-918 research studies of, 915 titration rate, 916-917 Medicinal herbs, 1731 Medium-chain acyl-CoA dehydrogenase deficiency, 1826 Medroxyprogestetone, 2531-2532 Medulla ischemic stroke syndrome of, 284—285, 285t, 286f lesions of, 341t Medullary hemorrhage, 1260t, 1263 Medulloblastoma characteristics of, 538, 538f, 1355-1356 imaging of, 1392f-1393f management of, 1416 metastases, 1416 postetiot fossa, 1425f Mces' lines, 2305 Mefenamic acid, 932t Mefloquine, 1561 Megaloblastic anemia, 1086 Meige's syndrome, 229 Meissner's corpuscle, 408t Mclanocytc-stimulating hormone appetite and, 855 characteristics of, 852t Melanoma choroidal, 578, 578 f ocular, 578 Mclarsoprol, 1556t, 1563 Ml'.I.AS syndrome, 1198, 1212,2336, 2496-2497 Melatonin, 2046 Melioidosis, 1504 Melodic intonation therapy, 1061 Memantine, 895 Memorial Delirium Assessment Scale, 34
Volume I pp. 1-1070 • Volume II p. 1071-2546
btiv
INDEX
Memory amnestic syndrome, 69t, 69-70 amygdala's role in, 68 anatomy involved in, 69-70, 70f animal research, 70 bedside tests of, 72-7.? classical conditioning, 71 conceptuaIizatioils of, 1907 declarative. 68 definition tit, 6N encoding of words, 70 episodic, 68 glutamaue's role in, 888t imaging studies of, 70 immediate, 68 implicit, 71 long-term, 68, 1907 Luria's test of alternating sequences, 68f, 73f Mini-Mental State Examination, 72t, 72-73 motor, 71 neuropeptide Y effects, 906 nondeclarative, 71 praxis testing of, 73 prefrontal cortex's role in, 70 priming, 71-72 procedural, 71 remote, 68, 72 semantic, 135 short-term Memory amnestic syndrome effects, 69r, 69-70 definition of, 68 testing of, 72 stages of, 68 types of, 71, 711 Memory impairment Alzheimer's disease description of, 686 treatment of, 873-874 delirium-related, 31 epilepsy-related, 694 Huntington's disease-related, 690 Korsakoff's syndrome, 1704 multiple sclerosis-re I a ted, 692 traumatic brain injury-related, 698t Memory loss in Alzheimer's disease dementia, 1906-1907 amnestic syndrome, see Amnestic syndrome partial, 70-71 Mendelian disorders autosomal dominant disorders, 781-783, 782t, 800f autosomal recessive disorders, 782t, 783 chromosomal aberrations, 785-788 description of, 785-786 Down syndrome, 785-786, 786f-787f two-hit phenomenon, 786 mitochondrial inheritance, 782t, 788-789 multifactorial disorders, 789 new mutations, 784 polygenic disorders, 789 sporadic cases, 784-785 uniparental disomy, 788 x-linked inheritance disorders, 782t, 783-784
Meniere's disease characteristics of, 239 drop attacks caused by, 26 endolymphatic hydrops in, 239 metabolic disorders associated with, 747 -.hum-, lor, 74S surgical treatment of, 748 vertigo caused by, 219 Meningeal biopsy, for parasitic infections, 1559 Meningeal leukemia, 1086 Meningeal sarcoma, 545 Meningioma anaplastic, 1357-1358 atypical, 1357 benign, 1356 brain, 546-547, 549f, 977-978 epidemiology of, 1356 genetic findings, 1357 headaches and, 2057 histologic features of, 1356-1357, 1357f imaging of, 1393, 1397f-1398f incidence of, 767, 1356 Meningioma locations of, 1356 magnetic resonance imaging of, 543, 544f managemenr of, 1417 metabolic polymorphisms associated with, 1339t optic nerve, 577f, 577-578 radiosurgery of, 990 spinal, 579 survival rates for, 766 variants of, 1357 Meningioma en-plaque, 1356 Meningismus, 49 Meningitis aseptic, 831, 1587-1588 bacterial adjunctive treatment of, 1482 age of patient and, 1477, 1478t algorithm for, 1479f cerebral dysfuncrion caused by, 1477 cerebrospinal fluid findings, 1478 clinical features of, 1477 complications of, I4S2-I4S! cytokine's role in, 1482 definition of, 1476 diagnosis of, 1478-1479 differential diagnosis, 1478-1479 electroencephalography evaluations, 475^176 epidemiology of, 1476 global distribution of, 1476 Haemophilus influenzae, 1476 increased intracranial pressure in, 1482 infection mechanisms, 1476 inflammatory reaction caused by, 1477, 1752 neonatal causes of, 2522 clinical features of, 2522 description of, 1477 management of, 2522 prognosis, 2522-2523 pathogenesis of, 1477 pathogens that cause antibiotic selection based on, 1479-1482
Meningitis [Continued) description of, 1476 Haemophilus influenzae, 1483 Listeria monocytogenes, 1483-1484 Neisseria meningitidis, 1483 Streptococcus pneumoniae, 1483 signs and symptoms of, 1477 Streptococcus pneumoniae, 1476 stroke risks, 1303 subarachnoid space effects, 1477 transmission merhods, 1477 treatment of adjunctive, 1482 antibiotics, 1478t, 1479-1482, 1481t-H82t corticosteroids, 1482 duration of, I 4S2 cerebrospinal fluid evaluations in, 459 chronic, 2219 coccidio mycosis, 1548 cryptococcal in AIDS patients, 1590-1591, LS93t description of, 1546 magnetic resonance imaging ot, 15901 prognosric. factors, 1591 treatment of, 1593t headaches caused by, 2060 herpes simplex virus, 1520, 1522 human immunodeficiency virus, 1587-1588 magnetic resonance imaging of, 559-560 meningococcal, 1483 Mollaret's, 1520, 2062 recurrent, 1520, 2220 syphilitic, 1497 tuberculosis, 1491-1492, 1494f . tuberculous, 560, 560f, 1940 viral acute, 833 characteristics of, 832t clinical features of, 833 course of, 833 coxsackievirus, 1528-1529 description of, 831 diagnosis of, 832-833, 1528-1529 etiology of, 1528 nonpolio enteroviruses, 1528 recurrence of, 833 treatment of, 1528-1529 Meningococcal meningitis, 1483 Meningococcemia, 1477 Meningococcus, 1483 Me ningo encephalitis in AIDS patients, 1592 enteroviruses and, 1529 granulomatous amebic, 1565 mumps, 1537 neonatal herpes simplex virus, 1519-1520 primary amebic, 1564—1565 Meningohypophyseal trunk, 995f Meningomyelocele, 1776, 1777t, 1778-1779 Menkes' kinky hair syndrome characteristics of, 805t, 1773, 1817t, 1828 clinical features of, 1887 connective tissue abnormalities in, 1887 copper replacement therapy for, 1888 cutaneous features of, 1887 definition of, 1886-1887 genetic studies of, 1888
INDEX Menkes' kinky hair syndrome (Continued] imaging of, 1888 infantile-onset, 1887t neurological features of, 1887-1888 treatment of, 1888 Menopause-related migraines, 2090 Mental retardation cerebral palsy and, 1794 developmental progress in, 83 diagnosis of, 1792 environmental factors associated with, 1792 genetics of, 1792, 1794 global developmental delay vs., 75 hypomclanosis of Ito, 1892 [Q levels, 1792 maternal smoking and, 1792 mild, 1792 neurological and neuropsychiatrie problems associated with, 1794 prevalence of, 1792 severe, 1792 treatment of, 1794 tuberous sclerosis and, 1871 Mental status examination bedside evaluation, 682-683 clock drawing test, 683-684, 685f delirium evaluations, 34 dementia rating scale, 682, 682f dizziness evaluations, 242 indications for, 679t Mini-Mental State Examination Alzheimer's disease findings, 679, 680f, 686, 1908 description of, 72t, 72-73, 679 Huntington's disease findings, 680/ internal validity of, 679 irrms on, 68 11 reliability of, 679 validity of, 679 word sets used on, 679, 682 Meperidine, 934t Meralgia paresthetica, 449t, 453, 2317, 2535 Mercaptans, 1680 Mercury, 1717 Merkel's discs, 4081 Merosin, 404 Merosinopathy, 2476-2477 Mesencephalic hemorrhage, 1260c, 1263, 1264f Mesial Temporal sclerosis, 1972-1973, 1973 f, 1977 Mesoneurium, 1181 Messenger RNA, 790 Metabolic acidosis, 1748f Metabolic disorders age at onset, 82t delirium caused by, 36, 36t intentional disorders caused by, 123 loss of consciousness caused by, 20 pediatric age at onset, 82r loss of consciousness caused by, 20 peripheral vestibular dysfunction and, 747 psychiatric disturbances associated with, 108-110 syncope caused by, 16
Metabolic encephalopathies clinical manifestations of, 1673-1674 electroencephalography evaluations, 473^174, 474f Metabolic myopathies carbohydrate metabolism disorders, 2491-2493 carnitine deficiency myopathy, 2494 definition of, 2463 description of, 2491 ^-Enolase deficiency, 2493 lipid metabolism disorders, 2493-2495 myoadenylare deaminase deficiency, 2495 phosphoglycerate mutase deficiency, 2492 Metabotropic receptors definition of, 877 glutamate, 885-886 Metachromatic leukodystrophy, 554, 554f, 1822t, 2334 Metals aluminum, 1714 arsenic, 1714-1716 lead, 1716 manganese, 1690, 1716-1717 mercury, 1717 tellurium, 1717 thallium, 1717-1718 tin, 1718 Metamorphopsia, 177 Metastases bladder dysfunction in, 1447 bowel dysfunction in, 1447 brain chemotherapy for, 1446 clinical features of, .534, 536-537, 1372f clinical presentation of, 1442-1443 computed tomography of, 1443 differential diagnosis, 1443 epidemiology of, 1441-1442 headache associated with, 1442 histopathology of, 1442 imaging of, 1443 incidence of, 1441 lung cancet and, 1441-1442 magnetic resonance imaging of, 1372f, 1442f, 1443 management of anticonvulsants, 1443-1444 Karnofsky performance score, 1443, 1443t prophylactic cranial irradiation, 1444-1445 radiation therapy, 1444 stereotactic radiosurgery, 1445-1446 supportive care, 1443-1444 surgery, 1445 parenchymal, 1441 pathology of, 1442 pathophysiology of, 1442 radiarion therapy for, 978, 1444 recurrent, 1446 signs and symptoms of, 1442-1443 sources of, 1371, 1441 survival rares for, 766 calvarial, 1455-1456 cerebral, 534, 536-537 characteristics of, 363, 365, 437, 1374, 1374f, 1446 chemotherapy for, 1449-1450 clinical presencarion of, 1447
Ixv
McEasrases (Continued) corticosreroids for, 1449 decompressive laminectomy for, 1449 description of, 1361-1362 differenrial diagnosis, 1447t, 1447-1448 dural, 1456 epidemiology of, 1446 hemorrhagic, 537f imaging of, 1374, 1374f, 1448-1449 intramedullary spinal cord, 1450 lepto meningeal acute lymphoblastic leukemia and, 1450 adenocarcinoma, 1450 cerebral symptoms of, 1451 clinical features of, 1451 description of, 1371, 1373f, 1374, 1450 diagnosis of, 1453 diagnostic tests for cerebral angiography, 1453 cerebrospinal fluid examination, 1451-1453 description of, 1451t imaging, 1453 lumbar puncture, 14511 magnetic resonance imaging, 1453 differential diagnosis, 1453t epidemiology of, 1450 non-Hodgkin's lymphoma, 1450 pathogenesis of, 1450-1451 prognosis for, 1455 survival rates, 1453 systemic relapse and, 1453 treatment of chemotherapy, 1454-1455 description of, 1453 goals, 1453-1454 hormonal therapy, 1455 radiation therapy, 1454 regimens, 1454t tumor cells, 1450-1451 magnetic resonance imaging of, 1448b, 1448-1449 management of, 1449-1450 motor system involvement, 1447 neuropathies associated with, 2366 opric nerve, 187 osteoarthritis vs., 1448 pathology of, 1446 pathophysiology of, 1446 peripheral nerve, 1457 pituitary gland, 862 plexopathy, 2286-2287 ptl'VLls
brachial plexopathy, 1456-1457 lumbosacral plexoparhy, 1457 radiotherapy for, 1449 sensory loss associated with, 1447 skull, 1455-1456 small cell carcinoma, 1362f spinal, 363-365, 364f, 582, 582f vertebral corpectomy for, 1449 Methadone, 934t, 1721 Methotrexate, 1405, 1454, 2506 Methyl bromide, 1712 3,4 - Merhy I c-ned ioxymetli amphetamine. see MDMA Methylmalonic acidemia, 1818 Methylmalonyl coenzyme A, 1696 Methyl mercury, 1717
Volume I pp. 1-1070 • Volume II p. 1071-2546
kvi
INDEX
Methyl p red n i so I one description of, 1169 human T-cell lymphocyrotropic virus treated with, 1540 multiple sclerosis uses, 1657 Methysergide, 2085, 2093 Metronidazole, 2384 bacterial meningitis treated with, L481t parasitic infections treated with, 1556t, 1566 Mctyraponc test, 8661 Mexiletine, 2310 Microadenoma, 545, 546f Microatheroma, 1210-1211 Microcystic myelomalacia, post-trauma tic, 1 162 Microdialysis, 946-947 Microcmbolisms, 657-658, 664 Microglial cells, 175 1 Micrographia, 300 Micropsia, 212 Microsaccadic ocular flutter, 222 Microscopic polyangiitis, 2370 Microsomal triglyceride transfer protein, 1826 Microsurgery, 988-989 Micturition,'41 9, 1171-1172 Micturition syncope, 16-17 Midazolam administration of, 198) for status epilepticus, 959 Midbrain anatomy of, 282f-283f ischemic stroke syndromes of, 280-281, 28If, 282t lesions of, 341t Midbrain reticular formation, 709 Middle carotid artery vasospasm, lOlOf Middle cerebral artery anatomy of, 636f aneurysms of, 619f, 635 branches of anatomy of, 632f-633f, 634t variability in, 634 computed tomography of, 1232, 1232f description of, 632 disorders of, 635t infarction of, 338-339, 570, 1204 intracranial vasculitis, 1218 Ml segment anatomy of, 632f, 634 branches of, 634 course of, 6341 M2 segment anatomy of, 632f, 634 branches of, 634 course of, 634t M4 segment compromise of, 635t description of, 634t, 634—635 stenosis of computed tomographic angiography of, 619 magnetic resonance angiography of, 611f stroke caused by, 656, 1001 transcranial Dopplcr ultrasonography of, 656, 6571 syndromes of, 1204 vasospasm of, 662
Middle car testing, 744 Middle interhemispheric holoproscnccphaly, 1777t, 1780 Midline myelotomy, for pain, 982 Midposition eyes, 54 Migraine abdominal, 2104 in adolescents, 2103-2104 basilar, 2075 cheiro-oral, 2073
in children, 2103-2104 classification of, 2072t clinical features of, 2072-2075 complications of, 2075-2076 definition of, 2072 delirium caused by, 37 dysphrenic, 2075
equivalents, 2074-2075 familial linnipluiic clinical features of, 1848t, 1857, 2076-2077 description of, 1222, 1305 diagnosis of, 1858-1859 genetic mutations associated with, 1857-1858 pathophysiology of, 1857-1858 treatment of, 1 859 focal electroencephalograph it" changes in, 472 frequency of, 266 genesis of, 2077-2078 genetics of, 2076-2077 hemiplegia caused by, 340 hormonal influences, 2086-2090 infarction caused by, 1221-1222 laboratory findings, 2076 location of, 267 mechanism of, 2078-2079 menopause-re I a ted, 2090 menstrual definition of, 2086 management of, 2086-2087 mechanisms of, 2086 nonsteroidal anti-inflammatory drugs for, 2087-2088 prophylactic therapy for, 2087-2088 monoplegia caused by, 343 neurogenic inflammation in, 2079 ophthalmoplegic, 2075 oral contraceptives and, 2088-2089 peak of, 266 physical findings of, 2076 platelets in, 2078 precipitating factors, 266—267 during pregnancy, 2089-2090 prophylaxis, 2084 retinal, 2074 serotonin and, 901t serotonin levels, 2078 spreading depression theory of, 2077-2078 stroke and, 1221, 1304 summary of, 2079-2080 teichopsia of, 2073-2074 treatment of ^-adrenergic blockers, 2084 anticonvulsants, 208 5 antidepressants, 2084-2085 botulinum toxin, 2086
calcium-channel blockers, 2085
Migraine {(Continued) cyproheptadine, 2085-2086 description of, 2080 dietary changes, 2080 dihydroergotamine, 2081-2083 ergotaminc tartrare, 2081 ergot preparations, 2081t, 2081-2082 meth; scrgide, 2l)Ji S monoamine oxidase inhibitors, 2084-2085 pharmacotherapy, 2080-2084 prophylactic, 2084 propranolol, 2084 riboflavin, 2086 selective serotonin reuptake inhibitors, 2084 serotonergic agents, 2085-2086 serotonin agonists, 2082t triptans, 2082-2084 triggers for, 2080 without aura, 2072-2074 in women, 1221 Migraine Disability Assessment Scale, 268 Migraine equivalents, 2074—2075 Migrainous syndrome with CSb plcocytosis, 2059-2060 Migrainous vertigo, 234 Mild cognitive impairment Alzheimer's disease and, 685, 1908 amnestic, 1908 criteria for, 685 heterogeneity of, 685 neuropsychological characteristics of, 684-686 outcome of, 684-685 prevalence of, 684 "Milkmaid grip," 309 Millard-Gubler syndrome, 341r, 2120t Miller-Dieker syndrome, 81t, 1767, 1777t, 1784-1785 Miller-fisher syndrome, 2338 Minimally conscious state, 44 Mini-Mental State Examination Alzheimer's disease findings, 679, 680f, 686 description of, 72l, 72-73. 679 frontotemporal dementia evaluations,
688 Huntington's disease findings, 680f internal validiry of, 679 items on, 681f reliability of, 679 validity of, 679 word sets used on, 679, 682 Mini poly myoclonus, 2238 Misomdazole, 2384 Missile wounds to head, 1141-1142 to peripheral nerves, 1187-1188 to spinal cord, 1161 Mitochondria evolution of, 1833 history of, 1833-1834 Mitochondrial disorders ataxia and, 2177 characteristics of, 1842 clinical features of, 1838t clinical presentation of, 383
INDEX Mitochondrial disorders [Continued) diagnostic approach biochemistry, 1841 cerebrospinal fluid tests, 1839-1840 description of, 1839 DNA-based, 1841-1842 electron microscopy, 1841 i m in i] noh is ttx.li em i st ry, 1841 laboratory studies, 1839-1840 metabolic tests, 1839 muscle biopsy, 1840-1841 neuro-ophthalmology, 1840 neuroradiology, 1840 dysphagia in, 168 i'.rlic l l l u t i H ii in-, i l l , I S ir,i
genetics of, 1834-1837 hypoxanthine production in, 378 inheritance patterns, 788-789 Keams-Sayre syndrome, 378, 1837, 1840, 1842, 2496f lactate production in, 378 Leber's hereditary optic neuropathy, 181, 187-188, 1639, 1834, 1843-1844 mitochondrial myopathics without progressive external ophthalmoplegia, 1843 mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes, 1840, 1843 myoclonic epilepsy with ragged red liber myopathy, 1843, 2496 neuropathy, ataxia, retinitis pigmentosa syndrome, 1843 overview of, 1833-1834 pathophysiology of, IS.'." I K3K progressive external ophthalmoplegia, 1842 pyruvate metabolism, 1837-1838 subacute necrotizing enccphalomyelopathy, 1843 treatment of, 1844-1845 types of, 788-789 valproic acid for, 1844 Mitochondrial D N A depletion syndrome, 2497-2498 discovery of, 1834 hetcroplasmy of, 1837 map of, 1835f maternal inheritance of, 1836-1837 mitochondrial disorders diagnosed using, 1841-1842 mitotic segregation of, 1837 threshold effects of, 1837 Mitochondrial encephalopathies, 551 Mitochondria] genes, 806t Mitochondrial inheritance disorders, 782t, 788-789 Mitoxanrrone, 1659 Mitral stenosis, 1212 Mirral valve prolapse, 1074 Mixed aphasia, 148 Mixed connective tissue disease, 1105 Mixed cryoglobulinemia, 2356 Mixed hearing loss, 253 Miyoshi's myopathy, 2482 M K - 8 0 1 , 1121 Mobius' syndrome, 2114 Modafinil, 1654 Molecular mimicry, 822, 1634
Mollaret's meningitis, 1520, 2062 Monitoring blood pressure, 943 body temperature, 943 intracranial pressure coma evaluations using, 62 devices for, 944-945 in neurosciences critical care units, 944-945 waveforms, 944, 944f Monoamine oxidase, 894 Monoamine oxidase inhibitors, 2084-2085 Monoclonal gam mo pa thy of undetermined significance, 1088 clinical features of, 2352 immunoglobulin M for, 2353 laboratory features of, 2352-2353 prevalence of, 2352 treatment of, 2353 Monoclonal protein, 2351 Monocular diplopia, 202 Monocular elevator deficiency, 720 Monocular nystagmus, 217, 2 l 7 t Monocytes, 810-811 Monomelic amyotrophy, 348 Mononeuritis multiplex, 1600 M o n on europa thy axon loss, 499-500, 500f cranial, 2362-2363 demyelinating, 499 fibular, 23 16 human immunodeficiency virus, 2388 limb, 2361 localized pcrineurial hypertrophic, 2318-2319 multiple, 2303, 2303t, 2362 needle electromyography diagnosis of, 511 physical examination findings, 2303 Monoplegia causes of brainstem lesions, 337 cerebral lesions, 337 diabetic amyotrophy, 347-348 femoral neuropathy, 345 migraine, 337 monomelic amyotrophy, 348 mononcuropathies, 344-346 multiple sclerosis, 337 neuronopathies, 348 peripheral lesions, 337 peroneal neuropathy, 346 plexopathics, 346-348 poliomyelitis, 348 pressure palsies, 344 radiculopathies, 346 radiculopathy, 346, 346t seizures, 337 spinal lesions, 337 thoracic outlet syndrome, 347 transient ischemic attacks, 337 tumors, 337 description of, 337 diagnostic difficulties, 348-349 M o n o radiculopathy, 22 10-2212 Monroc-Kellie doctrine, 1746 Monro-Kellie doctrine, 944 Morbidity rates brain tumors, 766 description of, 763-764
lxvii
Morbidity rates {Continued! epilepsy, 768-769 multiple sclerosis, 770-772 stroke, 765-766 M o r n i n g glory, 1730r, 1731 M o r o reflex, 399 Morphine, 934t Morphology, 142 Mortality rates acquired immunodeficiency syndrome, 773 arteriovenous malformations, 974, 1292 availability of, 764 botulism, 1510 brain tumors, 766, 1331 definition of, 764 description of, 763-764 epilepsy, 768, 769f human immunodeficiency virus, 773 multiple sclerosis, 770, 1637 seizures, 768 stroke, 764t, 764-765, 765f, 996, 1197 transient ischemic attacks, 1202 Mosaicism, 785 M o t i o n sickness, 747 muscarinic receptors and, 8931 Motor allochiria, I 20 M o t o r evoked potentials, 486-487 Motor extinction, 119 M o t o r function developmental disorders, 1800-1801 Motor impcrsistence, 117, I 19-120 M o t o r memory, 71 M o t o r nerve conduction studies compound muscle action potential measurements, 492 conduction velocity, 492-493 latencies, 492 measurements evaluated by, 492-493 principles of, 492 M o t o r nerves cell body of, HSOf description of, 1181 M o t o r neuron disease. see Amyotrophic lateral sclerosis M o t o r neurons of Onufrowicz, 2252 M o t o r perseveration, 117, 121 M o t o r speech disorders, definition of, 161 M o t o r system brainstem lesions effect on, 341t in comatose patient, 57-58 corticospinal tract neurons, 337 hemiplegia, see Hemiplegia
physiology of, 337 Motor tics, 313-314 Minor unit definition of, 502 muscle fibers i n , 502 M o t o r unit action potentials amplitude of, 507 duration of, 508 firing patterns, 509 interference pattern, 509 lower motor neuron lesions, 510 mononeuropathy findings, 5 I I morphology of, 507-509 phases of, 508-509 recruitment frequency, 509 recruitment ratio, 509 stability of, 509, 509f voluntary, 507-509 Volume I pp. I UFO . Volume II p. U T I 254r>
Ixviii
INDEX
Motor vehicle crashes, 1127, 1129 Motrin, see Ibuprofen Movement disorders akathisia, 317-318 hallism, 310, 310t, 320 basal ganglia and, 2125—2130 chorea, see Chorea description of, 293 DNA tests for, 320 drug-induced parkinsonism, 2144 dystonia, see Dystonia electromyography of, 321 fron tote in p oral degeneration with parkinsonism linked to chromosome 17, 2142-2143 gait, see Gait disturbances guadcloupcan parkinsonism, 2143 hemifacial spasm characteristics of, 2163-2164 description of, 230, 230f, 317, 2117 etiology of, 984 neurosurgical treatment of, 983-984 hi story-taking, 293-294 idiopathic, 293 imaging studies for, 320-321 investigative approach to, 319-321 laboratory investigations for, 319—321, 320t magnetic resonance imaging of,
320-321 Mcl.eod's syndrome, 2152 mixed, 332 myoclonus, see Myoclonus neuroacanthocytosis, 319, 2152 neurodegeneration, 2130-2131 neuroleptic-induced, 309r neurosurgical treatment of, 988 painful legs-moving toes syndrome, 318, 2164 parkinsonism. see Parkinsonism park ins on ism-dementi a complex of Guam, 2143 Parkinson's disease, see Parkinson's disease postanoxie coma and, 1668 postencephalitic parkinsonism, 2143-2144 progressive supranuclear palsy. see Progressive supranuclear palsy psychogenic, 319, 319r, 2164 restless legs syndrome, 318 stiff-person syndrome, 2164 tardive dyskinesia description of, 309-310, 2154 dopamine's role in, 896t drug-induced, 310 Huntington's disease vs., 309-310 respiratory irregularities in, 309 tics, see Tics toxin-induced parkinsonism, 2144 tremors, see Tremor(s) vascular parkinsonism, 2143 Movement therapy, constraint-induced, 1057-1058 Moyamoya disease, 979-980, 980f, 12l7f, 1217-1218 MS Contin, 935-936 "Tc-cthylene cysteinate dimer, 667 ''^Tc-hexamethylpropyleneamine, 667 MTHFR gene defect, 1304, 1309
Mucolipidosis, 803r Mucolipidosis II, 1822t Mucopolysaccharidoses, 1822t Mucormycosis, 1549, 1554 Multifactorial inheritance, 789 Multifocal motor neuropathy chronic idiopathic de myelin a ring polyradiculoneuropathy vs., 2235 clinical features of, 2234, 2234t with conduction block clinical features of, 2350 description of, 2349-2350 differential diagnosis, 2351t intravenous immunoglobulin G for, 235 I laboratory studies of, 2350 treatment of, 2350-2351 differential diagnosis, 2235 etiology of, 2234 history of, 2234 laboratory studies, 2234-2235 rrearment of, 2235-2236 Multi-infarct dementia history of, 1930 magnetic resonance imaging of, 549-550, 550f psychiatric disturbances associared with, 106 Multiple mononeuropathy characteristics of, 23h2, 2.i(>lJ human immunodeficiency virus, 2388 physical examination findings, 2303, 2303t, 2354 Multiple myeloma, 1087 Multiple sclerosis acute attacks, 1657 acute myelopathy and, 1647 acute tumorlike, 1652-1653 age at onset, 1636f, 1636-1637, 1646 albumin levels, 1650 animal studies of, 824 anxiety in, 96, 96r at-risk populations, 772 autoimmune causes of, 1635-1636 behavioral disturbances in, 95-97, 110 benign, 1645 bladder dysfunction in characteristics of, 426-427, 759f, 1641 treatment of, 1654—1655 blood-brain barrier disruptions in, 1633 bowel dysfunction in, 1641 brain atrophy associated with, 1633 brainstem auditory evoked potentials findings, 482-483 central nervous system damage in, 823 cerebrospinal fluid findings, 1650-1651 chronic myelopathy and, 1647 chronic progressive, 693 clinical features of, 1632 bladder dysfunction, 426-127, 759f, 1641, 1654-1655 bowel dysfunction, 1641 cerebellar pathways impairment, 1641 cognitive impairment, 692, 692t, 1639, 1655-1656, 1945 confusional state, 1639 constipation, 1641 corticospinal tract dysfunction, 1640 cranial nerve dysfunction, 1639-1640 description of, 1638
Multiple sclerosis (Continued) facial nerve impairment, 1640 fatigue, 1642, 1654 gait impairments, 1641 heat sensitivity, 1642 Lhcrmitie's phenomenon, 1641 motor pathways impairment, 1640-1641 ocular motor pathways impairment, 1639-1640 optic neuritis, 1639, 1647, 1663 overview of, 1641t paroxysmal attacks of motor and sensory systems, 1641-1642, 1656 sensoty pathways impairment, 1640 sexual function impairments, 1641, 1655 Uhthoffs phenomenon, 1639 visual pathways impairment, 1639 weakness, 1640-1641 computed tomography of, 1649-1650 course of factors that affect, 1645-1646 pregnancy effects, 1646, 1646t relapses, 1644-1645 schematic diagram of, 1644f studies regarding, 1644M645 definition of, 823 dementia in, 1945 demographics of, 772 depression associated with, 96, 1655 description of, 1631 diagnosis of cerebrospinal fluid findings, 1650-1651 computed tomography, 1649-1650 criteria for, 1642t, 1642-1644 evoked potentials, 1651 magnetic resonance imaging, 551-553, 552f, 1643t, 1647-1649 magnetic resonance spectroscopy, 1649 differential diagnosis, 1643t, 1643-1644 dysphagia in, 170-171 economic costs of, 1631 epidemics of, 773, 774f epidemiology of, 1636-1638 erectile dysfunction in, 42*. I655 etiology of, 1635-1636
euphoria associated with, 96-97 evoked potentials for, 1651 expanded disability status score for, 1645-1646, 1653 familial occurrence of, 1638 lanuly studies in. 7 ^ 2 foramen ni.is;rnini syndrome vs., 2~N fulminant, 1646
genetic factors, 772, 823 geographic distribution of, 770-771, 771 f, 1637-1638 hemiplegia and, 339 high-risks locales for, 772 histologic findings, 1634f immunopathogenesis of, 824 incidence of, 1631
infections and, 1636 inflammation associated with, 823 inpatient rehabilitation for, 1040-1041, 1069 inrernuclear ophthalmoplegia and, 1640
INDEX Multiple sclerosis [Continued) lesions B cells in, 1635 burden of, 693 characteristics of, 823 histologic findings, 1635, 1635f T cells in, 1634-1635 magnetic resonance imaging uses diagnosis, 551-553, 552f, 1643r, 1647-1649 monitoring of disease activity, 1653 magnetic resonance spectroscopy of, 1649 malignant, 1645-1646 memory deficits in, 692 in migrants, 772-773 monitoring of disease activity, 1653 monoplegia caused by, 343 morbidity rates for, 770-772 mortality rates, 770, 1637 myelin basic protein targeting, 1636 myelopathic syndromes associated with, 1647 neuroimaging of, 1647-1650 neuropsychological characteristics of, 692-693 nystagmus associated with, 1640 olfactory dysfunction in, 261 oligodendroglia in, 1633 optic neuritis in, 1639, 1647 outpatient rehabilitation for, 1069 pathologic findings, 823, 1632-1633 pathologic laughing and crying in, 97 pathophysiology of, 1632 personality disturbances in, 95-97, 110 plaque associated with description of, 1632-1633 gadolinium-enhanced magnetic
resonance imaging of, 1648 hisrology of, 1633 illustration of, 1633f inactive, 1635 lymphocytes in, 1634 T cells in, 1634 pregnancy and, 1646, 1646t, 1658, 2536 primary affection, 773 primary-progressive definition of, 1645 description of, 692
treatment of, 1658-1659 prognosis for, 1646-1647 progressive-relapsing, 1645 racial distribution of, 1637-1638, 1638 rehabilitation for description of, 1068-1069 inpatient unit',, 1040- 1041
outpatient, 1041 relapses of, 1644-1645 relapsing-remitting azathioprine for, 1659 definition of, 1645 description of, 692 epidemiology of, 1636-1637 treatment of, 1659 secondary-progressive definition of, 1645 treatment of, 1658-1659 sensorimotor processing in, 692 sex distribution of, 1637 sexual function impairments in, 1641, 1655
Multiple sclerosis (Continued) sleep disorders and, 2029-2030 somatosensory evoked potentials findings, 486 spasticity associated with, 1653-1654 stress and, 1646 suicide risks, 110 survival rates for, 770 T-helper cells in, 823-824 Treatment of acute attacks, 1657
altered peptide ligands, 824-825 anti-VI,A4 antibody, 825 cyclophosphamide, 1658-1659 description of, 824-825 disease-modifying, 1657-1658 glatiramcr acetate, 824, 1658 goals, 1653 immune globulins, 1659 interferon-/), 824
interferon-/*, h , 1657-1658 mitoxantrone, 1659
strategics for, 1656t, 1656-1657 symptoms-based, 1653-1656 tremors associated with, 1654 types of, 692-693, 823 variants of description of, 1651
Devic's disease, 1651-1652 Marburg, 1652-1653 recurrent optic neuropathy, 1651 slowly progressive myelopathy, 1652 viral infections and, 1636, 1645-1646 viruses and, 838 worldwide distribution of, 770-77), 77If Multiple Sclerosis Functional Composite Scale, 1645 Multiple sleep latency test, 2040-2041 Multiple system atrophy apnea in, 2420 bladder dysfunction in, 424-425 cerebellar, 2420 clinical iiianilourions of. 2lU0[ description of, 1928, 2140-2141 diagnosis of. 2141 epidemiology of, 2140-2141 erectile dysfunction in, 425-426 glial intraneuronal cytoplasmic nuclei inclusions, 2409, 2409f neurological abnormalities in, 2409 neuronal degeneration in, 424 Parkinson's disease vs., 2141, 2408 pathologic findings, 2409 postural instability associated with, 301, 330 sexual dysfunction in, 425^426 signs and symptoms of, 8 sites of, 2409 sleep disorders in, 2032 treatment of, 2141 urinary incontinence and, 753 urogenital symptoms in, 424-425, 753-754 Mumps, 832t, 1520t, 1537 Mu-receptor, 924 Murine typhus, 1502 Murmurs coma evaluarions, 50 syncope evaluations, 13 Murray Valley encephalitis virus, 1533
Ixix
Murray Valley virus, 832t Muscarinic receptors description of, 404 disorders associated with, 893t neuronal, 891-892 types of, 892 Muscle anatomy of, 2466 atrophy of, 352, 2466, 2467f bulk, 370-372 denervarion of, 352 energy metabolism for, 382 fatigue floppy infant findings, 399 weakness evaluations, 373 fatty acids for, 382 ghitamate levels in, 387 hypertrophy of, 371-372 maturation, suprasegmenial influences on, 1774 overuse syndromes of, 390-392 percussion of, 372 power of assessments, 351 floppy infant findings, 395, 398t range of motion assessment of, 372 floppy infant findings, 396-397 rigidity of, 352 segment-pointer, 351, 352t skeletal, see Skeletal muscle spasticity of, 352 strength of assessments, 351, 372-373 floppy infant findings, 395, 398t Medical Research Council scale for, 372-373, 373t, 434 striated, 2463 wasting of extensor digitorum hrevis, 371f gait disturbances and, 328 muscle weakness and, 370-371 weakness evaluations and, floppy infant findings, 399-400 Muscle biopsy denervation changes, 2464-2465, 2465f Duchcnne's muscular dystrophy findings, 2471f-2472f facioscapulohumeral dystrophy findings, 2466, 2467f floppy infant evaluations, 405 Fukuyama type congenital muscular dystrophy findings, 2478f lower motor neuron diseases, 2231 mitochondrial disorders evaluated by, 1840-1841 myopathic changes, 2465-2466 myotonic dystrophy type 1 findings, 2485f myotubular myopathy findings, 2500-2501 normal, 2464f polymyalgia evaluarions, 392 ragged-red fibers, 1840 skeletal muscle disorders evaluated by, 2463-2467 weakness evaluations, 377 Muscle contraction syndromes, 392 Muscle discomfort causes of, 389-392 drugs rhat cause, 390t
Volume I pp. 1-1070 • Volume II p. 1071-2546
Ixx
INDEX
Muscle discomfort {Continued) evaluation of, 389 syndromes associated with, 392 Muscle-eye-brain disease, 2478-2479 Muscle fibers fibrillation potentials of, 505 in motor unit, 502 resting potential of, 502 single-fiber electromyography of, 518-519 Muscle pain clinical features of, 389 description of, 387 exercise-induced, 388 myopathies that produce, 389-390, 390t nociceptors afferent axons, 388 description of, 387 sensitization of, 387-388 stimulation of, 387 pathologic conditions that cause, 388-389 polymyalgia syndromes that produce, 392 Muscle phosphor rue rokmase, 803t Muscle rigidity, in parkinsonism, 300 Muscle soreness, delayed-onset, 388 Muscle spasm, 433 Muscle spindles, 408l Muscle tone abnormal, 396f developmental stage and, 397t evaluations in comatose patients, 58 in gait disturbances, 328 floppy infant findings, 393-395, 395t-W,| infant, 395f-396f spinal cord lesion localization and, 352 Muscle vasculitis, 1466 Muscle weakness algorithm for evaluating, 378, 379f amyotrophic lateral sclerosis, 383-384, 2249-2250 axial muscles, 369 bulbar muscles description of, 368 disorders with, 378-379 chronic, 383 constant, 383-386 description of, 367 examination of
algorithmic approach, 378, 379f arising from floor movements, 374-375 cramps, 374 description of, 369-370 electromyography, 376 exercise testing, 377-378 fasciculations, 374 fatigue, 373 genetic testing, 377 initial approach, 368 labial sounds, 370 muscle biopsy, 377 muscle bulk, 370-372 muscle movement abnormalities, 374 observation, 370 palpation of muscle, 372 percussion of muscle, 372 peripheral nerve enlargement, 374 range of motion of muscle, 372 reflexes, 373 scapula winging, 370, 371f
Muscle weakness [Continued] sensory disturbances, 373-374 serum creatine kinase levels, 376 stepping onto a stool, 375 strength assessments, 372-373 tests, 376-378 walking, 374 extraocular muscles description of, 368 diagnostic approach to, 378 facial muscles description of, 368 diagnostic approach to, 378-379, 380f disorders with, 378-379 labial sounds associated with, 370 fluctuating, 382 gait disturbances caused by, 324, 335 hand muscles, >4K hip-girdle description of, 369 disorders with, 381 lifelong, 384-386 lower extremity, 369 myotonic dystrophy, 379, 380f neck, 368-369 oropharyngeal, 2442, 2443 f periodic paralysis and, 382 progressive, 386 psychogenic, 375-376 shoulder-girdle diagnostic approach to, 379-381 disorders associated with, 379-381 neurogenic disorders associated with, 380-381 postural changes associated with, 370 subacute, 383 symptoms of, 367-368 trunk, 369 upper extremiry, 369 upper motor neuron, 367 Muscular dystrophies Becker's characteristics of, 2473 epidemiology of, 2469-2470 genetics of, 2469 congenital description of, 2476 Fukuyama type, 2477-2478 laminin a^ deficiency, 2476-2477 with rigid spine syndrome, 2479 type 1, 2477, 2477f Ullrich's, 2479 Walker-Warburg syndrome, 804t, 1768, 1777t, 1785 definition of, 2463, 2468-2469 Duchenne's bracing for, 2472 cardiac involvement, 2470 clinical features of, 2470f, 2470-2471 creatine kinase levels, 2471 diagnosis of, 2470-2471 epidemiology of, 2469-2470 gene therapy for, 2472-2473 generic counseling for, 2473-2474 genetics of, 2469 muscle biopsy findings, 2471f-2472f muscle weakness in, 2472-2473 pharmacological treatment of, 2472 physical therapy for, 2471-2472 surgery for, 2472
Muscular dystrophies [Continued) treatment of, 2471-2473 Ernery-Drei fuss dystrophy, 2479 facioscapulohumeral characteristics of, 2480 clinical features of, 2480 description of, 368, 2466, 2467f diagnosis of, 378-379, 380f, 2480-2481 DNA studies for, 2480, 248 If genetics of, 2480 scapular winging associated with, 370, 371 f, 378 severity of, 2480 treatment of, 2480-2481 limh-girdle dystrophies 1A, 2474 IB, 2474-2475 1C, 2475 2A, 2475 2B, 2475 2C, 2475 2D, 2475 2E, 2475 2F, 2475 2G, 2476 2H, 2476 21, 2476 autosomal dominant, 2474-2476 description of, 2474 molecular defects, 24681 oculopharyngeal, 166-167, 378, 805t, 2481-2482 seapuloperoneal syndromes, 2481 Musculocutaneous nerve entrapment of, 2315 lesions of, 356t Mushroom poisoning, 1732t, 1732-1733 Mutations, 785 Muteness, 143 Myasthenia gravis acetylcholine receptors description of, 2443, 2444t diagnostic testing, 2446 autoantibodies in, 2444-2445 autoimmune, 826 B cells in, 826 characteristics of, 826-827 clinical presentation of, 2441-2442 course of, 2441-2442 defininon of, 2441 diagnostic procedures for antibodies against acetylcholine receptors, 2446 edrophonium chloride test, 2445-2446 electromyography, 2446-2447 ocular cooling, 2447 diseases associated wirb, 2452 drugs that affect, 2458 dysphagia in, 168-169 epidemiology of, 2441 generalized, 2453 genetic factors, 826 immune responses in, 1468 immunosuppressives for, 827 incidence of, 826-827 influenza vaccinations, 2452 inheritance of, 2443 juvenile, 2453
INDEX Myasthenia gravis {Continued) nicotinic receptors and, 893c ocular, 2442, 2453 pathophysiology of, 2443-2445 D-penicillamine-induccd, 2455 physical findings facial patterns, 2442, 2443f ocular muscles, 2442 oropharyngeal muscles, 2442, 2443f during pregnancy, 2454, 2533-2534 pro sis associated with, 204, 378 repetitive nerve stimulation in rapid, 517-518 slow, 516-517 respiratory failure associated with, 872 seronegarivc, 2453 signs and symptoms of, 1468 striational antibodies in, 2444 thymus' role in, 2445 transitory neonatal, 2454-2455 treatment of azathioprinc, 2450 cholinesterasc inhibitors, 2447-2448, 2448t corticosteroids, 2449-2450 cyclophosphamide, 2450-2451 cyclosporine, 2450 description of, 826-827, 1468, 2447 ephedrine, 2452 guidelines for, 2452-2455 immunosuppressants, 2450-2451 intravenous immunoglobulin, 2451-2452 mycophenolate mofctil, 2451 neostigmine, 2447, 24481 plasma exchange, 2451 prednisone, 2449 pyridostigmine bromide, 2447, 2448t thymectomy, 826, 2448-2449, 2533 tumors associated with, 1468 Myasthenia gravis Crisis definition of, 958 mechanical ventilation lot, 958-959, 2454 ncurosciene.es critical care unit management of, 958-959 precipitating factors, 9581 treatment of, 2453-2455 Myasthenic syndromes congenital characteristics of, 2455 description of, 1856 with episodic apnea, 2455-2456 quinidine for, 1856 slow-channel, 2456 1 amberr-Eaton cholinesterasc inhibitors for, 2457 clinical features of, 2456 compound motor action potenrials in, 517t definition of, 2456 diagnosis of, 2456-2457 drugs that affect, 2458 fluctuating muscle weakness associated with, 382 immune responses, 1468 i mm u no pathology of, 2457 muscle weakness associated with, 2456 prognosis for, 2457
Myasthenic syndromes [Continued) repetitive nerve stimulation in, 517t, 518f symptoms of, 1467-1468 tteatment of, 1468, 2457 Mycobacterium leprae, 1493, 2390-2391 Mycobacterium tuberculosis, 1491 Mycophenolate moferil, 2451 Mycoplasma syndromes, 1507 Mydriasis, 223-224 Myelin description of, 1632 physiology of, 1632 Myelin-associated glycoprotein, 2352 Myclination description of, 1772 disorders of, 1773 Myelin basic protein, 1636 Myelitis acute demyelinating transverse, 967 acute transverse, 1663 epidemiology of, 835 herpes simplex virus, 835-836 incidence of, 835 subacute transverse, 1663 syphilitic, 416 viral, 835-836 Myelography clinical uses of spinal epidural abscess, 1490 spinal epidural hemorrhage, 1321-1322 spinal subdural hemorrhage, 1322 description of, 531 spinal cord injury evaluations, 1166 Myelomalacia, 590, 590f Myelomatosis, 1087 Myelomeningocele, 2197, 2198f Myelopathy cervical spondylotic, 2207 differential diagnosis, 985 drug abuse-related, 1725 falls associated with, 25 human T-cell lymphocytotropic virus-associated, 1540 human T-lymphocytic virus type 1, 836, 2227-2228 human T-lymphocytic virus type 2, 2228 multiple sclerosis and, 1647 radiation, 1741-1742 sensory toss associated with, 416 slowly progressive, 1652 spinal arteriovenous malformation vs., 985 vacuolar, HIV-associated, 1596-1598 vitamin B|i deficiency, 1694f Mycrson's sign, 301 Myoadcnylate deaminase deficiency, 2495 Myocardial infarction description of, 1074 stroke risks after, 1212 MyocIonic-astatic seizures, 1966 Myoclonic epilepsy benign myoclonic epilepsy of infancy, 1964 familial adult-onset, 1864-1865 juvenile, 1964-1965, 2025-2026 with ragged-red fiber myopathy, 1843, 2496 severe myoclonic epilepsy of infancy, 1864 Myoclonic jerking, 58 Myoclonic seizures, 1962
Ixxi
Myoclonus
action, 317, 332-333 benign neonatal sleep, 2037 causes of, 316t central nervous system, 315 cottical reflex, 1962 definition of, 315, 1962 distribution of, 315 dtug-induced, 2163 epileptic description of, 316 electroencephalography findings, 469, 469f primary generalized, 1962 essential, 2161 etiological classification of, 3 I fit examination for, 315 focal, 315 hereditary geniospasm, 2161-2162 investigative approach to, 321 jerks associated with, 315-316 negative, 315 neurological findings associated with, 315 nocturnal, 318 ocular, 223-224 palatal, 315 patterns of, 315 posthypoxic, 2162 primary generalized epileptic, 1962 propriospinal, 2162 reticular reflex, 1962 segmental, 315 serotonin and, 9 0 I t
somatosensory evoked potentials findings, 486, 487f spinal, 2162 startle, 2162 symptoms of, 315-317 toxin-induced, 2163 Myoclonus dystonia, 2158 Myoclonus epilepsy with tagged-red fibers characteristics of, 1843, 2496 description of, 551 pedigree for, 788f Myofascial pain syndromes, 388-389 Myofascial syndrome, 441-442 Myofibrillar myoparhy, 2501-2502 Myoglobinuria, 376 Myokymia, 1859 facial, 230 needle electromyography, 504t superior oblique, 213, 217, 221t, 224 Myokymic discharge, 506f, 507 Myopathies acute necrotizing, 1469 congenital, 404-405 drug abuse-related, 1725 floppy infant and, 404^105 HIV-associated, 1600 infantile ncmaline, 404 motot unit action potentials in, 509 muscle pain caused by, 389-390, 390t needle electromyography diagnosis of, 512, 513t ocular, 712t
zidovudine, 1600 Myopathy autosomal recessive hereditary inclusion body, 2483 carnitine deficiency, 2494
Volume 1 pp. 1-1070 - Volume II p. 1071-2546
lxxii
INDEX
Myopathy [Continued) centronuclear, 2 5 0 0 - 2 5 0 1 critical illness, 2 3 8 0 Laing's distal, 2 4 8 3 Markcsbery-Griggs-Udd, 2 4 8 3 Miyoshi's, 2482 muscle biopsy findings, 2 4 6 5 - 2 4 6 6 myoclonic epilepsy with ragged-red fiber, 184.3 myofibrillar, 2 5 0 1 - 2 5 0 2 myorubular, 2 5 0 0 - 2 5 0 1 nemaline, 2499f-2500f, 2 4 9 9 - 2 5 0 0 Nonaka's, 2483 proximal myotonic, 2 4 8 6 Welander's, 2 4 8 2 - 2 4 8 3 Myophosphorylase deficiency, 2491-2492 Myorhythmia, oculoinasticatory, 2 1 6 , 22h Myoshimyopathy, 8031 Myositis dermatomyositis blood tests, 2504 characteristics of, 1 4 6 8 - 1 4 6 9 definition of, 2 5 0 3 description of, 168, 8 2 7 diagnosis of, 2 5 0 3 - 2 5 0 4 needle electromyographv diagnosis of, 512, 2504 neoplasia and, 2 5 0 5 treatment of, 2 5 0 5 - 2 5 0 6 description of, 837 inclusion body, 3 8 1 , 8 2 7 , 2 5 0 6 - 2 5 0 7 polymyositis description of, 168, 3 8 4 , 8 2 7 , 1468-1469 epidemiology of, 2 5 0 4 in HIV-infected patients, 1 5 9 3 , 1600 immune system's role in, 2505 natural history of, 2 5 0 4 - 2 5 0 5 needle electromyography diagnosis of, 512 neoplasia a n d , 2 5 0 5 Treatment of, 2 5 0 5 - 2 5 0 6 vascular findings, 2 5 0 4 Myotonia paramyotonia congenita clinical features of, 1851t, 1853 description of, 3 7 2 , 1848r diagnosis of, 1853, 1854 pathophysiology of, 1853, 1854 treatment of, 1 8 5 3 , 1854 warm up phenomenon associated with, 1854 potassium-aggravated clinical features of, 1 8 5 I t , 1854 diagnosis of, 1855 pathophysiology of, 1 8 5 4 - 1 8 5 5 Treatment of, 1855 Myotonia congenita clinical features of, 1851r, 1 8 5 3 - 1 8 5 4 , 2490-249 I description of, 1848t diagnosis of, 2491 Myotonia fluctuans, 2 4 9 0 Myotonic discharges, 5 0 5 - 5 0 7 , 506f Myotonic dystrophy bladder dysfunction associated with, 4 2 9 chromosomal aberrations, 8031 congenital, 2 4 8 6
Myotonic dystrophy (Continued) description of, 1 6 7 - 1 6 8 diagnostic approach to, 3 7 9 , 380f excessive daytime sleepiness caused by, 2007' pregnancy a n d , 2 5 3 4 trinucleotide repeat expansions in, 7 9 3 , 794f type 1, 2 4 8 3 - 2 4 8 6 type 2, 2 4 8 6 Myotubular myopathy, 2 5 0 0 - 2 5 0 1 Myxoviridae, 8 4 3 t
N N-Acerylaspartatc, 1649 Naegleria fowlers, 1556r, 1565 Naloxone hydrochloride opiate overdose-induced coma managed using, 4 5 , 1721 spinal cord injury uses, 1169 N a p r o s y n , see N a p r o x e n Naproxen adverse effects of, 9 3 2 t pain management using, 9 3 1 , 932t Naratnptan, 2082t Narcolepsy clinical manifestations of automatic behavior, 2 0 1 5 cataplexy, 2 0 1 4 - 2 0 1 6 , 2 0 4 6 description of, 2 0 1 4 hypnagogic hallucination, 2 0 1 5 minor types of, 2 0 1 5 night sleep disturbances, 2 0 1 5 periodic leg movements in sleep, 2015 sleep attacks, 2 0 1 4 sleep paralysis, 2 0 1 5 differential diagnosis, 2 0 1 5 - 2 0 1 6 environmental factors, 2 0 1 7 epidemiology of, 2 0 1 3 family studies of, 2 0 1 3 - 2 0 1 4 genetic factors, 2 0 1 7 genetics of, 2 0 1 3 - 2 0 1 4 history of, 2 0 1 3 hypocrctin peptide system dysfunction and, 2 0 1 4 , 2 0 1 7 neurochemical mechanisms of, 2016-2017 obstructive sleep apnea in, 2 0 1 5 pathophysiology of, 2 0 1 6 treatment of, 2 0 4 6 Nasopharyngeal carcinoma, 5 7 3 , 573f Nasotracheal intubation, 1133 National Acute SCI Study, M 69 National Institutes of Health Sttoke Scale, 9 5 5 , 1008t Natural killer cells, 8 1 0 N-butylcyanoacrylatc, 996 Near-infrared spectroscopy, brain monitoring using, 946 N e a r reflex spasm, 7 2 2 , 723t W a r viMial acuity, 729 Neck muscle spasm ot, 45 ! muscle weakness, 3 6 8 - 3 6 9 Neck pain causes of cervical spondylosis, 4 3 6 - 4 3 7 epidural spinal cord compression, 4 3 7 extramedullar}' lesions, 4 3 6 ^ 4 3 7
Neck
pain (Continued) muscle spasm, 4 3 3 nerve roots, 433—434 occipital neuralgia, 4 3 7 pyogenic epidural abscess, 4 3 7 radiculitis, 4 3 7 - 4 3 8 rheumatoid arthritis of cervical spine, 441 spinal cord sensory tracts, 4 3 3 suprascapular nerve entrapment, 438^139 thoracic outlet syndrome, 438 whiplash, 4 4 1 hi story-taking, 4 3 3 - 4 3 4 non-neurological causes of description of, 4 3 4 fibromyalgia, 4 4 1 - 4 4 2 myofascial syndrome, 4 4 1 ^ ( 4 2 polymyalgia rhcumatica, 4 4 2 physical examination for description of, 4 3 4 motor signs, 4 3 4 - 4 3 5 sensory signs, 4 3 5 tendon reflexes, 4 3 5 Neck-tongue syndrome, 2 0 9 9 Necrosis, glial, 1 7 6 5 - 1 7 6 6 Necrotizing myelopathy, paraneoplastic, 1465 Necrotizing myopathies, tihiill.iiiiiii p n i c m i a k in, 505 Necrotizing vasculitis, 2 3 7 2 Needle electromyography amyotrophic lateral sclerosis, 5 1 1 - 5 1 2 anterior horn cell disorders, 51 I - 5 1 2 disadvantages of, 5 1 2 endplate noise, 5 0 3 , 5 0 4 t cndplatc spikes, 5 0 3 , 5 0 4 t insertional and spontaneous activity abnormal, 5 0 3 - 5 0 7 complex repetitive discharge, 506f, 5 0 7 c r a m p discharges, 5 0 7 decreased, 5 0 3 , 5 0 5 fasciculation, 5041 fasciculation potentials, 505 tibriHaiion potentials, S05 myokymic discharge, 506f, 5 0 7 myotonic discharges, 5 0 5 - 5 0 7 , 506f ncuromyotonic discharges, 5 0 7 normal, 5 0 3 prolonged, 5 0 3 , 5 0 5 lower motor neuron lesions, 5 I Of, 510-512 mononeuropathies, 5 11 motor unit action potential amplitude of, 5 0 7 duration of, 508 firing patterns, 5 0 9 interference pattern, 5 0 9 lower motor neuron lesions, 5 1 0 m o n o n c u r o p a t h y findings, 511 morphology of, 5 0 7 - 5 0 9 peripheral polyneuropathy findings, 511 phases of, 5 0 8 - 5 0 9 recruitment frequency, 5 0 9 recruitment ratio, 5 0 9 stability of, 5 0 9 , 509f voluntary, 5 0 7 - 5 0 9 myopathic disotdcrs, 5 1 2 , 5 1 3 t peripheral polyneuropathies, 511 plexopathies, 5 1 1
INDEX Needle electromyography (Continued) principles of, 502-503 radiculopathies, 510-511 steps involved in, 503 techniques for, 502-503 tipper motor neuron lesions, 510, 510f Negative myoclonus, 315 Neisseria meningitidis, 1483 Nelfiuavir, 1587: Nelson's syndrome, 860-861 Ncmaline myopathy, 803t, 2499f-2500f, 2499-2500 Nematodes angiostrongyliasis, 1573-1574 gnarhostomiasis, 1574-1575 strongyloidiasis, 1575-1576 toxocariasis, 1576 trichinosis, 1575 Neologisms, 143 Neonatal glycine encephalopathy, 888t Neonate, see also Children; Infant benign familial neonatal convulsions, 1848t, 1862-1863 brachial plexus injury, 2527 congenital toxoplasmosis, 1567, 1567f cytomegalovirus in, 2523 drug effects, 2528-2529 epidural hemorrhage, 2526t extracranial hemorrhage, 2525 facial paralysis, 2526-2527 herpes simplex virus infection congenital, 2524 meningoencephalitis in, 1519-1520 human immunodeficiency virus-associated progressive encephalopathy in, 1608, 2524 hypoxic-ischemic brain injury in asphyxia, 2515 brain swelling assochrinl with, 25 IS clinical features of, 2515t computed tomography of, 2516f cortical evoked responses for, 2515-2516 description of, 2514 diagnosis of, 2514 electroe nceph a logra phy responses, 2515-2516 management of, description of, 2516-2517 metabolic parameters, 2516 neuroimaging of, 2516 neuropath "logical patterns, 2515t perfusion maintenance for, 2516 prognosis, 2518 ventilation adequacies, 2516 intracranial hemorrhage, 2524-2525, 2528 intraventricular hemorrhage in, 2521-2522 meningitis in causes of, 2522 clinical features of, 2522 description of, 1477 management of, 2522 prognosis, 2522-2523 myasthenia gravis in, 2454-2455 neurological problems in description of, 2511 investigation of, 2511-2512 management of, 2511-2512
Neonate {Continued) parasitic infections in, 2523 passive addiction in, 2528-2529 peripheral nervous system injuries, 2526-2527 peri v entricu la r- i n 11 a ventricular hemorrhage clinical features of, 2519 computed tomography of, 2519, 2520f diagnosis of, 2518-2519 epidemiology of, 2518 management of, 2519-2521, 2520t pathogenesis of, 2519-2521, 252()t prognosis, 2521 rubella, 2523 seizures in causes of, 2512-2513, 2513t clonic, 25 12t descriprion of, 2512 diagnosis of, 2512, 2512t electroencephalography of, 2513 management of, 2513-2514 myoclonic, 2512t noncoiivulsive movements vs., 2512 phenobarbital for, 2513 pyridoxine deficiency and, 2513—2514 tonic, 2512t treatment of, 2514, 2514t i \ p ^ nt, 25 I2i skull fractures, 2525 spinal cord injury, 2525-2626 stroke in, 1299 subarachnoid hemorrhage, 2526t subdural hemorrhage, 2526! teratogens, 2528 toxoplasmosis, 2524 viral infechons in, 2523 vitamin K deficiency in, 1303 withdrawal syndrome in, 2528-2529 Neoplasms dementia caused by, 1946 positron emission tomography evaluations 670, 670f psychiatric disturbances caused by, 110-111 single-photon emission computed tomography evaluations, 670 Neoplastic polyradiculoneuroparhy, 2276-2277 Neostigmine, 2447, 24481 Nephrotic syndrome, 1230 Nerve biopsy floppy infant evaluations, 4 0 5 ^ 0 6 peripheral nerve disorders evaluated by, 2306, 2307t Nerve blocks, for pain management, 937 Nerve conduction studies accessory deep peroneal nerve effecrs on, 497 aging effects, 496 anomalies that affect, 496-A97 clinical uses of amyotrophic lateral sclerosis, 512 axonal polyneuropathies, 501, 502f axon loss mo no neuropathy, 499-500, 500f carpal tunnel syndrome, 415, 439 conduction block, 499, 500f demyelinating mononeuropathy, 499, 500f
kxiii
Nerve conduction studies {Continued) demyelinating polyneuropathies, 413, 501, 502f floppy infant, 405 focal nerve lesions, 498-501 low back pain, 450 lower limb pain, 450 lumbosacral radiculopathy, 451 preganglionic lesions, 500-501 ulnar neuropathy, 415 electrodes for, 492 entrapment neuropathy localization by, 494 error sources in, 495-498 heighr of patient and, 496 incremental stimulation, 494-495, 495f interttial variability in, 498 Martin-Grubcr anastomosis effect on, 496^97 mixed, 494 motor compound muscle action potential
measuremenrs, 492 conduction velocity, 492-493 latencies, 492 measurements evaluated by, 492^193 principles of, 492 physiological variability in, 495-498 principles of, 491-492 recording procedure, 492 segmental stimulation in shun miremi'iin., 494^195 sensory antidromic, 493, 494f principles of, 493 sensory nerve action potential measurements, 493^194 skin temperature effects, 495-496 sleep disturbances and disorders evaluated using, 2044 stimulators for, 491-492 temporal dispersion effects, 497-498, 498f Nerve grafts, for peripheral nerve trauma, 1192-1193 Nerve growth factor, 1122 Nerve growth factors, 851t Nerve root disorders anatomical features, 2267-2269 avulsion clinical features of, 2270 description of, 2269-2270 diagnosis of, 2270 treatment of, 2270 cytomegalovirus polyradiculoneuropathy, 2278, 2279f description of, 2267 diabetic polyradiculoneuropathy, 2275-2276 herpes zoster, 2279-2280 human immunodeficiency virus polyradiculoneuropathy, 2278 Lyme radiculoneuropathy, 2278-2279 neoplastic polyradiculoneuropathy, 2276-2277 traumatic radiculopathy disc herniation cervical, 2273 clinical features of, 2271-2272 description of, 2270-2271 diagnosis of, 2273-2275 Volume 1 pp. 1-1070 • Volume II p. 1071-2546
Ixxiv
INDEX
Nerve root disorders (Continued) L4, 2273 L.5, 2273 lumbosacral, 2271-2272 needle electromyography of, 2274 neurophysiological tests, 2274 SI, 2273 treatment of, 2275 nerve root avulsion clinical features of, 2270 description of, 2269-2270 diagnosis of, 2270 treatment of, 2270 Nerve root stimulator, 7.59-760 Nerve sheath tumors characteristics of, 579, 579f-580f, 1358-1359 malignant peripheral, 1417 Nerve uanslcrs, for peripheral nerve trauma, I 193-1 144 Nerve vasculitis, 1466 Nervous system tumors astrocytomas anaplastic characteristics of, 1348 imaging of, 1376, 1377f-1378f management of, 1413 optic pathway, 1382f brainstem, 539f-540f, 539-540 cerebellar, 538 circumscribed, 1349 classification systems for, 1330t diffuse characteristics of, 1344f, 1347-1348 imaging of, 1374-1376 juvenile pilocystic, 1385, 1390f, 1426-1428 low-grade, 532, 1330, 1412, 1430-1431 magnetic resonance spectroscopy evaluations, 671f-673f metabolic polymorphisms associated with, 1339t pilocystic characteristics of, 975 imaging of, 1349-1350, 1350f management of, 1412 spinal, 580 subependymal giant cell, 541, 1350, 1381, 1413 Toxoplasma gondii and, 1338 atypical teratoid/rhabdoid tumor, 1356, 1426 biology of, 1341-1342 brain, see Brain tumors cell proliferation assessments, 1346 central neurocytoma characteristics of, 541, 542f, 1354 in children, 1429-1430 imaging of, 1381, 1383f management of, 1415 in children, 1343t choroid plexus rumors, 1352-1353 classification of, 1342, 1347 craniopharyngioma characteristics of, 546, 547f, 862, 1360-1361 in children, 1434-1435 clinical presentation of, 1434 illustration of, 547f, 976f
Nervous system tumors (Continued) imaging of, 1400f, 1401 management of, 1419, 1434-1435 neurosurgical treatment of, 975-976 prognosis, 1435 definition of, 1347 DNA expression profiling techniques for, 1346-1347 dysemhryoplastic neuroepithelial tumor, 532-533, 1354, 1381, 1429 in elderly, 1343t electron microscopy findings, 1345 embryonal tumors, 1354-1355 ependymomas anaplastic, 1384-1385 characteristics of, 538-539, 580f-581f, 580-581, 1344f, 1352, 1384-1385 in children, 1432-1433 imaging of, 1384-1385, 1389f management of, 1414 riiyxopapill.ity. 1.552
prognosis, 1433 subependymoma, 1352, 1385, 1414-1415 frozen section findings, 1344-1345 gangliocytoma, 1353 ganglioglioma characteristics of, 533, 534f, 1353 in children, 1429 imaging of, 1381 management of, 1415 genetic syndromes associated with, 1338t germ cell tumors characteristics of, 541-542, 1359-1360 management of, 1418-1419 glioblastoma
clinical features of, 1348-1349, 1349f electroencephalography findings, 473f endothelial hyperplasia associated with, 1348 genetic findings, 1349 histologic findings, 1344f-1345f incidence of, 1348 sites of, 1348 survival rates for, 766 variants of, 1348 glioneuronal tumors, 1353 grading of, 1342 hemangioblasroma characteristics of, 540, 540f, 581, 1360 embolization of, 994 histologic findings, 1360 imaging of, 1392, 1394f hemangiopericytoma, 544, 545f, 1358, 1417-1418 histopathological features of anaplasia, 1342 description of, 1342 desmoplasia, 1344 microvascular proliferation, 1344, 1345f palisading, 1342
pseud opal is a ding, 1342 rosettes, 1342-1343 historical descriptions of, 1342 i m m Li no h i stoch cm is try findings cytokeratins, 1346 description of, 1345 glial markers, 1345
Nervous system tumors (Continued) neuronal markers, 1345-1346 S-100 protein, 1346 medulloblastoma characteristics of, 538, 538f, 1355-1356 imaging of, 13921-1393f management of, 1416 posterior fossa, 1425f meningioma anaplastic, 1357-1358 atypical, 1357 benign, 1356
brain, 546-547, 549f, 977-978 epidemiology of, 1356 genetic findings, 1357 histologic features of, 1356-1357, 1357f imaging of, 1393, 1397f-1398f incidence of, 767, 1356 locations of, 1356 magnetic resonance imaging of, 543, 544f management of, 1417 metabolic polymorphisms associated with, 1339t optic nerve, 577f, 577-578 radiosurgery of, 990 spinal, 579 survival rates for, 766 variants of, 1357 molecular diagnostic methods, 1346-1347 myxopapillary ependymoma, 1352 neuronal tumors, 1353 oligoastrocytoma, 1351, 1414 oligodendroglioma anaplastic, 1376, 1381f, 1414 characteristics of, 1350-1351, 13.51 f imaging of, 1376, 1380f management of, 1414 pleomorphic x a nth oa s troc y toma characteristics of, 532, 1350, 1412-1413 in children, 1428 management of, 1412-1413 principles of, 1341-1342 subependymal giant cell astrocytomas characteristics of, 541, 1350, 1381, 1413 in children, 1428-1429 imaging of, 1381 management ot, 14 I i subependymoma, 1352, 1385, 1414-1415 touch imprints/smears of, 1344-1345 World Health Organization classification of, 1342 Neuralgia geniculate, 2101-2102 glossopharyngeal, 14, 267, 2101 occipital, 2102 postherpetic, 1523-1524, 2102, 2280 trigeminal anesthesia dolorosa and, 983, 2101 description of, 266-267, 414t, 417 epidemiology of, 2100 laboratory findings, 2100
neurosurgical treatment of, 983 pain associated with, 926 pathogenesis of, 2100 pathology of, 2100 physical findings of, 2100
INDEX Neuralgia {Continued} symptoms of, 2099-2100 treatment of, 2100-2101 Neural integrator, 705, 710 Neurally mediated syncope, 2411 Neural maturation apoptotic mechanisms, 1765 description of, 1764 neuronogenesis description of, 17(54 disorders of, 1764-1765 Neural prostheses, 1059 Neural transplantation, for traumatic brain injury recovery, 1124 Neurapraxia, 498, 1160, 1182t Neuroacanrhoeytosis, 319, 2152 Neuroa ngi og ra p hy anatomic considerations, aortic arch branches, 625-626 contraindications, 625 description of, 625 high-risk groups, 625 success rate for, 625 Neuroblast! s) apoprosis of, 1765 disorders of, 1764-1765 mitotic proliferation of, 1764 Neuroblasr migration axon growth during, 1770 cell membrane excitability and polarity, 1771 dendrite growth during, 1770 description of, 1 766 disorders of description of, 1768 lissencephaly, 805t, 1767-1768, 1777t, 1783-1785, 1784f pachygyria, 1769 poly microgyria, 1769 schizenccphaly, 1769 myelination description of, 1772 disorders of, 1773 processes involved in, 1766 radial glial fiber guides in, 1766-1768 syiiaplngcncsi^ description of, 1771 disorders of, 1771 Neuroblastoma, 1464 Neurohorreliosis, 1499 Neurobrucellosis, 1940 Neurocritically ill patients critical approach, 947 description of, 947 respiratory care for, 947-948 Neurocutaneous melanosis cutaneous features of, 1892-1893 definition of, 1892 diagnosric criteria for, 1893 laboratory studies of, 1893, 1894f neurological features of, I 89 S Neurocutaneous syndromes ataxia-telangiectasia cancer risks, 1886 cutaneous features of. 1885 description of, 313, 1885 epidemiology of, I 885 genetics of, 1886 incidence of, 1885 laboratory diagnosis of, 1886
Neurocutaneous syndromes [Continued) lymphoid malignancies and, 1886 neurological features of, 1885-1886 si no pulmonary infections in, 1886 cerebrotendinous xanthomatosis biochemical features of, 1889-1890 clinical features of, 1889t description of, 803t, 1889 neurological features of, 1889 peripheral neuropathy in, 1889 treatment of, 1 890 xanthomas, 1889 Ehlcrs-Danlos syndrome arterial dissecrion in, 1879 carotid-cavernous fistula in, 1878-1879 clinical features of, 1877-1878 computed tomography of, 1878f cutaneous hyperelasticity associated with, 1877f description of, 1224 intracranial aneurysms associated with, 1878, 1878f subtypes of, 1 877 type IX, 1887 epidermal nevus syndrome cutaneous features of, 1890 definition of, 1890 imaging of, 1891 neurological features of, 1890-1891 ocular abnormalitres associated with, 1891 seizures in, 1 890 tumors in, 1 891 Fabry's disease clinical features of, 1880-1881 description of, 805t, 1224, 1304, 1880 ocular abnormalities associated with, 1880, I88lf treatment of, 188 1 hypomelanosis of Ito, 1891-1892 neurofibromatosis brain tumors and, 1338 in children, 1302 cutaneous features of, 1874, 1875f description of, 1873 diagnostic criteria for, 1877, 1877t genetic mutations in, 791, 79If magnetic resonance imaging of, 548f, 568-569 molecular biology of, 1873-1874 stroke risks, 1302 systemic features of, 1874-1875 type 1 characteristics of, 568, 1302, 1338, 18"; computed tomography of, 1876f neurological features of, 1875-1876 optic nerve glioma caused by, 1875, 1876f type 2 characteristics of, 568-569, 1873 clinical features of, 1876-1877 magnetic resonance imaging of, 1877f progressive facial hemiatrophy, 1884-1885 pseudoxanthoma elasticum, 1224, 1879 Rendu-Oslcr-Weber disease, 1224, 1880 Sturge-Weber syndrome characteristics of, 1881 computed tomography of, I883f
lxxv
Neurocutaneous syndromes [Continued) cutaneous features of, 1881 diagnostic studies, 1883f, 1883-1884 glaucoma associated with, 1881 hemispherectomy for, 1884 magnetic resonance imaging of, 1883f mental deficiency in, 1882-1883 neurological features of, 1881-1883 ocular features of, 1881 port-wine nevus of, 1882f seizures associated with, 1882 treatment of, 1884 tuberous sclerosis angiomyolipomas in, 1872, 1874f autistic spectrum disorders and, 1797 cardiac findings, 1872 characteristics of, 541, 542f, 567-568, 804t, 1428 cutaneous features of, 1869, 1869f-1870f definition of, 1867-1868 diagnostic criteria tor, 18681 epidemiology of, 1868 genetics of, 1868-1869 imaging of, 1871, 1871f magnetic resonance imaging of, 1871, 1871f-1872f mental retardation and, 1871 neurological features of, 1869-1870 pulmonary findings, 1873 renal findings, 1872-1873 retinal features of, 1872, 1873f seizures associated with, 1869 subependymal giant cell astrocytomas in, 1871 systemic features of, 1872-1873 von Hippel-l.indau disease clinical features of, 1894-1895 definition of, 1894 description of, 193f, 581, 803t genetics of, 1895 pancreatic cysts in, 1895 pheochromocytomas in, 1895 prevalence of, 1894 retinal hemangioblastomas associated with, 1894-1895 risk categories for, 1894t screening for, 1895-1896, 1896c systemic features of, 1895 rreatment of, 1895-1896 Wy burn-Ma son disease arteriovenous malformations in, 1896 clinical features of, 1896 definition of, 1896 description of, 193f treatment of, 1896-1897 vascular malformations associated with, 1896 xeroderma pigmentosum complementation groups, 1897 cutaneous features of, 1898c, 1898-1899 definition of, 1897 description of, 803t ocular features of, 1898c, 1898-1899 syndromes related to, 1897-1898 treatment of, 1899 Neurocystieercosis, 768, 1568-1572
Volume 1 pp. 1-1070 • Volume 11 p. 1071-2546
Ixxvi
INDEX
Neurocytoma central characteristics of, 5 4 1 , 542f, 1354 in children, 1 4 2 9 - 1 4 3 0 imaging of, 1381, 1383f management of, 1415 characteristics of, 5 4 1 , 5 4 2 / Neurodegeneration, 2130—21 3 I Neuroenteric cysts, 1361 Neuroepidemiology. see Epidemiology Neuroepithelial tumors astrocytoma anaplastic, 1348 circumscribed, 1349 diffuse, 1347-1348 pilocystic, 9 7 5 , 1 3 4 9 - 1 3 5 0 , 13501, 1 3 8 5 , 1390f, 1412 atypical teratoid/rhabdoid rumor, 1356, 1426 central neurocytoma characteristics of, 5 4 1 , 542f, 1354 in children, 1 4 2 9 - 1 4 3 0 imaging of, 1 3 8 1 , 1383f management of, 1415 choroid plexus tumors, 1 3 5 2 - 1 3 5 3 classification of, 1347 definition of, 1347 dvsemhryoptasric neuroepithelial minor, 5 3 2 - 5 3 3 , 1354, 1 3 8 1 , 1429 embryonal tumors, 1 3 5 4 - 1 3 5 5 ependymomas anaplastic, 1 3 8 4 - 1 3 8 5 characteristics of, 5 3 8 - 5 3 9 , 58()f-5K1f, 5 8 0 - 5 8 1 , 1344f, 1352, 1384-1385 in children, 1 4 3 2 - 1 4 3 3 imaging of, 1 3 8 4 - 1 3 8 5 , 1389f management of, 1414 my x opa pi I lar y, 1352 prognosis, 1433 subependymoma, 1352, 1 3 8 5 , 1414-1415 gaugliocytoma, 1353 ganglioglioma characteristics of, 5 3 3 , 534f, 1353 in children, 1429 imaging of, 1381 management of, 1415 glioblastoma clinical features of, 1 3 4 8 - 1 3 4 9 , 1349f electroencephalography findings, 473f endothelial hyperplasia associated with, 1348 genetic findings, 1349 histologic findings, 1344f-1345f incidence of, 1348 sites of, 1348 survival rates for, 766 variants of, 1348 glioneuronal tumors, 1353 mcdullohlasroma characteristics of, 5 3 8 , 538f, 1 3 5 5 - 1 3 5 6 imaging of, 1392f-1393f management of, 1416 metastases, 1416 posterior fossa, 1425f myxopapiilary ependymoma, 1352 neuronal tumors, 1353 oligo astrocytoma, 1351, 1414 oligodendroglioma
Neuroepithelial t u m o r s {Continued) anaplastic, 1376, 1381f, 1414 characteristics of, 1 3 5 0 - 1 3 5 1 , 1351f imaging of, 1 3 7 6 , 1380f pleomorphic xanthoastrocytoma, 5 3 2 , 1350, 1 4 1 2 - 1 4 1 3 subependymal giant cell astrocytomas characteristics of, 5 4 1 , 1350, 1 3 8 1 , 1 4 1 3 in children, 1 4 2 8 - 1 4 2 9 imaging of, 1381 management of, 1413 subependymoma, 1 3 5 2 , 1 3 8 5 , 1 4 1 4 - 1 4 1 5 Neurofibrillary tangles, 1619, 1911 Neurofibroma, 5 7 9 , 579f, 1 3 5 8 - 1 3 5 9 , 1 8 7 4 , 1875f Neurofibromatosis brain t u m o r s and, 1338 in children, 1302 cutaneous features of, 1 8 7 4 , 1875f description of, 1873 diagnostic criteria for, 1877, 1877t genetic mutations in, 7 9 1 , 791f magnetic resonance imaging of, 548f, 568-569 molecular biology of, 1 8 7 3 - 1 8 7 4 stroke risks, 1302 systemic features of, 1 8 7 4 - 1 8 7 5 type 1 characteristics of, 5 6 8 , 1302, 1338, 1873 computed t o m o g r a p h y of, 1876f neurological features of, 1 8 7 5 - 1 8 7 6 optic nerve glioma caused by, 1875, 1876f type 2 characteristics of, 5 6 8 - 5 6 9 , 1873 clinical features of, 1 8 7 6 - 1 8 7 7 magnetic resonance imaging of, 1877f Neurofilaments, 1345 Neurogenic atrophy, 3 5 2 Neurogenic detrusor overactivity, 7 5 2 Neurogenic hyperthermia, 48 Neurogenic pulmonary edema, 952 Neurogenic thoracic outlet syndrome, 2 2 8 6 NVuroiiuaging angiography, 5 3 0 - 5 3 1 cerebral angiography, 5 3 0 - 5 3 1 compured Tomography. see Coniputcd tomography cchoplanar imaging, 5 3 0 flu id-attenuated inversion recovery imaging, 5 2 9 - 5 3 0 , 531f functional activation studies, 6 7 3 - 6 7 4 description of, 6 6 7 electroencephalography. See Electroencephalography magnetic resonance spectroscopy, see Magnetic resonance spectroscopy magn etoen ce p ha logra p hy, 4 7 8 , 668-669 nctirochemistry uses of, 6 7 4 neutral state studies, 6 7 0 , 673 positron emission t o m o g r a p h y . see Positron emission tomography research applications of, 6 7 0 , 6 7 3 - 6 7 4 single-photon emission computed t o m o g r a p h y , see Single-photon emission computed tomography treatment studies using, 6 7 4
Neuroimaging {Continued) intraoperative neurosonography, 531-532 magnetic resonance angiography, see Magnetic resonance angiography magnetic resonance imaging, see Magnetic resonance imaging magnetization transfer contrast imaging, 524 myelography, 531 urogenital disorders, 755 Neurointensivist definition of, 941 family relationship with, 9 4 7 Neuroleptic agents hyper prolactinemia a n d , 8 6 0 neurological disturbances caused by, 6 Neuroleptic malignant syndrome, 8 5 3 - 8 5 4 Neurological diagnosis, see Diagnosis Neurological disease and disorders, see also specific disease or disorder diagnosis of. see Diagnosis genetic counseling, 8 0 2 , 8 0 5 , 8 7 4 - 8 7 5 incidence of, 7 7 6 t management of, 9, 8 6 9 mode of onset, 4 overview of, 7 7 5 - 7 7 8 prevalence of, 7 7 7 t - 7 7 8 t prognosis for, 874 psychologic reactions, 874 respiratory failure associated with, 872-873 secondary effects of, 8 7 4 treatment goals for arresting an attack, 8 7 0 description of, 8 6 9 - 8 7 0 functional disability avoidance, 8 7 0 - 8 7 1 slowing of disease progression, 8 7 0 symptom relief, 870 Neurological examination description of, 6 hard signs, 7 screening, 6 - 7 , 7t soft signs, 7 Neurological impairment, 869 Neurological interview, 4 Neurological rehabilitation activities of daily living, 1029 acupuncture, 1058 affective disorders, 1065 aphasia, 1 0 3 4 , 1034t duration of treatments, 1060 melodic intonation therapy, I 06 I outcomes, 1061 pharmacological adjuncts, 1061 stimulation-facilitation techniques, 1060-1061 studies of, 1060 assessments for, 1 0 3 5 - 1 0 3 6 behavioral disorders, 1 0 6 4 - 1 0 6 5 biofeedback, 1058 biological bases for acriviry in partially spared pathways, 1043 axonal regeneration, 1046 behavioral strategies, 1 0 4 3 - 1 0 4 4 biological interventions, 1 0 4 6 - 1 0 4 7 cortical adaptations, 1046 description of, 1042 distributed networks, 1044t, 1 0 4 4 - 1 0 4 6
INDLX Neurological rehabilitation (Continued] network plasticity, 1042t neuronal excitability, 1042 neuronal plasticity, 1042t overview of, 1042t subcortical adaptations, 1046 clinical trials, 1039-1040 cognitive therapy disorders managed by, 1059t overview of, 1059-1060 complications and neuromedical problems that affect bladder dysfunction, 1052-1053 central pain, 1053 contractures, 1051 deep venous thrombosis, 1050-1051 description of, 1047 dysautonomia, 1051-1052 dysphagia, 1049-1050 frequency of, 1047-1049 seizures, 1051 skin ulcers, 1050 sleep disorders, 1053 spasticity, see Spasticity constraint-induced movement [herapy, 1057-1058 definition of, 1027 depression, 1065 description of, 870-871, 1027, 1040 documentation of, 1040 iunanmal neuromuscular stimulation, 1057-1058 goals description of, 1027-1028 setting of, 1036 hem i-in attention, 1063-1064, 1064t locomotor training, 1056-1057 measures for Rarthel Index, 1037, 1038t clinical usefulness of, 1038-1039 disease-specific, 1037, 1037t Functional Independence Measure, 1037, 1038t general types of, 1037, 1037t outcome levels, 1037 scientific soundness of, 1039 types of, 1036-1037 validity of, 1039 memory disturbances aids and devices for, 1062, 1063t cognitive remediation for, 1060 frequency of, 1060 outcomes, 1063 pharmacological adjuncts for, 1060-1061 treatments for, 1060 motor learning approaches, 1030-1031 multidisciplinary approach to, 1028f multiple sclerosis, 1068-1069 neural prostheses, 1059 options for, 871 organization of, 1040-1041 orthopedic procedures for, 871 orthotic devices, 1033, 1033f, 1035, 1036f Parkinson's disease, 1068 patient education, 1028-1029 personnel for description of, I 028 occupational therapist, 1032-1033 orthotist, 1035
Neurological rehabilitation {Continued) physical therapist, 1029-1032 physicians, 1028-1029 psychologist, 1034-1035 recreational nuT.ipiM. HI 54 rehabilitation nurse, 1029 social worker, 1035 speech and cognitive therapist, 1033-1034 pharmacological interventions, 1047, 1059 physical therapy programs adaptive equipment, 1032, 1032t Bobath technique, 1030 conditioning and strengthening, 1029-1030 description of, 1029 motor learning approach, 1030-1031 neuropilysiological school, 1030 reflexive movements, 1030 sensory stimuli, 1030 task-oriented, 1031-1032 process of, 1035-1036 robotics, 1058 services delivery of, 1041 organization of, 1041 types of, 1040-1041 settings community-based, 1041 inpatient rehabilitation unit, 1040-1041 spinal cord injury, 1048, 1048t stroke, 1047-1048, 1048t team-based approach to, 1028f traumatic brain injury complications in, 1048-1049 outcomes for, 1067-1068 Neurologists, practicing, 776-777 Ncurolymphomatosis, 2369 Neurolysis, 1192 Neuromuscular blocking, 519 Neuromuscular blocking agents, 1133 Neuromuscular junction medications that affect, 1030 quanta at, 515 Neuromuscular junction disorders causes of, 2459-2460 compound muscle action potentials in, 517t description of, 712t floppy infant and, 403-404 human immunodeficiency virus-related distal sensory polyneuropathy, 1598-1599 inflammatory demyelinating polyradiculoneuropathies, I 599 lumbosacral poIyradiculomyelitis, 1599-1600 mononeuritis multiplex, 1600 myopathies, 1600 neuropathies, 1598-1600 nucleoside analogue-associated toxic neuropathy, 1599 overview of, 1583t peripheral neuropathies, 1598-1600 myasthenia gravis acetylcholine receptors description of, 2443, 2444t diagnostic testing, 2446 autoantibodies in, 2444-2445 autoimmune, 826 B cells in, 826
lxxvii
Neuromuscular junction disorders {Continued) characteristics of, 826-827 clinical presentation of, 2441-2442 course of, 2441-2442 definition of, 2441 diagnostic procedures for antibodies against acetylcholine receptors, 2446 edrophonium chloride test, 2445-2446 electromyography, 2446-2447 ocular cooling, 2447 diseases associated with, 2452 drugs that affect, 2458 dysphagia in, 168-169 epidemiology of, 2441 generalized, 2453 genetic factors, 826 immune responses in, 1468 immunosuppressives for, 827 incidence of, 826-827 influenza vaccinations, 2452 inheritance of, 2443 juvenile, 2453 nicotinic receptors and, 893t ocular, 2442, 2453 pathophysiology of, 2443-2445 D-penieillamine-induccd, 2455 physical findings facial patterns, 2442, 2443f ocular muscles, 2442 oropharyngeal muscles, 2442, 2443f during pregnancy, 2454 ptosis associated with, 204, 378 repetitive nerve stimulation in rapid, 517-518 slow, 516-517 respiratory failure associated with, 872 seronegative, 2453 signs and symptoms of, 1468 striational antibodies in, 2444 thymus' role in, 2445 transitory neonatal, 2454-2455 treatment of azathioprine, 2450 cholinesterase inhibitors, .144~ 244.S. 2448t corticosteroids, 2449-2450 cyclophosphamide, 2450-2451 cyclosporine, 2450 description of, 826-827, 1468, 2447 cphednne, 2452 guidelines for, 2452-2455 immunosuppressants, 2450-2451 intravenous immunoglobulin, 2451-2452 mycophenolate mofetil, 2451 neostigmine, 2447, 24481 plasma exchange, 2451 prednisone, 2449 pyridostigmine bromide, 2447, 2448t thymectomy, 826, 2448-2449 tumors associated with, 1468 repetitive nerve stimulation in, 517t sleep disorders associated with, 2027 venom toxicity effects, 2459-2460 Neuromyasthenia, epidemic, 1542 Neuromyelitis optica, sec Dcvic's disease
Volume I pp. 1-1070 • Volume II p. 1071-2546
Ixxviii
INDEX
Neuromyotonia iiei'illr i'livrr8<S signs and symptoms of, 1 2 8 6 - 1 2 8 8 stereotactic radiosurgical therapy for, 1294 treatment of, 1294 cerebtal angiography of, 5 6 9 , 569f classification of, 1285 clinical features of, 974f clinical manifestations of, 1288 computed tomography of, 1289, 1290f course of, 1290, 1 2 9 3 - 1 2 9 4 definition of, 1285 embolization for, 9 7 4 endovascular embolization of, 1 0 1 5 - 1 0 1 6 , 1296t epidemiology of, 1014, 1288 frontal, 1017f frontal lobe, 1293f functional imaging of, 1 2 8 9 , 1290f grading of, 9 7 4 headaches associated with, 1 0 1 5 , 1288, 2 0 6 2 - 2 0 6 3 hemorrhagic stroke caused by, 1014-1016 illustration of, 1017f incidence of, 974 intra-arterial digital subtraction angiography of, 6 1 2 - 6 1 3 intracerebral hemorrhage associated with, 1015, 1 2 5 2 - 1 2 5 3 , 1288 intracranial hemorrhage associated with, 1290 intramedullary, 1318 intraventricular hemorrhage caused by, 1264 laboratory studies of, 1289, 1290f magnetic resonance angiography of, 1289, 1291f magnetic resonance imaging of, 1289, 129 If metabolic findings, 1289 microsurgical excision of, 1296t mortality rares, 9 7 4 , 1292 natural history of, 9 7 4 neurosurgical treatment of, 9 7 3 - 9 7 5 parenchymal, 2 0 6 2 parietal lobe, 1292f pathological characteristics of, 1285 physical findings of, 1288 physiology of, 1289 in pregnancy, 1 2 9 6 , 2 5 4 0 prevalence of, 1014 prognosis for, 1 2 9 0 , 1 2 9 3 - 1 2 9 4 radiographic features of, 1015 radiosurgery for, 9 9 0 , 1 2 9 6 seizures associated with, 1 2 8 8 , 1294 signs and symptoms of, 1288 Spetzlcr-Martin grading scale for, 1294t spinal classification of, 9 8 4 description of, 5 7 0 myelopathy vs., 985 neurosurgical Treatment of, 984-985 surgical treatment of, 1 2 9 4 - 1 2 9 6 temporal, 1295f
cxvii
Vascular malformations {Continued) ill contrast-enhanced magnetic resonance angiography of, 613 treatment of, 9 7 4 - 9 7 5 , 1 0 1 5 - 1 0 1 6 , 1288, 1 2 9 4 - 1 2 9 6 true, 1285 venous a n g i o m a s , 1285 in Wy b u r n - M a s on disease, 1896 capillary telangiectasia, 9 7 0 cavernous angiomas, 9 7 2 - 9 7 3 cavernous malformations in children, 1300 description of, 1285 epidemiology of, 1 2 8 6 - 1 2 8 8 signs a n d symptoms of, 1 2 8 6 - 1 2 8 8 stereotactic radiosurgical therapy for, 1294 treatment of, 1294 spinal arteriovenous fistulac, 1318 classification of, 1317 clinical presentation of, 1318 course of, 1318 description of, 1317 distribution of, 1318 dural arteriovenous fistulae, 1318-1319 magnetic resonance angiography of, 1318-1319 magnetic resonance imaging ot. 1 3 1 8 - 1 3 2 0 , 1319f-1320f pain associated with, 1318 prevalence of, 1 3 1 8 signs and symptoms of, 1318 trearment of, 1 3 2 0 - 1 3 2 1 venous a n g i o m a , 9 7 0 , 9 7 2 , 972f in Wy b u r n - M a s o n disease, 1896 Vascular parkinsonism, 1929, 2 1 4 3 Vasculitic neuropathy, 1079 Vasctilitic plcxopathy, 2 2 9 5 Vasculitis central nervous system cerebrospinal fluid tests for, 1324 cerebrovascular amyloid and, 1326 definition of, 1323 description of, 1323 diagnostic a p p r o a c h , 1 3 2 4 - 1 3 2 5 graft-versus-host disease a n d , 1326 herpes / O M I T infection and, 1.525 intravenous d r u g use a n d , 1 3 2 5 - 1 3 2 6 isolated, 1 3 2 3 - 1 3 2 4 lymphoma and, 1326 treatment of, 1325 cerebral, 1218 clinical features of, 2371 dementia related t o , 1938 drug abuse-related, 1 7 2 4 - 1 7 2 5 intracranial, 1218 laboratory fcatutes of, 2 3 7 1 - 2 3 7 2 muscle, 1466 necrotizing, 2 3 7 2 nerve, 1466 paraneoplastic, 1 (69 pathogenesis of, 2371 peripheral nerve, 2370—2373 retinal, 191 treatment of, 2 3 7 2 - 2 3 7 3 Vasoactive intestinal polypeptide, 850t, 852t, 909 Vasodepressor syncope, 12
Volume I pp. 1-1070 • Volume 11 p. 1071-2546
cxviii
INDEX
Vasogenic cerebral edema, 1366-1367 Vasogenic edema, 1366, 1751 Vasopressin, 954 brain pathways for, 862-863 characteristics of, 849, 850t, 862 Vasospasm angioplasty for, 969, 970f, 1010-1011 calcium-channel blockers for, 969, 1009 drug abuse-related, 1724-1725 endovascular treatment of, 1280 internal carotid artery, LOlOf mechanical therapies for, 1009-1011 subarachnoid hemorrhage and, 1279-1280 description of, 661-662, 957, 969 treatment of, 1009-1011 symptoms of, 1009 Vasovagal syncope, 2434 Vectors, 796-797 Vecuronium, 1133 Vegetative state, persistent clinical features of, 44t Glasgow outcome scale for, 1049t postanoxia coma and, 1667 Vein of Galen, 640 Veins cerebral cortical, 639 cervical, 642t cortical, 6421 deep cerebral, 639-640, 642t dural, 642t posterior fossa, 640-641 scalp, 642t Velocardiofacial syndrome, 1793r, 1801 Velocity storage, 703 Vena caval filters, 1367, 1368f Venezuelan equine encephalitis virus, 15311, 1532-1533 Venlafaxinc, 2310 Venom neuromuscular junction disorders caused by, 2459-2460 scorpion, 1728t, 1729 snake, 1727-1728, 1728t, 2460 Venous angiomas, 569-570, 570f, 970, 972, 972f, 1285, 1286f Venous occlusive disease, 1018, 1020 Venous stasis retinopathy, 1203 Ventilation, mechanical aspiration pneumonia prophylaxis, 950 assist-control mode ventilation, 949 chest physiotherapy during, 950 chronic, 951 for Guillain Barre syndrome, 959 indications for, 948-949, 949t medical management during, 950 modes of, 949 myasthenia gravis crisis managed by, 958-959, 2454 rapid sequence intubation, 949 rapid shallow breathing index, 950 ventilators, 949-950 weaning from, 950 Ventral root dysfunction, 351-352 Ventral simultanagnosia, 133 Ventricular arrhythmias, 1102 Ventricular fibrillation, 14 Ventricular tachycardia, 14 Ventriculoencep ha litis, 1591-1592 Vemriculomegaly, 571-572
Ventriculostomy, for intracranial pressure monitoring, 1137 VEPs. see Visual evoked potentials Verbal auditory agnosia, 1806 Verbal dyspraxia, 1 805 Vergenee eye movements, 703, 709 Vergence system, 703 Vernet's syndrome, 2120t Verocay bodies, 1342, 1358 Versions, 204-205, 207f Vertebral artery anastomoses with, 627 anatomy of, 626f, 635, 636f anterior spinal arteries from, 635 nrhcrosderoric narrowing of, 606 basilar artery and, 636
branches of, 635 compression of, 2207 course of, 635 dissection of, 979 lateral medullary syndrome caused by occlusion of, 1207 left, 635, 636f magnetic resonance angiography of, 607f-608f occlusion of, 1207 origin of, 635 posterior inferior cerebellar artery, 635 posterior meningeal artery, 635, 637f right, 626 stenosis of, 657 ultrasound examination of, 653 V4 segment, 657 Vertebral body fractures, 1167 Vertebral osteomyelitis, 455-456 granulomatous, 2214-2215 pyogenic, 2213-2214 Vertebrobasilar dolichocctasia, 638 Vertebrobasilar insufficiency, 24, 1203 Vertebrobasilar ischemia, 279 Vertebrobasilar sysrem syndromes anrerior inferior cerebellar artery occlusion, 1207
anrerior inferior cerebellar artery syndrome, 1205 Benedict's syndrome, 1206 Claude's syndrome, 1206 description of, 1205 lateral pontomedullary syndrome, 1207 Nothnagcl's syndrome, 1206 Parinaud's syndrome, 1206 superior cerebellar artery infarction, 1205 top of the basilar syndrome, 1206 Weber's syndrome, 1206 Vertebrobasilar junction, fusiform aneurysm of, 1015f Vertical eye movements, 709-710 Vertical gaze disorders causes of, 719 description of, 718 oculogyric crises, 721-722 ophthalmoplegia, 273-274, 274t paresis, 720 skew deviation, 721 Vertical pendular nystagmus, 216 Vertical saccades, 718 Vertical suspension test, for floppy infant evaluations, 401
Vertigo, see also Dizziness acute peripheral vestibular abnormality and, 234, 235f benign paroxysmal positional in children, 241 description of, 236, 237f exercise therapy for, 746-747 causes of acute cerebellar infarction, 240 afferent sensory loss, 241 brainstem ischemia and infarction,
239-240 central, 239t cerebellopontine angle tumors, 240 cranial neuropathy, 240 drug toxicity, 237, 239, 239t, 241 endocrine disorders, 241 hyporension, 241 labyrinthitis, 236 Meniere's disease, 239 overview of, 2361 peripheral vesribulopathy, 235-236, 243-244 peripheral vs. central, 237t posterior fossa lesions, 240 Ramsay Hunt syndrome, 236 seizure disorders, 240-241 systemic, 239t, 241 cerebellar system examination for, 242-243 in children, 241 definition of, 233 differenrial diagnosis, 235-241 episodic, 241 examination for, 242-243 history-taking, 234, 235f migrainous, 234 motor system examination for, 242 muscarinic receptors and, 893t ne uro-otologic a 1 examination for, 243 ocular motor examination for, 242 post-trau ma tic, 236-237 screening tests for, 243 seasonal outbreaks of, 236 sensory examination for, 242 signs and symptoms of, 233-234 treatment of, 746t Vestibular disorders central description of, 244 medical treatment of, 748 surgical trearment of, 748 dizziness, see Dizziness falls caused by, 26 peripheral diagnosis of, 243-244 medical treatment of, 746-748 riH'i.'ilnjIk- abnormalities associated with. 747 surgical treatment of, 748 vertigo caused by, 235-236, 243-244 vertigo, see Vertigo Vestibular neuronitis, 235-236 Vestibular nystagmus, 217 Vestibular schwannoma, 977, 1393, 1396f Vestibular suppressants, 746 Vestibular system functions of, 241 vertigo caused by, 241
INDEX Vestibular testing bithermal caloric testing, 739 directional preponderance, 741 elecrronysragmogram, 7.19, 740f-741f posturography, 742 rotational testing, 742 Vestibulocochlear nerve tumors cochlear dysfunction vs., 254 description of, 240 vHLgene, 1360 Viagra, see Sildenafil Vibration-induced injuries, 1743 Vicodin. see Hydrocodone Videomanofluorometry, 174 Videx, see Didanosine Vidian artery, 629 Vigabatrin, 1982t, 1986-1987 psychotropic effects of, 98t Viliuisk encephalomyelitis, 1541 Villaret's syndrome, 2120t, 2122 Vinca alkaloids, 1405-1406, 2386-2387 Vincristine, 1406, 2386-2387, 2411 Vioxx. see Rofecoxib Viraccpt. sec Nclfinavir Viral infections adenovirus, 1541 central nervous system antiviral drugs for, 847 arboviruses, see Arboviruses arenaviruses, 1537-1538 causes of, 1516t-1517t description of, 1515 diagnosis of antigen detection for, 845 criteria for, 845 immunofluorescent techniques, 844 immunological tests, 845 improvements in, 844 molecular techniques for, 845 polymerase chain reaction, 845-846 differential diagnosis, 1519t herpesviruses, see Herpesviruses historical studies of, 844 measles, see Measles mucous membrane findings associated with, 1517t mumps, 832t, 1520t, 1537 nonpolio enteroviruses, 1528 pathogenetic stages of capillary endothelial cell infection, 840 central nervous system invasion, 840-841 entry, 838-839 neural spread, 841-842 neurotropism, 842 polarized infection, 839 receptors, 842, 8431 spread, 839 systemic invasion, 839 target cell effects, 842-843 Trojan horse entry, 840-841 vircmia, 839-840 poliovirus, 1527-1528 polymerase chain reaction diagnosis of, 1520t rabies, see Rabies rubella, 832t, 835, 1537 skin findings associated with, 1517t
Viral infections iContimied) supportive therapy for, 847 symptomatic therapy for, 847 symptoms associated with, 845 treatment of, 846-848 vaccines for, 846-847 encephalitis brainstem, 172 cerebrospinal fluid pattern in, 833-834 computed tomography findings, 834 description of, 833 epidemics of, 833 epidemiology of, 833 herpes simplex description of, 62, $33 diagnosis of, 834 electrocnccphalography evaluations, 471f, 475, 834 magnetic resonance imaging of, 558-559, 559f treatment of, 834 human immunodeficiency virus, 562 manifestations of, 834 symptoms of, 833-834 toxoplasma, 560-562, 561f encephalomyelitis acute disseminated, 553, 553f, 825, 838 description of, 111 paraneoplastic, 1463-1464 postviral, 1535 progressive encephalomyelitis with rigidity, 1541-1542 Viliuisk, 1541 ganglionitis, 836 Guillain-Barrc syndrome and, 838 hemorrhagic fever dengue, 1538 filoviruscs, 1538-1539 yellow fever, 1538 hepatitis viruses, 1541 immune system and, 837-838 influenza, 832t, 1540-1541 meningitis acute, 833 characteristics of, 832t clinical features of, 833 course of, 833 description of, 831 diagnosis of, 832-833 recurrence of, 833 multiple sclerosis caused by, 1636, 1645-1646 myelitis epidemiology of, 835 herpes simplex virus, 835-836 incidence of, 835 syphilitic, 416 viral, 835-836 myositis, 837 p a pova viruses, 1539 parvovirus B-19, 1520t, 1541 polyneuroparhy, 836-837 polyradiculitis, 836 Viral meningitis acute, 833 characteristics of, 832t clinical features of, 833 course of, 833 coxsackievirus, 1528-1529
cxix
Viral meningitis {Continued) description of, 831 diagnosis of, 832-833, 1528-1529 etiology of, 1528 nonpolio enteroviruses, 1528 recurrence of, 833 treatment of, 1528-1529 Viramunc. see Nevirapine Viread. see Tinofovir Vircmia active, 839 passive, 839 phases of, 839-840 Viruses apoptosis caused by, 843 blood-brain barrier effects, 840 central nervous system, pathogenetic stages of capillary endothelial cell infection, 840 central nervous sysrem invasion, 840-841 entry, 838-839 neural spread, 841-842 neurotropism, 842 polarized infection, 839 receptors, 842, 843t spread, 839 systemic invasion, 839 target cell effects, 842-843 Trojan horse entry, 840-841 viremia, 839-840 classification of, 831 conjunctival entry of, 838 cultunng of, 845 definition of, 831 latency of, 843 multiple sclerosis and, 838 neurotropic, 843-844 receptors for, 842, 843t respiratory tract entry of, 838 transmission of, 838 Vision brain tumor symptoms, 1364 central, 727 color vision testing, 730 contrast sensitivity testing of, 729-730 light stress test, 730 nonorganic disturbances of
albinism, 738 description of, 735-736 diagnosis of, 736-737 Leber's congenital amaurosis, 737-738 prevalence of, 735 visual evoked potentials for, 737 paraneoplastic effects, 1469-1470 peripheral, 727 Vision loss bright light-induced, 178 cancer-associated retinopathy syndrome, 182 central, 177-178 in children, 737t description of, 1 77 gradual onset, 181-182 progressive, 181, 181t progressive multifocal leukoenccphalopathy and, 339-340 psychogenic, 737f radiation damage-induced, 182 righr homonymous hemianopia, 177f
Volume I pp. 1-1070 > Volume II p. 1071-2546
cxx
INDEX
Vision loss {Continued) stroke-tela ted, 1043 sudden onset description of, 178-180 nonprogressive bilateral, 180, 181t unilateral, 180, 180t transient bilateral, 179-180, 180t unilateral, 178-179 transient visual obscuration, 178-179 transient monocular, 1203 Visual acuity best corrected, 728 examination of, 728-729 near, 729 Visual agnosia apperceptive associative agnosia vs., 131-132 characteristics of, 132 perceptive categorization deficit, 133, 133f share perception impairments, 132, 132f simultaiiagnosia, 133 syndromes related to, 132-133 assessment of, 136 associative apperceptive agnosia vs., 131-132 brain damage patterns in, 134-135, 135f definition of, 133-134 dissociations in, 134 lesions that cause, 134-135 neuropathology of, 134-135 with prosopagnosia, 134, 135f pure alexia, 134 syndromes related to, 135-136 historical investigations of, 131 Visual cortex, primary, 727-728 Visual evoked potentials abnormal, 48It description of, 479 flash, 473 functional visual loss evaluations, 737 migraine evaluations, 2076 neurological disease uses of, 481, 481f normal, 479^180, 480f pattern reversal, 480^181, 481f Visual field abnormalities and defects of binasal hemianopias, 733, 735 bitemporal, 7 bitemporal hemianopias, 735 homonymous defecrs, 735 homonymous hemianopias, 735, 736f optic disc drusen as cause of, 186 optic nerve lesions, 733, 735 pituitary adenomas, 1095 progression of, 1 86 topographic diagnosis of, 179f loss of central, 177-178 description of, 177 funcrional, 735-738 right homonymous hemianopia, 177f testing of confrontation methods for, 731-732 descriprion of, 731-733 perimeters for, 732-733, 734f
Visual pathways description of, 727 multiple sclerosis-related impairment of, 1639 schematic diagram of, 728f ViMiospatial skills in Alzheimer's disease dementia, 1907 disability of, 1801t, 1801-1802 Vitamin A, l 5 2 i t Vitamin A deficiency, 1707 Vitamin B,, deficiency of, 1700-1701, 2376, 2513 inborn errors of metabolism managed using, 1819t Vitamin B ]2 deficiency of biochemistry of, 1636 clinical features of, 1694-1695 course of, 1697 dementia caused by, 1946 description of, 1086, 1694 differential diagnosis, 1697 etiology of, 1696-1697 gastric surgery and, 6 laboratory studies of, 1694-1695 magnetic resonance imaging findings, 1694-1695 myelopathy associared with, 1694f pathogenesis of, 1696-1697 pathologic findings, 1696 pernicious anemia associated with, 1696-1697 physiology of, 1695-1696 polyneuropathy, 2376-2377 prognosis for, 1697 psychiatric disturbances associated with, 109 treatment of, 1697 inborn errors of metabolism managed using, 1819t Vitamin D deficiency, 1707 Vitamin E deficiency, 1698-1699, 2175-2176,2377-2378 Vitamin K deficiency of, 1303 description of, 954, 1108 pregnancy indications, 2539 Voltage-gated ion channels action potential duration and, 909 calcium channels anticpilcptic drug effects on, 913 disorders associated with, 911t, 913 l.-type, 912 N-type, 912 operating cycle of, 913 pharmacology of, 913 physiology of, 913 P-type, 912 structure of, 1849 T-type, 912 chloride channels in cystic fibrosis, 914 description of, 914 disorders associated with, 91 It description of, 909, 1974 distribution of, 1847-1848 potassium channels calcium-dependent, 914 depolarization of, 914 disorders associated with, 91 It
Voltage-gated ion channels {Continued) hippocampal pyramidal neurons and, 914 structural features of, 913, 1848-1849, 1849f subumts of, 913 sodium channels anticonvulsant drug effects on, 912 antiepileptic drug binding to, 911-912 disorders associated with, 910, 91 It extracellular loop, 910 function of, 910-912 intracellular loop, 910 pharmacology of, 910-912 sequences in, 910 structure of, 910, 1849 tetrodotoxin-resistant, 912 Voluntary nystagmus, 221 von Hippel—l-indau disease clinical features of, 1894-1895 definition of, 1894 description of, 193f, 581, 803t genetics of, 1 895 pancreatic cysts in, IS95 pheochromocyramas in, 1895 prevalence of, 1894 retinal hcmangioblastonias associated with, 1894-1895 risk categories for, 1894t screening for, 1895-1896, 1896t systemic features of, 1895 treatment of, 1895-1896 von Recklinghausen's disease, 568 von Willcbrand's factor, 1200 Voriconazole, 1553 V-pattern prerectal pseudobobbing, 223 W Wakefulness behavioral criteria of, 1994t conrrol of, 2000 neurobiology of, 1998-1999 periodic limb movements in, 2022, 2024 physiological criteria of, 1994t Waldenstrom's macroglobulinemia, 1087, 1467, 2353 Walker-Warburg svndrome, 804t, 1768, 1777t, 1785, 2478-2479 Walking, see also Gair examination of checklist fot, 326t gait initiation, 327 stepping, 327 festinarion, 330 muscle weakness effects, 374 shuffling, 330 slowness in, 324—325 Wallenberg's syndrome, 285, 1207, 2117 Wallerian degenerarion corticospinal tract, 1043, 1043f peripheral nerves, 1183-1186 Warfarin description of, 954 skin necrosis caused by, 1226 srroke prophylaxis using, 1236 tctraogenicity of, 2541 Water homeostasis of, 863, 1687, 1688f hypo-osmolaliry, 1687-1689
INDEX Water deprivation test, for diabetes insipidus, 863 Water hemlock, 1730t, 1731 Watershed infarcts, 1209, 1666, 1775 Water taste, 262 Watson, James, 6.5 Weakness gait disturbances caused by, 324 leg, 348-349 muscle algorithm for evaluating, 378, 379f amyotrophic lateral sclerosis, 383-384 axial muscles, 369 bulbar musclo description of, 368 disorders with, 378-379 chronic, 383 constant, 383-386 description of, 367 examination of algorithmic approach, 378, 379f arising from floor movements, 374-375 cramps, 374
description of, 369-370 electromyography, 376 exercise testing, 377-378 fasciculations, 374 fatigue, 373 genetic testing, 377 initial approach, 368
labial sounds, 370 muscle biopsy, 377 muscle bulk, 370-372 muscle movement abnormalities, 374 observation, 370 palpation of muscle, 372 percussion of muscle, 372 peripheral nerve enlargement, 374 range of motion of muscle, 372 reflexes, 373 scapula winging, 370, 37] f sensory disturbances, 373-374 serum creatine kinase levels, 376 stepping onto a stool, 375 strength assessments, 372-373 tests, 376-378 wa iking, 374 extraocular muscles description of, 368 diagnostic approach to, 378 facial muscles description of, 368 diagnostic approach to, 378-379, 380f disorders with, 378-379 labial sounds associated with, 370 fluctuating, 382 gait distutbances caused by, 324, 335 hand muscles, 348 hip-girdle description of, 369 disorders with, 381 lifelong, 384-386 lower extremity, 369 in multiple sclerosis, 1640-1641 myotonic dystrophy, 379, 380f neck, 368-369 periodic paralysis and, 382 progressive, 386
Weakness (Continued) psychogenic, 375-376 shoulder-girdle diagnostic approach to, 379-381 disorders associated with, 379-381 neurogenic disorders associated with, 380-381 postural changes associated with, 370 subacute, 383 symptoms of, 367-368 trunk, 369 upper extremity, 369 upper motor neuron, 367 spinal cause of, 356-357 treatment of, 871-872 Weber's syndrome, 34It, 1206, 2120t Weber test, 248 Wechsler Adult intelligence Scale, 676 Wegener's granulomatosis, 1080, 1104 Welandcr's myopathy, 381, 2482-2483 Wcrdnig-Hoffmann disease, 2238, 2239f Wernicke-Korsakoff syndrome, 69 Wernicke's aphasia bedside features of, 146t causes of, 67 clinical features of, 39t, 145-146 delirium and, 38 language disturbances in, 146 lesions associated with, 146-147 magnetic resonance imaging of, 146f-148f psychiatric manifestations of, 146 pure word deafness and, 137 Wernicke's encephalopathy alcoholism and, 1702-1703 clinical features of, 1702-1703 coma and, 47 course of, 1704 dialysis and, 1093 epidemiology of, 1703-1704 history-taking, 1702 labotatory studies, 1703 pathologic findings, 1703 physiology of, 1703 pregnancy and, 2535 ptevention of, 45 prognosis for, 1704 treatment of, 1704 Western blotting, 796 Western equine encephalitis vitus, 832t, 833, 1531t, 1532 West Nile virus, 832t, 1520t, 1530-1531, 1531c West Nile virus motor tieutonopathy, 2390 West's syndrome, 469, 470f, 1965-1966 Wet keratin, 1361 Wheelchairs, 1032, 1032t Whiplash, 441 Whipple's disease in adults, 1092 characteristics of, 1506 in children, 1110 dementia and, 1940 description of, 274 treatment of, 1506 White-matter lesions in Alzheimer's disease, 1910 in vascular dementia, 1932-1934
cxxi
Wide dynamic range neurons definition of, 923-924 sensitization of, 926 Wide Range Achievement Test-3, 678 Wilhelmsen-Lynch disease, 2261 Williams syndtome, Sit, 1793t Wilson's disease clinical features of, 2158 description of, 805t, 1828, 1929-1930 differential diagnosis, 319 dysphagia in, 171-172 dystonia in, 313 epidemiology of, 2158 etiology of, 2158 family history of, 293 Kayser-Flcisher rings in, 113, 294, 19.30 kinky hair syndrome and, 1888 laboratory investigations for, 319, 320t pathogenesis of, 2158 pathology of, 2158 psychiatric distutbances in, 112 treatment of, 2158-2159 Wolf-Flirschhorn syndrome, 81t, 785 Women cryptogenic falls in, 26 falls in, 26 sexual dysfunction in, 760 urinary retention in, 430, 751 Word recognition tests, 743 World Federation of Neurological Surgeons scale, 1270t World Health Organization impairments, disabilities, and handicap classification, 1037t netvous system tumor classification by, 1342, 1343t pain management approach, 930
poliovirus eradication goals, 1528 Worstet-Drolight syndrome, see Opercular syndrome Wrist tendonitis, 4A2-AA3 Writing disturbances of, in delirium, 31-32 parkinsonism effects, 300 tremors of, 303 Wrong-way eyes, 715-716 Wuehereria bancrofti, 1557t Wyburn-Mason disease arteriovenous malformations in, 1896 clinical features of, 1896 definition of, 1896 description of, 193f
ttcatment of, 1896-1897 vasculat malformations associated with, 1896
Xaliproden, 2255 X a n t hoa stroc y torn a, pleomorphic characteristics of, 532, 1350, 1412-1413 in children, 1428 management of, 1412-1413 Xenon-133, 946 Xeroderma pigmentosum complementation groups, 1897 cutaneous features of, I898t, 1898-1899 definition of, 1897 description of, 803t oculat features of, 1898t, 1898-1899 Volume I pp. 1-1070 • Volume II p. 1071-2546
exxii
INDEX
Xeroderma pigmentosum {Continued) syndromes related to, 1897-1898 treatment of, 1899 Xctostomia, 2418, 2435 X-linked dystonia-parkinsonism, 2157-2158 X-linked Emery-Drei fuss dystrophy, 2479 X-1 inked hydrocephalus, 805t X-linkcd inheritance disorders chromosomal assignments of, 805t description of, 782t, 783-784 X-linked myotubular central nuclear myopathy, 8051 X-linked periventricular nodular heterotopia, 1768 X-linked spinohulbar muscular atrophy, 373, 384
Y chromosome, 784
Volume I: 9997625889 ISBN 0 - 7 5 0 ^ - 7 4 ^ - 5
Yeast artificial chromosomes, 796-797 Yellow fever, 1538 Yersinia pestis, 1503
Zalcitahin, 15S7t Zanaflex. see Tizanidine Zanamivir, 1521t Zeiosis, 843 Zellweger syndrome, H03t-804t, 1768, J817t, 1824t Zerit. see Stavudine Ziagen. see Abacavir Zic-2 gene, 1779 Zidovudine characteristics of, 1587r myopathy caused by, 1600 Zofran. see Ondansetron
Zolmitriptan, 2082t Zona occludin-1 protein, 1747 Zonisamide, 1982t Zoonotic infections anthrax, 1503 Australia hat lyssavirus, 1535 brucellosis, 1502-1503 cat-scratch disease, 1504 glanders, 1503 Hendra virus, 1535 melioidosis, 1504 Nipah virus, 832t, 834, 1517t, 1535 pasteurellosis, 1503 plague, 1503 rat-bite fever, 1504 tularemia, 1503 Zygomycetes, 1549
Volume II
Neurology in Clinical Practice The Neurological Disorders Fourth Edition Edited by
Walter G. Bradley, D.M., F.R.C.P Professor and Chairman, Department of Neurology1, University of Miami School of Medicine; Chief, Neurology Service, University of Miami-Jackson Memorial Medical Center, Miami, Florida
Robert B. Daroff", M.D. Chief of Staff and Senior Vice President for Academic Affairs, University Hospitals of Cleveland; Professor of Neurology and Associate Dean, Case Western University School of Medicine, Cleveland, Ohio
Gerald M. Fenichel, M.D. Professor of Neurology and Pediatrics, Vanderhilt University School of Medicine; Director, Division of Pediatric Neurology; Neuroiogist-in-Chief Vanderhilt Children's Hospital, Nashville, Tennessee
Joseph Jankovic, M.D. Professor of Neurology; Director, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas
With 120 contributing authors
U T T E R W O R T H E I N E M A N N An
Imprint of Elsevier
Chapter 55 Neurological Complications of Systemic Disease A. IN ADULTS Michael J. Aminoff Cardiac Disorders and the Nervous System Cardiogenic Embolism Syncope Cardiac Arrest Complications of Cardiac Catheterization and Surgery Neurological Complications of Medication Infective Endocarditis Diseases of the Aorta Aortic Aneurysms Aortitis Coarctation of the Aorta Subclavian Steal Syndrome Complications of Aortic Surgery Connective Tissue Diseases and Vasculitidcs Polyarteritis Nodosa, Churg-Strauss Syndrome, and Overlap Syndrome Ciant Cell Arteritis Wegener's Granulomatosis Isolated Angiitis of the Nervous System Rheumatoid Arthritis Systemic Lupus Erythematosus Sjogren's Syndrome Progressive Systemic Sclerosis Behcet's Disease Relapsing Polychondritis Respiratory Diseases Hypoxia Hypercapnia Hypocapnia Systemic hidammatorv Response Syndrome Sarcoidosis Hematological Disorders with Anemia Megaloblastic Anemia Sickle Cell Disease Thalassemias Acanthocytic Syndromes Proliferative Hematological Disorders Leukemias
1073 1074 1074 1075 1075 1076 1077 1078 1078 1078 1079 1079 1079 1079 1079 1080 1080 1080 1080
nisi 1083 1083 I0S.5 1083 1084 1084 1084 1084 1084 1084 1086 [086 1086 1086 1086 1086 1086
This c h a p t e r discusses neurological c o m p l i c a t i o n s of systemic disease in adults. C h a p t e r 5 5 B discusses t h e same subject in children. Some disorders a r e discussed in both chapters but with a different e m p h a s i s .
Plasma Cell Dyscrasias Lymphoma Polycythemia Hemorrhagic Diseases Hemophilia Other Hemorrhagic Disorders Iatrogenic Hemorrhagic Disorders Antiphospholipid Antibody Syndromes Liver Disease Portal Systemic Encephalopathy (ilironic Non-Wilsoiiian Hepatocerebral Degeneration Liver Transplantation Pancreatic Encephalopathy Gastrointestinal Diseases Renal Failure Neurological Complications of Dialysis Neurological Complications of Renal Transplantation Electrolyte Disturbances Sodium Potassium Calcium Magnesium Pituitary Disease Pituitary Adenomas dishing*s Disease and Syndrome Hypopituitarism Diabetes Insipidus Thyroid Disease Hyperthyroidism Hypothyroidism Hashimoto's Thyroiditis Parathyroid Disease Hyperparathyroidism Hypoparathyroidism Adrenal Glands Pheochromocytoma Addison's Disease Diabetes Mellitus Hypoglycemia
1087 1088 10SK 1088 1088 5089 1089 1089 1090 I 070 1091 1091 1091 1091 1093 1093 1093 1093 1093 1094 1094 1094 1095 1095 1095 1095 1095 1095 1095 1097 1097 1097 1097 I 097 1098 1098 1098 1098 1099
CARDIAC; DISORDERS AND THE NERVOUS SYSTEM N e u r o l o g i c a l c o m p l i c a t i o n s arc an i m p o r t a n t cause of morbidity in patients with c a r d i a c disease. Cardiogenic 1073
1074
NFUROl.OCICAL DISEASES
emboli may result from cardiac disease or its surgical treatment, and cardiac dysfunction can cause global cerebral hypoperfusion leading to syncope, stroke, or death, depending on the severity and duration of cerebral ischemia.
Cardiogenic Embolism Cardiogenic emboli are most prevalent in patients with mitral stenosis and atrial fibrillation, intramural thrombi, prosthetic cardiac valves, atrial myxoma, infective endocarditis, sick sinus syndrome, and atrial fibrillation. Other causes include recent myocardial infarct, left atrial thrombus or turbulence, mitral valve prolapse, mitral annulus calcification, atrial fluttct, hypokinetic left ventricular segments, and congestive cardiac failure. Emboli from congenita) heart disease are discussed in Chapter 55B. The possibility of cardiac emboli must be considered in young people with either valvular heart disease or mitral valve prolapse. Echocardiography is an important investigative procedure when cardiogenic emboli arc suspected. Transesophageal echocardiography is preferable to the transthoracic approach in the evaluation of suspected atrial disease, such as myxoma or thrombus, and to demonstrate a patent foramen ovale, but transthoracic echocardiography is an important method of visualizing the ventricular apex, mitrai or aortic valvular disease, and left ventricular thrombus. Transesophageal echocardiography is an appropriate method to investigate people younger than 45 years with suspected cardiogenic emboii who may need anticoagulation or surgery and older people without signs of cardiacdisease, but transthoracic echocardiography is generally adequate when clinical evidence of cardiac disease is present.
Emboli are more likely when atrial fibrillation is associated with valvular heart disease. The incidence of stroke among patients with atrial fibrillation is increased 17-fold or 5-fold, respectively, depending on the presence or absence of rheumatic heart disease. Atrial fibrillation, in the absence ol cardiovascular disease or other predisposing illness, has a considerably lower risk of neurological complications. The neurological prognosis of paroxysmal atrial fibrillation is not established, but the risk of embolism is probably less than with chronic atrial fibrillation. The benefit of anticoagulation in reducing the risk of stroke in people with atrial fibrillation is established. A consensus has developed that long-term oral warfarin therapy for atrial fibrillation unless there were specific contraindications or the atrial fibrillation was an isolated finding in people younger than 60 years without other evidence of cardiovascular disease. Aspirin (325 mg per day) is recommended when warfarin is contraindicated. Warfarin is usually started at least 3 weeks before elective cardioversion in people with atrial fibrillation of more than
2 days' duration and continued until normal rhythm has been maintained for 4 weeks. Myocardial infarcts, especially apical, anterolateral, or large infarcts, have a risk of embolic stroke. Most occur within a week, but the risk persists for approximately 2 months. Therefore patients not on thrombolytic therapy arc heparinized after myocardial infarction and then treated for 3 months with warfarin if they have an increased risk of embolism. The groups with increased risk are those with congestive heart failure, previous emboli, evidence of a mural thrombus, left ventricular dysfunction, or atrial fibrillation. Emboli are an important cause of death in people with rheumatic valvular disease. The risk of embolism is increased in the presence of atrial fibrillation, intra-attial thrombus, ot a histoty of emboli, and long-term warfarin treatment is recommended. Aspirin (160-325 mg per day) is added for recurrent systemic emboli despite adequate warfarin therapy. Mitral valve prolapse is a common anomaly, especially among young women, and its relationship to cerebral emboli is now recognized. The risk of emboli is relatively small, and long-term warfarin therapy is recommended only tor people who have had previous embolic phenomena or are in atrial fibrillation. Eong-term aspirin therapy (325975 mg per day) is recommended for people with mitral valve prolapse and transient cerebral ischemic attacks of uncertain nature. Among patients with a history of cardiogenic emboli, recurrent stroke is more likely in those with cardiac valve disease and congestive heart failure. Nevertheless, the main cause of death in such patients is from the heart disease rather than neurological complications. The conversion of a cerebral infarct into a hemorrhage is a concern when patients with stroke from cardiogenic emboli are anticoagulatcd. The concern is especially justified in patients with large infarcts or when imaging studies suggest pre-existing hemorrhagic transformation. It is good practice to delay anticoagulation therapy after a small infarct for at least 24 hours, and then to initiate u only if computed tomographj shows no evidence of major hemorrhagic transformation. Anticoagulation is best delayed for 7 days after large infarcts. Atrial fibrillation is associated with an increased mortality during the acute phase of a stroke and in the subsequent year.
Syncope Transitory global cerebral ischemia secondary to cardiacarrhythmia causes syncope, sometimes preceded by nonspecific premonitory symptoms such as visual disturbances, paresthesias, and lightheadedness (Sotcriades et al. 2002). Syncope is usually associated with loss of muscle tone, but prolonged ischemia causes tonic posturing and irregular jerking movements that are easily mistaken for seizures
(Adams-Stokes attacks). The syncopal patient is pale, and postictal confusion is either absent or short lived, usually lasting for less than 30 seconds. Obstructed outflow from aortic stenosis or left atrial tumor or thrombus is one cardiac cause of syncope; other causes are arrhythmias, especially from ventricular tachycardia or fibrillation, chronic sinoatrial disorder or sick sinus syndrome, and paroxysmal tachycardia. Additional causes of syncope are central and peripheral dysautonomias, postural hypotension, and endocrine and metabolic disorders. Vasovagal syncope, the most common variety, and the prolonged QT-interval syndrome are discussed in Chapter 55B.
Cardiac Arrest Brain function is critically dependent on the cerebral circulation. The brain receives approximately 1 5 % of the total cardiac output. Ventricular fibrillation or asystole causes circulatory failure that depending on its duration can cause irreversible anoxic-ischemic brain damage. The prognosis generally depends on age, the duration of the arrest before cardiopulmonary resuscitation is started, and the interval before starting defibriHating procedures. The prognosis is better when circulatory arrest is caused by ventricular fibrillation rather than asystole. The pathophysiology of neurological damage caused by transitory interruption of cerebral blood flow is unclear. Suspected mechanisms are the accumulation of intracellular calcium, increased extracellular concentrations of glutamate and aspartate, and increased concentrations of free radicals. In the mature brain, gray marter is generally more sensitive to ischemia than white matter, and the cerebral cortex is more sensitive than the brainstem. The premature brain has the reverse pattern of sensitivity (see Chapter 86). Cerebral or spinal regions lying between the territories supplied by the major arteries (watershed areas} are especially vulnerable to ischemic injury. The severity of neurological complications of circulatory arrest correlarcs with the duration of the arrest. Brief (50%) lower proximal as compared with distal CMAP amplitude, with abnormal neurogenic motor unit action potentials or even their complete absence. The distal CMAP amplitude (if stimulating and recording beyond the site of conduction block) should be within normal limits in cases of conduction block. There may be a limited amount of axon loss if injury has occurred to some axons at the site of the conduction block. Therefore there may be some positive sharp waves or fibrillation potentials on NEE. It is important to remember that many nerve injuries involve components of both conduction block and axon loss (Wilbourn 1998). There is no way to clearly differentiate a predominantly demyelinating conduction block process from an axon loss lesion on the basis of clinical symptoms or signs or of an EDX performed within 7 days of the injury. An avulsion injury that involves both anterior and posterior preganglionic segments ma) produce a characteristic EDX pattern; there will be loss of CMAP amplitudes but preservation of SNAP amplitudes. This is because the lesion affects the dorsal root proximal to the ganglion that lies outside the spinal canal in the intervertebral foramen. Repeat examination should always be performed to assess for electrophysiological recovery or worsening. One must assess for recovery of SNAP and CMAP amplitudes; during regeneration, the SNAP amplitude characteristically recovers before the motor amplitude. Furthermore, one may appreciate some degree of normalization of motor unit recruitment and morphology. One particularly important NEE feature is the appearance of low-amplitude, polyphasic unstable nascent motor unit potentials, which is important EDX evidence of early motor unit reinnervation. Somatosensory evoked potentials (SSEPs) resulting from distal stimulation of the injured nerve may also be useful in evaluating peripheral nerve trauma, giving information about the integrity of posterior sensory tracts in the spinal cord and therefore useful in evaluating suspected posterior nerve root avulsion. However, the presence of an intact SSEP does not reliably indicate satisfactory nerve root function. SSEPs are so sensitive that they may yield positive waveforms in the presence of only a few hundred intact nerve root axons (Kline 2000). Furthermore, they do not provide enough localizing information to be of great assistance in postganglionic peripheral nerve injuries and do not provide information about injury to anterior (motor) rootlets in the spinal canal. Intraoperative SSEPs have been shown not to decrease the incidence of iatrogenic sciatic neuropathies during surgical repair ot acetabular fractures.
1190
NEUROLOGICAL DISEASF.S
Neuroradiology Assessment Even the most careful clinical and EDX examinations may be limited in certain situations. A very proximal injury to the sciatic nerve or brachial plexus may be inaccessible to a proximal motor stimulation point, thus pteventing assessment of proximal conduction. It may be difficult to accurately localize axon loss lesions either clinically or by EDX in certain sections of a peripheral nerve; for example, the ulnar nerve lacks any motor branch above the elbow. Furthetmore, in the earliest stages of closed-wound nerve trauma, it is not possible to differentiate a nerve transection from a lesion that remains in continuity. Radiological techniques have always had a part to play in nerve trauma evaluation, in cases of multiple trauma, plain films of the skull base, spine, and long bones may disclose fractures at sites that may compromise local nerve structures. Computed tomography myelogtaphy often is used to diagnose nerve root avulsions; conttast may be seen passing through the torn meningeal sheaths of avulsed nerve roots (pseudomeningoceles). Magnetic resonance imaging (MRI) of the spinal cotd has replaced computed tomography myelography as the first-line investigation in cases of suspected nerve root avulsion. The most exciting advances have been in the emerging field of MRI neurography, which is based on the longitudinally orientated water diffusion properties of nerve as opposed to surrounding tissues. Diffusion images of nerve require high-field-strength MRI scanners, but one may also obtain detailed images using 1.5-Tesla scanners in conjunction with phased atray coils. For example, signal hypcrintensity can be seen on T2-weighted and short time inversion tecovery images of traumatized netve segments; abnormal high signal is seen both at and distal to the injury site. This MRI modality can diffetentiate between axonotmesis and neutotmesis lesions and also detect neutoma formation at nerve repair sites; using specialized phased array coils, one may even be able to identify which fascicles in a nerve trunk are injured and which are spared. These signal changes may be ttansient in cases of mild nerve injury or may be prolonged (up to many years) in severe preganglionic brachial plexus avulsion injuries. Early (within 1 week) signal hyperintensity may also be seen in denervated muscle on T2-weightcd and shott time inversion recovery (STIR) images, which will persist if nerve discontinuity picvents reinnervation (Figure 56D.5}.
site of the injury, and the likelihood of satisfactory functional recovery. Surgical intervention is not indicated in an obvious case of neurapraxia because it is likely that the patient will enjoy an excellent outcome. However, one cannot be certain in cases of axonotmesis, which account for approximately 7 0 % of all setious nerve injuries. Although connective tissue elements are intact and therefore the lesion is in continuity, a neuroma may develop that bars the progress of axonal sprouts from the proximal to the distal stump. One may suspect such a problem in a patient who docs not make a clinical recovery at the expected rate or in the patient who complains of significant spontaneous pain at the site of the injury. It is important for the surgeon to be aware that neuromas often are invisible to the naked eye and impalpable during wound exploration. A specialized intraoperative technique called nerve action potential (NAP) recording has been developed to enable the surgeon to locate abnormal sites of nerve conduction caused by axon loss or neurapraxia and to define the healthy margins of the nerve. This technique entails placing stimulating and recording electtodes directly onto the nerve surface proximal and distal to an obvious or suspected site of nerve trauma that has remained in continuity. If the netve is healthy, the segment will transmit a normal NAP between the stimulation point and the recording point. NAP recordings provide evidence of regeneration within 8 weeks of a focal in-continuity lesion; the presence of a reasonable NAP in the distal segment indicates the ptesenee of 3000-5000 moderate-diameter myelinated axons at the recording site (Spinner and Kline 2000). Conversely, a neuroma or severely scarred intraneural site may fail to transmit an impulse and will manifest as a dropout in NAP waveform at the recording point. Absence of a NAP 6 weeks or more after the injury generally indicates a Sunderland grade IV lesion and is an indication for surgical repair of the injury.
SURGICAL REPAIR OF NERVE TRAUMA
Neurotmesis lesions do not regenerate spontaneously and necessitate some form of surgical intervention, the extent and timing of which depend on the severity of the injury. If the wound is open, it may be easy to inspect the site and make an immediate decision about the need for repair. For example, a nerve transection caused by a sharp blade in a clean wound may be repaired within 72 hours by direct end-to-end anastomosis (primary repair). A rapidly worsening neurological deficit in a closed wound may indicate the need for early intervention; one must also considet vascular lesions such as pscudoancurysms, expanding hematomas, or arteriovenous fistulas that may damage the netve in the wound site. Furthermore, the incteased interstitial pressures characteristic of compartment syndrome may cause a rapidly worsening neurological deficit necessitating emergency fasciotomy.
The necessity for peripheral nerve surgery depends on several key factors, including the nature of the injury, the
On the other hand, a blunt nerve laceration with a ragged epineurium (e.g., from a propeller blade) should be formally repaired at a later stage when it is easier to judge
MRI neurography is still a developing field, As the technique is perfected and experience grows, it will become a standard part of the evaluation of nerve injury,
PERIPHERAL NERVE TRAUMA
1191
FIGURE 56D.5 MRl in nerve injury. (A) A scarred suture repair site after a laceration injury to the peroneal nerve was repaired using two sural nerve grafts (double white arrows). (B) High signal (T2-weighted) both at [small arrow) and distal to (large arrowhead) the scarred suture repair site 6 months after the original injury and suture repair but before the graft repair. (C) incomplete resolution of high signal seen several months after graft repair. Patient showing signs of clinical improvement. (D) 16 months later, the patient has made significant recovery. Almost complete resolution of high signal from the distal nerve segment (large arrowhead). High signal remains at the graft repair site (arrow). (Reproduced with permission from Grant, G. A., Britz, G. W., Goodkin, R., et a I. 2002, "The utility of magnetic resonance imaging in evaluating peripheral nerve disorders," Muscle Nerve, vol. 25, no. 3, pp. 314-331, Figure 10, p. 327. Wiley Periodicals, Inc., 2002.)
1192
NEUROLOGICAL DISEASES
the true extent of the injury. For example, there may be a long segment of in-continuity injury proximal and distal to the transection or other areas of compression or axonotmesis at distant sites. One must also account for injury to vascular structures, bone, and soft tissues in the wound site. In such situations, it is prudent to delay formal nerve repair for at least 2 weeks. At the initial surgical debridement of the wound, the surgeon tacks the proximal and distal nerve stumps to local healthy fascial and muscular tissue and later reinspects the wound at a time when wallerian degeneration has occutred, the stumps have retracted, and easily detectable neuromas have formed. This is called a delayed primary repair. Most nerve injuries occur in closed wounds and thetefore are more difficult to judge. One must pay close attention to clinical or EDX signs of recovery during serial evaluation; one should follow the patient for 2-3 months in the case of a suspected focal lesion and 4-5 months for a suspected lengthy lesion. Failure to progtess usually indicates a mote severe injury that warrants surgical inspection (Spinner and Kline 2000). In general, surgical repair of nerve trauma is needed for most grade IV and all grade V injuries.
Surgical Procedures Great advances in peripheral nerve surgery have been made since the introduction and refinement of microsurgical techniques in the last half century. A detailed account of peripheral nerve surgery is beyond the scope of this chapter, but the basic techniques that are currently used in most specialized centers are outlined in the following sections. Neurolysis (External and Internal) The presence of scar tissue either around or within the nerve can significantly impede regeneration. Therefore one of the most important ptocedures is debridement of the wound, isolation of the nerve injury site, and mobilization of vascular and connective tissues above and below the nerve injury. This external neurolysis frees the nerve from surrounding scar tissue and may be sufficient to manage incontinuity lesions with recordable NAPs. Incomplete lesions may include scat tissue that involves the cpifascicular epineurium or the interfascicular epineurium. Internal neurolysis entails surgically freeing the nerve trunk or fascicles from such scar tissues using the surgical microscope. If the epifascicular epineurium is the only site of scat formation, a longitudinal incision called an epineurotomy may be sufficient. However, interfascicular scars may necessitate more intricate separation of involved from uninvolved nerve fascicles. The latter procedure usually is performed as part of the preparation for nerve graft repairs during which NAPs are used to identify damaged nerve fascicles. Review of outcomes after neurolysis of in-continuity radial and median nerve injuries at a
major nerve trauma center showed good motor functional recovery in 9 8 % and 95% of cases, respectively, Primary
Neurorrhaphy
Primary repair (primary neurorrhaphy) of a neurotmesis lesion involves the direct suturing of the proximal to the distal stump and is the procedure of choice. If the parent nerve trunk contains few fascicles that are easy to align, an epineurial repair often is the preferred option. Consequently, this kind of repair usually is carried out on the distal segments of smaller nerves in the distal upper and lower extremity (e.g., digital nerves). Sutures are placed through the epineurium of the proximal and distal stumps, which ate then tightened into approximation without causing undue tension on the newly repaired nerve. Local landmarks, such as the orientation of blood vessels, are used to ensure the correct alignment of the nerve endings. As mentioned previously, the proximal portions of larger nerves may have a complex intetlaced fascicular pattern (Sunderland's plexus), making it difficult to align transected whole nerve endings. If one were to carry out a whole nerve coaption and fail to pay attention to the fascicular pattern, a predominantly motor fascicle in the proximal stump could come into contact with a predominantly sensory fascicle in the distal stump, which would result in an unsatisfactoty functional outcome. In fascicular repair, the preferred technique in such proximal extremity nerve injuries, the surgeon coapts the proximal and distal ends of individual fascicles rather than the entire nerve trunk. Sutures are placed through the fascicular perineurium (Figure 56D.6). Histochemical staining of stumps, local landmark orientation, and intraoperative NAPs help the surgeon to choose the correct fascicular stumps. Overall, good functional outcome is seen in about 7 0 % of primary neurorrhaphies, but results vary. In one major nerve trauma center, good functional outcome was observed in 9 1 % of radial and 8 6 % of median nerve injuries repaired by primary neurorrhaphy.
Nerve Grafts If there is a significant gap between the proximal and distal stump, as in a sevete neurotmesis lesion from a highvelocity gunshot, it may not be possible to perform primary neurorrhaphy because excessive tension will be placed on the nerve. This will increase intraneural pressure to the point at which blood flow is compromised. Excessive stretch leads to scat formation, especially when there is passive stretch across bony protuberances and joints. In Mich situations, nerve grafting is the preferred choice. This entails suturing a piece ot nerve harvested from elsewhere between the proximal and distal stumps of the injured nerve. In most centers, an autologous nerve graft is used
PERIPHERAL NERVE TRAUMA
1193
FIGURE 56D.6 Basic techniques in surgical repair. Schematic diagram illustrating the basic concepts of epineurial, fascicular, and graft repair. Direct end-to-end neurorrhaphy of small distal nerves usually is carried out using an epineurial repair approach (top), which entails placing sutures through the epifascicular cpincurium and bringing the nerve stumps into approximation. Fascicular repair (top) is preferred for more proximal nerves that have a more complex interlaced fascicular pattern. Stumps are approximated using sutures that have been placed through the perineurium. Graft repairs {bottom) are performed when direct end-to-end neurorrhaphy would cause excessive tension on the repair site. The graft material is harvesred from a nonessential sensory nerve (e.g., the sural nerve), which is then sutured between fascicles. (i.e., a healthy segment of nerve is removed from the patient's body and sutured between the stumps at the trauma site; Millesi 1998). In general, these grafts are sutured via a fascicular rather than an epineurial approach (see Figure 56D.6). Common donor nerves are those that are nonessential and largely sensory in function such as the sural nerve, lateral antebrachial cutaneous nerve, and lateral tumoral cutaneous nerve. It is important to counsel the patient that once such a nerve is sacrificed, there will be an area of permanent sensory loss in the sensory distribution of the donor nerve. The success rate of nerve grafting varies, but a satisfactory functional outcome occurs in about 5 0 % of cases. Results vary depending on the experience and skill of the nerve trauma team and the particular nerve involved. For example, good functional recovery of motor function was observed in 6 8 - 7 5 % of median and 80% of radial nerve injuries that were repaired by nerve grafting at one major nerve trauma center. Retrospective review of functional outcomes after repair of sciatic nerve injuries at the same center reported good outcomes after repair of tibial but not peroneal (6%) division injuries. A number of factors influence whether successful functional regeneration takes place after graft repair, such as the distance between the proximal and distal stump and the type of
nerve graft or conduit used. However, a recent primate study showed that the single most important prognostic factor is the time interval between the nerve injury and reinnervation of the target motor or sensory organ. The authors of this study postulate that there may be a timedependent degeneration of Schwann cells in the bands of Biingner together with fragmentation of the basal lamina in the distal nerve. In addition, the neuron proximal to the injury site may also lose some of its ability to support axon regeneration. They suggest that, at least in nonhuman primates, the optimum time to successful reinnervation of the target organ using nerve grafts occurs within 100 days of sustaining the nerve lesion (Krarup, Archibald, and Madison 2002). In general, a better outcome is seen in younger, healthier patients. Regeneration is better across shorter nerve grafts. Pure motor and pure sensory nerves recover more satisfactotily than mixed nerves.
Nerve Transfers Avulsion injuries create a special problem in nerve repair because there is often no proximal stump with which an anastomosis may be made to a distal stump or an
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NEUROLOGICAL DISEASES
intervening nerve graft. A specialized nerve transfer technique, also called neurotization, has been developed to improve the outcome of these functionally debilitating injuries. Neurotizations in the upper extremity usually are performed to provide shoulder abduction, elbow flexion, and hand sensation. The technique entails the transfer of the prn\im;i] stump of .1 healthy donor nerve to the distal stump of an injured (transected) nerve so that a target muscle of particular functional or mechanical importance becomes reinnervated. An example is the transfer of the spinal accessory nerve to the distal stump of the injured musculocutaneous nerve in a case of proximal upper extremity nerve root avulsion; the patient gains useful elhow flexion in the process. Other axon donor nerves depend on the exact injury and include the phrenic nerve, the suprascapular nerve, the thoracodorsal nerve, the medial pectoral nerve, and an intercostal nerve. Some common axon recipients include the musculocutaneous nerve, the suprascapular nerve, and the axillary nerve. Certain researchers have assessed the feasibility of direct reimplantation of avulsed nerve roots back into the spinal cord, with mixed results. Although some patients regain useful function of proximal limb muscles, more distal hand muscles are not successfully reinnervated, and there is a risk of causing operative injury to spinothalamic tracts within the spinal curd. A similar problem also arises when the very terminal segments of a nerve have lost contact with the target organ, thus failing to leave a distal stump for reanastomosis. Although it is performed in highly specialized centers, a technique has been developed in which the distal nerve stump is split into fascicles, which are then implanted directly into the endplate region of the target muscle belly. One may even transfer an entire muscle together with its blood and nerve supply to the site of a functionally more important muscle that is nonfunctioning through prior injury. For example, a chronically denervated and degenerated biceps muscle in the upper extremity may be replaced by a neurotized and vascularized gracilis muscle that has been harvested from the lower extremity.
OTHER ASPECTS OF NERVE INJURY MANAGEMENT Patients often complain of pain in the distribution of an affected nerve, which may be deep-seated, burning, stabbing, or ice cold in nature. Such pain may be caused by persistent distortion, compression, or ischemia of the nerve and may also represent a subtype of complex regional pain syndrome (type I or II) or post-traumatic neuralgia or in others may be psychological in origin. Some patients also complain of pain for secondary gain, which may or may not be apparent in the history. For many patients it is the most significant symptom of their injury and affects all aspects of daily living. The most severe pain syndrome is seen after
avulsion of preganglionic posterior nerve roots and is very difficult to treat. A number of pharmacological and surgical procedures may assist these patients. Some of the mote commonly prescribed agents include amitriptyline, carbamazepine, mexiletinc, gabapentin, clonazepam, opioids, and topiramate. Coagulation of the dorsal root entry zones (the DREZ procedure) may be useful in managing the deafferentation pain of nerve root avulsion. Novel drugs are under development to improve pain, including modulators of sodium channels, modulators of nicotinic acetylcholine receptors, and N-type voltage-sensitive calcium channel blockers. Physical and occupational therapy are integral parts of nerve injury management for both surgical and nonsurgical patients. It is imperative that range of motion exercises be instituted early after an injury to prevent joint contractures and muscle wasting, This form of therapy may also stimulate and enhance sensory and motor relearning in cerebral cortex. It is best to allow a brief interlude after a surgical nerve repair to allow wound healing and revascularization before performing full physical therapy, but passive movements may be instituted early. A range of specialized assist devices and splints are available to ensure adequate functional positioning of a weak limb. It is preferable to custom fit these lightweight devices so that agonist muscles are not overstretched and antagonists arc not excessively shortened.
FUTURE DIRECTIONS Although the gold standard in nerve gap management is the autologous nerve graft, there are some disadvantages to its use. As already mentioned, the technique requires that a perfectly functioning nerve from elsewhere be sacrificed to repair the injured nerve. This may present a significant problem if multiple nerve trauma occurs or the gap between stumps is very great. Furthermore, nerve regeneration across the graft may not be as effective as across a direct end-to-end repair; the regenerating axon must make its way across two suture lines and the intervening graft tissue before making contact with the distal stump. The intrafascicular pattern may be very different between the nerve and graft stumps, and although the graft is from the same patient, it may not produce as much tropic and trophic support as local nerve tissue. The more suture lines present, the greater the chance of in situ neuroma formation, and in cases of severe multiple trauma there is the possibility of an inadequately vascularized graft bed. One approach may be to use human cadaveric nerve grafts (allografts) rather than autologous nerve grafts, which would obviate the sacrifice of perfectly healthy nerves from the patient to treat a damaged nerve and would also provide a more plentiful supply in the event that multiple grafts are needed. However, this foreign material triggers graft rejection, which necessitates the administration of potent immunosuppressive therapy.
PERIPHERAL NERVE TRAUMA For these reasons, there have been moves to develop alternative conduits to bridge the gap between separated nerve stumps. Much of this research has been carried out in animal models using many absorbable and nonabsorbable synthetic, semisynthetic, and biological devices, including collagen, epincurium, mesothelium, muscle, vein, glycolide trimethylene carbonate, silicone, poly-3-hydroxybutyrate, and poly-L-lactic acid. Although the results have been variable, most such devices have not been quite as effective as autologous grafts; nevertheless, they hold promise for the future. A recenr randomized prospective trial in humans showed favorable results using polyglycolic acid conduits for repair of digital nerves. Superior functional sensory outcome was observed when conduits were used to repair gaps of 4 mm or less compared with primary neurorrhaphy, and superior results occurred when conduits were used to repair gaps of 8 mm or more compared with autologous nerve grafts. A number of ingenious modifications have been used to improve the effectiveness of conduits, the most widely reported of which is to seed the lumen of the entubulation device with a monolayer or scaffold of Schwann cells. Research in cell cultures and animals indicates that these seeded grafts may approach autologous graft levels in their ability to support nerve regeneration. Another experimental approach is to seed synthetic conduits not with whole cells but with molecules, such as neurotrophic factors, that are known to promote regrowth of axons. For example, nerve growth factor has been studied extensively in the treatment of peripheral neuropathy. It is selectively trophic for small-caliber, unmyelinated sensory and autonomic (sympathetic) nerve fibers, and reduced levels may play a significant part in the pathogenesis of small fiber sensory neuropathy. Several trials have already been undertaken to assess the potential effect of subcutaneous recombinant human nerve growth factor in the management of diabetic and HIVrclated small fiber polyneuropathies, but despite promising early results a placebo-controlled phase III trial did not show any clear benefit in the treatment of diabetic neuropathy. However, when one considers this in the context of nerve trauma repair, the delivery of neurotrophic factors via a local matrix bypasses many of the problems of systemic administration and also ensures a steady local concentration of agent along the course of the conduit. There is additional early evidence that vascularizing synthetic conduits containing vascular endothelial growth factor may also improve target organ reinnervation. As further inroads arc made into the understanding of the molecular basis of nerve injury and regeneration, it is likely that other novel drug treatments will be evaluated in human trials to maximize functional recovery in both surgical and nonsurgical settings. Such agents may include modulators of cell signaling, cell adhesion, or inflammation and immunosuppressant drugs such as cyclosporine and
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rapamycin that also promote axon regeneration. Nonpharmacological strategies may also be of benefit. For example, it has been shown in an animal model of nerve injury that it may be possible to rescue muscles from denervation-induccd degeneration by transplanting embryonic anterior spinal cord cells into peripheral nerve. Furthermore, there is some evidence that continuous electrical stimulation using an implantable device may improve functional outcome after nerve injury. A gene therapy approach may be used to deliver neurotrophic and other substances to target tissue, bypassing the problems encountered by systemic administration, such as low bioavailability, short half-life, and frequent side effects caused by high dosage needs. Several groups have reported beneficial effects in animal models of nerve root avulsion using viral vectors to deliver the coding sequences of adhesion molecules, antiapoptotic proteins, and neurotrophic factors to both glial and neuronal cells in the dorsal and ventral horns of the spinal cord. Other advances undoubtedly will include detailed studies on brain plasticity after nerve injury and how this might be enhanced by various stimulation techniques to improve functional outcome. Magnetoencephalography is an exciting new technique that may prove invaluable in the finely detailed mapping of cortical responses to peripheral nerve injury.
REFERENCES Clark, W. L.,Trumble,T. E.,Swiontkowski, M. F., & Tencer, A. F. 1992, "Nerve tension and blood flow in a rat model of immediate and delayed repairs," / Hand Surg, vol. 17, no, 4, pp. 677-687 Kline, D. G. 2000, "Nerve surgery as it is now and as it may be," Neurosurgery, vol. 46, no. 6, pp. 1285-1293 Krarup, C, Archibald, S. J., & Madison, R. D. 2002, "Factors that influence peripheral nerve regeneration: An electrophysiological study of the monkey median nerve," Ann Neurol, vol. 51, pp. 69-81 Millesi, H. 1998, "Nerve grafts: Indications, techniques, and prognoses," in Management of Peripheral Nerve Problems, eds G. E. Omcr, M. Spinner, & A. L. van Beek, WFS Saunders, Philadelphia, pp. 280-290 Murray, B. & Wilbourn, A. J. 2002, "Brachial plexus," Arch Neurol, vol 59, pp. 1186-1188 Nguyen, Q. T., Sanes, J. R., & Lichtman, J. W. 2002, "Preexisting pathways promote precise projection patterns," Nat Neurosci, vol. 5, no. 9, pp. 861-867 Noble, J., Munro, C. A., Prasad, V. S. S. V., & Midha, R. 1998, "Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries," / Trauma, vol. 45, pp. 1 16-122 Scddon, H. J. 1942, "A classification of nerve injuries," BMj, August 29, pp. 237-239 Spinner, R. J. & Kline, D. G. 2000, "Surgery for peripheral nerve and brachial plexus injuries or other nerve lesions," Muscle Nerve, vol. 23, pp. 680-695 Wilbourn, A. J. W. 1998, "Iatrogenic nerve injuries," Neurol Clin N Am, vol. 16, no. I, pp. 55-82
Chapter 57 Vascular Diseases of the Nervous System A. ISCHEMIC CEREBROVASCULAR DISEASE Jose Biller and Betsy B. Love Epidemiology and Risk Factors 1197 Pathophysiology of Cerebral Ischemia 1201 Pathology of Ischemic Stroke 1201 Clinical Syndromes of Cerebral Ischemia 1202 Transient Ischemic Attacks 1202 Carotid Artery System Syndromes 1203 Lacunar Syndromes 1205 Vertebrobasilar System Syndromes 1205 Syndromes of Thalamic Infarction 1208 Watershed Ischemic Syndromes 1209 Diagnosis and Treatment of Threatened Ischemic Stroke 1209 Large Artery Athcrothromboric Infarctions 1209 Small Vessel or Penetrating Artery Disease 1210 Cardiogenic Embolism 1211 Nonarherosclerotic Vasculopathies 1214 Inherired and Miscellaneous Disorders 1223
Hypercoagulable Disorders Primary Hypercoagulable Srates Secondary Hypercoagulable States Infarcts of Undetermined Cause Essential investigations for Patients with Threatened Strokes Preventing Stroke Recurrence: Medical Therapy Platelet Antiaggregants Oral Anticoagulants Trcarment of Acute Ischemic Stroke Thrombolytic Therapy Defibrinogenating Agents Neuroprotective Agents Surgical Therapy General Management of Acute Ischemic Stroke Cerebral Venous Thrombosis
EPIDEMIOLOGY AND RISK FACTORS
A number of factors that may be classified as modifiable and unmodifiablc increase the risk of ischemic stroke (Table 57A.1). Risk factors for stroke include older age, male gender, black ethnicity, low socioeconomic status, family history, arterial hypertension, diabetes mellitus, dyslipidemia, heart disease, cigarette smoking, excessive alcohol intake, and body mass index. Clinicians cannot assume that these risk factors express themselves exclusively by accelerating atherosclerosis. There are also considerable data implicating hemostatic and microcirculatory disorders in stroke as well as circadian and environmental factors.
Every year, at least 750,000 Americans experience a new or recurrent stroke. Despite gradual declines in overall stroke death rates in many industrialized countries, stroke remains the third leading cause of death, with 160,000 strokerelated fatalities annually in the United States. Stroke is also the leading cause of disability in adults. Of the hundreds of thousands of stroke survivors each year, approximately 3 0 % require assistance with activities of daily living, 2 0 % require assistance with ambulation, and 1 6 % require institutional care. The human and financial costs of stroke are immense, and its estimated annual economic impact on our society, both directly in health care and indirectly in lost income, is approximately $41 billion. Steep decreases in stroke incidence and mortality have occurred in industrialized nations in recent years. The reduction in stroke mortality in the United States has been attributed to a declining stroke incidence, with suggestive evidence favoring a trend in declining stroke severity. Despite these trends in developed countries, stroke mortality and incidence are still high in many other countries. Socioeconomic factors, dietary and lifestyle behaviors, different patterns of risk factors, and environmental conditions may explain the different incidences of stroke observed in different parts of the world.
1226 1226 I221-1 1232 1232 1234 1234 1236 1236 1237 1238 1239 1240 1242 1243
The incidence of stroke increases dramatically with advancing age, and increasing age is the most powerful risk factor for stroke. The incidence of stroke doubles each decade past 55 years of age. Half of all srrokes occur in people older than 70 to 75 years. Men develop ischemic strokes at higher rates than women up to the age of 75 years. With an estimated 2 0 % of the population being older than age 65, and with greater than 10 million octogenarians, and an increasing life expectancy in the United States, it is predicted that in the near future, the incidence of stroke will reach 1 million per year. The rate of cerebral infarction is higher in blacks than in whites; this could be partially explained by the higher prevalence of diabetes and arterial hypertension experienced by blacks. 1197
1198
NFUROT.OGICAl. DTSF.ASFS
Table 57A.1:
Risk factors for ischemic stroke
Nonmodifiable
Modifiable
Age Gender Race/ethnicity Family history Genetics
Arterial hypertension i'r.siiMrnl ischemic ;imicks Prior stroke Asymptomatic carotid hruit/sluisusis Cardiac disease Aortic arch atheromatosis Diabetes mellitus Dyslipidemia Cigarette smoking Alcohol consumption Increased fibrinogen Elevated homocyst(e)ine Low serum folate Elevated anticardiolipin antibodies Oral contraceptive use Obesity
Blacks also have higher rates of intracranial atherosclerotic occlusive disease, compared with whites (Sacco et al. 1995). The stroke incidence and case fatality rates are also markedly different among the major ethnic groups in Auckland, New Zealand. Maori and Pacific Islands people have a higher mortality within 28 days of stroke when compared with Europeans, especially men (Bonita ct al. 1997}. Heredity seems to play a minor role in the pathogenesis of cerebral infarction. However, an increased risk is seen with a family history of stroke among first-degree relatives. There are also a number of genetic causes of stroke. Some inherited diseases, such as the hereditary dyslipoproteinemias, predispose to accelerated atherosclerosis. A number of inherited diseases ate associated with nonatherosclerotic vasculopathies, including Ehlcrs-Danlos (especially type IV) syndrome, Marfan's syndrome, Rendu-Osler-Weber disease, and Sturgc-Wcbcr syndrome. Familial atrial myxomas, hereditary cardiomyopathies, and hereditary cardiac conduction disorders are examples of inherited cardiac disorders that predispose to stroke. Deficiencies of protein C and S or antithrombin (AT) III are examples of inherited hematological abnormalities that can cause stroke. Finally, rare inherited metabolic disorders that can cause stroke include mitochondrial encephalopathy, /actic acidosis, and stroke-like episodes (MELAS), Fabry's disease, and homocysrinuria. Controversial evidence shows that the presence of the apolipoprotein K2 allele in elderly individuals and deletion of the gene for the angiotensinconverting enzyme may increase the risk of stroke (Slooter et al. 1997). At least 2 5 % of the adult population has arterial hypertension, defined as systolic blood pressure (SBP) greater than 140 mm Hg, or diastolic blood pressure (DBP) greater than 90 mm Hg. High notmal blood pressure is defined as SBP between 130-139 mm Hg or DBP
between 85-89 mm Hg; normal blood press Lire as SBP less than 130 mm Hg and DBP less than 85 mm Hg, and optimal blood pressure as SBP less than 120 mm Hg, and DBP less than 80 mm Hg (National Institutes of Health |NIH| 1997), Arterial hypertension predisposes to ischemic stroke by aggravating atherosclerosis and accelerating heart disease, increasing the relative risk of stroke three- to fourfold. The risk is greater for patients with isolated systolic hypertension and elevated pulse pressure. Arterial hypertension is also the most important modifiable risk factor for stroke and the most powerful risk factor for all forms of vascular dementia. Lowering blood pressure in stroke survivors helps prevent recurrent stroke and is more important than the specific hypotensive agent used. Blood pressure treatment, resulting in a reduction in SBP of 10-12 mm Hg and 5-6 mm Hg diastolic, is associated with a 3 8 % reduction in stroke incidence (MacMahon et al. 1996). Treatment of isolated systolic hypertension in the elderly is also effective in reducing stroke risk. The Systolic Hypertension in the Elderly Program showed a 3 6 % reduction in nonfatal plus fatal stroke over 5 years in the age 60 and older group when isolated systolic hypertension was treated. Treating systolic hypertension also slows the progression of carotid artery stenosis. The PROGRESS Trial evaluated the effects of perindopril and indapamide on the risk of stroke in patients with histories of stroke or transient ischemic attack (TIA). Regardless of blood pressure at entry, patients clearly benefitted from treatment (PROGRESS Collaborative Group 2001). Six million Americans have diabetes mellitus, and there are at least 5 million more people in which it is undiagnosed. Diabetes mellitus increases the risk of ischemic cerebrovascular disease two- to fourfold compared with the risk in people without diabetes. In addition, diabetes mellitus increases morbidity and mortality after stroke. Macrovascular disease is the leading cause of death among patients with diabetes mellitus. The mechanisms of stroke secondary to diabetes may be caused by cerebrovascular atherosclerosis, cardiac embolism, or rheological abnormalities. The excess stroke risk is independent of age or blood pressure status. Diabetes associated with arterial hypertension adds significantly to stroke risk. There is a fourfold increase in the relative risk of cardiovascular event among patients with diabetes and hypertension than among those without the two conditions (Hypertension in Diabetes Study [HDS] 1993). Diabetic persons with retinopathy and autonomic neuropathy appear to be a group at particularly high risk for ischemic stroke. High insulin levels increase the risk for atherosclerosis and may represent a pathogenetic factor in cerebral small vessel disease. However, presently no evidence exists that tighter diabetic control or normal HbA u . levels over time decrease the risk of stroke or stroke recurrence. High total cholesterol and high low-density lipoprotein (LDL) concentration are correlated with atherosclerosis. Although overwhelming evidence relates low levels of
ISCHEMIC CEREBROVASCULAR DISEASE
high-density lipoprotein (HDL) cholesterol with coronary heart disease, the association with cerebrovascular disease is less clear. Some studies have shown a positive relationship between serum cholesterol levels and death resulting from nonhemorrhagic stroke. The relationship has not been consistent, however, possibly because different risks are associated with different lipoprotein subtypes. Lipidmodifying therapy with 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitors (statins) have definitively established that reduction of LDL cholesterol reduces cardiovascular risk. Statins appear likely to benefit stroke survivors as well. The frequency of hemorrhagic strokes is not increased by the use of statins. Lipid-lowcring agents may slow progression of atherosclerotic plaque growth and may possibly cause a regression in plaque formation. The Scandinavian Simvastatin Survival Study (4S) (Scandinavian Simvastatin Survival Study Group 1999} investigated cholesterol lowering in persons with coronary heart disease and hypercholesterolemia and reported a highly significant relative reduction in the total mortality rate, major coronary events, and number of cardiac revascularization procedures. Post hoc analysis also showed a 2 8 % reduction in fatal or nonfatal stroke and TIAs (Pedersen et al. 1998). The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study investigated cholesterol lowering with pravastatin in patients with a previous myocardial infarction or unstable angina who had cholesterol levels between 155 and 271 mg/dL, and reported a remarkable reduction in myocardial infarction, cardiac tevascularizations, and cardiovascular deaths, as well as a 2 0 % reduction in the risk of stroke (The Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID] Study Group 1998). An estimated 1 to 2 million Americans have chronic nonvalvular atrial fibrillation (NVAF), a condition that is associated with an overall risk of stroke of approximately five to sixfold, and a mortality of approximately twice that of age- and sex-matched individuals without atrial fibrillation. The prevalence of atrial fibrillation increases with advancing age and is 0.5% for patients aged 50 to 59 years and 8.8% for those aged 80 to 89 years (Wolf et al. 1991). Approximately 7 0 % of individuals with atrial fibrillation are between 65 and 85 years of age. NVAF is associated with a substantial risk of stroke. Heart failure, arterial hypertension, diabetes, prior stroke or TIA, and age older than 75 years increase the risk of embolism in patients with NVAF. High-risk patients have a 5 - 7 % yearly risk of thromboembolism. The use of warfarin therapy with the international normalized ratio (INR) adjusted to between 2.0 to 3.0 decreases the relative risk of stroke in patients with NVAF by approximately two thirds. Left atrial enlargement increases the risk of stroke in men. Likewise, left ventricular hypertrophy as demonstrated by electrocardiography (KCG) in men with pre-existing ischemic heart disease is a major risk factor for stroke.
1199
Smoking is the leading cause of preventable death in the United States. Cigarette smoking is a major risk factor for coronary artery disease, stroke, and peripheral arterial disease. Cigarette smoking is an independent risk factor for ischemic stroke in men and women of all ages, and a leading risk factor of carotid atherosclerosis in men. The risk of stroke in smokers is two to three times greater than in nonsmokers. The mechanisms of enhanced atherogenesis promoted by cigarette smoking are incompletely understood, but include reduced capacity of the blood to deliver oxygen, cardiac arrhythmias, and triggering of arterial thrombosis and arterial spasm. More than 5 years may be required before a reduction in stroke risk is observed aftet cessation of smoking. Switching to pipe or cigar smoking is of no benefit. Nicotine replacement therapy and bupropion are efficacious smoking cessation treatments. There is a J-shaped association between alcohol consumption and ischemic stroke; light to moderate use (up to two drinks a day) evenly distributed throughout the week offers a reduced risk, whereas heavy drinking is associated with an increased risk of total stroke. Heavy drinking may precipitate cardiogenic brain embolism. Alcohol consumption increases the risk of hemorrhagic stroke; alcohol-induced hypertension predisposes to spontaneous intracranial hemorrhage. Furthermore, active drinkers have a higher frequency of obstructive apneas and more severe hypoxemia. Conversely, moderate alcohol consumption may reduce the risk of ischemic stroke and may elevate HDL concentration. The prevalence of obesity (body mass index of 30 or higher) has increased nationwide. More than 6 1 % of adult Americans are overweight, and 2 7 % are obese. Obesity, particularly abdominal or truncal, is an important risk factor for cardiovascular disease in men and women of all ages. There is some evidence that physical activity can teduce the risk of stroke. Regular exercise lowers blood pressure, decreases insulin resistance, increases HDL cholesterol, and is associated with lower cardiovascular morbidity and mortality. Habitual snoring increases the risk of stroke and adversely affects outcome of patients admitted to the hospital with stroke. Mounting evidence also suggests that inflammation, impaired fibrinolysis, and increased thrombotic potential are important nontraditional cardiovascular risk factors. Atherosclerotic lesions of the carotid bifurcation are a common cause of stroke. Asymptomatic carotid disease carries a greater risk of vascular death from coronary artery disease than from stroke. Persons with an asymptomatic carotid bruit have an estimated annual risk of stroke of 1.5% at 1 year and 7.5% at 5 years. Asymptomatic carotid artery stenosis less than 7 5 % carries a stroke risk of 1.3% annually; with stenosis greater than 7 5 % , the combined TIA and stroke rate is 10.5% per year, with most events occurring ipsilatcral to the stenosed carotid artery. Plaque composition may be an important factor in the pathophysiology of carotid artery disease. Plaque structure rather
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NEUROLOGICAL DISEASES
than degree of carotid artery stenosis may be a critical factor in determining stroke risk. Ultrasonographic carotid artery plaque morphology may identify a subgroup of patients at high risk of stroke. Ulcerated, echoluccnt, and heterogeneous plaques with a soft core represent unstable plaques at high risk for producing arterioarterial embolism. Patients who suffer TIAs are at greater risk than normal controls for stroke or death from vascular causes. The risk of stroke is approximately three times higher. Symptomatic carotid artery stenosis greater than 7 0 % carries an annual risk of stroke of approximately 15%. Approximately 1 0 15% of those experiencing a stroke have TIAs before theit stroke. Patients with hemispheric TIAs arc at greater risk of ipsilatctal stroke than patients with tetinal TIAs. Patients with a first stroke arc at greater risk of recurrent stroke, especially, but not exclusively, early aftet the first stroke. Those who suffer a recurrent stroke have a higher mortality than patients with first stroke. If the recurrence is contralateral to the first stroke, prognosis for functional recovery is poor. The risk of stroke recurrence is increased also by the presence of underlying dementia. The aorta is the most frequent site of atherosclerosis. Protruding atheroma may be the cause of otherwise unexplained TIAs ot strokes. Aortic arch atheromatosis detected by transesophageal echocardiography is an independent risk factor for cerebral ischemia; the association is particularly strong with mobile and thick atherosclerotic plaques measuring greater than or equal to 4 mm in thickness (The French Study of Aortic Plaques in Stroke Group 1996). Hemostatic factors may be important in assessing the risk of cerebrovascular disease. Elevated hematocrit, hemoglobin concentration, and increased blood viscosity may be indicators of risk for ischemic stroke. Elevation of plasma fibrinogen is an independent risk factor for the development of cerebral infarction. An elevated plasma fibrinogen level may reflect progression of atherogenesis. Plasminogen activator inhibitor-! excess and factor VII are independent risk factors for coronary heart disease. Compared with while Americans, black Americans have higher mean levels of fibrinogen, factor VIII, von Willebrand's factor, and AT, and lower mean levels of protein C. Fibrinogen levels are closely correlated with other stroke risk factors such as cigarette smoking, arterial hypertension, diabetes, obesity, hematocrit levels, and spontaneous echocardiographic contrast. Antiphospholipid (aPL) antibodies are a marker for an increased risk of thrombosis, including TIAs and stroke, particularly in those younger than 50 years of age. The factor V Leiden mutation is associated with deep venous thrombosis in otherwise healthy individuals with additional prothtombotic risk factors. An overall association of the factor V Leiden mutation and arterial thrombosis has not been found. Elevated von Willebrand's factor is a risk factor for myocardial infarction and ischemic stroke. Elevated levels
of fasting total homocysteine (normal 5-15 mmol/L), a sulfhydryl-containing amino acid, have been associated with an increased risk of stroke and thrombotic events in case-controlled studies. Metabolism of homocysteine requires vitamin B 6 (pyridoxine), vitamin Bi 2 (cobalamine), folate, and betaine. Plasma homocysteine concentrations may be reduced by folic acid alone or in combination with vitamin B 6 and vitamin B| 2 . Conversely, serum folate concentrations less than or equal to 9.2 nmol/liter have been associated with elevated plasma levels of homocyst e i n e , and a decreased folate concentration alone may be a risk factor for ischemic stroke, particularly among blacks (Giles et al. 1995). Stroke is uncommon among women of childbearing age. The relative risk of stroke is increased among users of high-dose estrogen oral contraceptives, particularly with coexistent arterial hypertension, cigarette smoking, and increasing age. New agents containing lower doses of estrogen and progestogen have reduced the frequency of oral contraceptive-related cerebral infarction. Two recent postmenopausal hormone replacement studies with equine estrogen (Premarin) showed no benefit in reducing the incidence of stroke in a cohort of women with coronary heart disease (Hulley et al. 1998; Herrington et al. 2000). In addition, the Women's Health Initiative, a prospective randomized trial of estrogen therapy in healthy postmenopausal women, was halted prematurely because the risks outweighed the benefits. Absolute excess risks per 10,000 person-years attributable to estrogen plus progestin were sevenfold for coronary heart disease events, eightfold for strokes, eightfold for pulmonary thromboembolisms, and eightfold for invasive cancers, whereas absolute risk reductions per 10,000 person-years were sixfold for colorectal cancers and fivefold for hip fractures (Writing Group for the Women's Health Initiative Investigators. 2002). The risk of thrombosis associated with pregnancy is high in the postpartum period. The risk of cerebral infarction is increased in the 6 weeks after delivery but not during pregnancy. A diurnal and seasonal variation of ischemic events occurs. Orcadian changes in physical activity, catecholamine levels, blood pressure, blood viscosity, platelet aggregability, blood coagulability, and fibrinolytic activity may explain the circadian variations in onset of myocardial and cerebral infarction. Although an early morning peak occurs for all subtypes of stroke, most clinical trials on the use of platelet antiaggregants or other antithrombotic agents do not take these circadian variations into account. Rhythmometric analyses support the notion that stroke is a chrono-risk disease, in which cold temperatures also represent a risk factor. A history of recent infection, particularly of bacterial origin and within 1 week of the event, is also a risk factor for ischemic stroke in patients of all ages. A number of recent reports suggest that Chlamydia pneumoniae, a causative organism of respiratory infections, has a role in carotid and coronary atherosclerosis. Some studies have also identified an association with chronic
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infections with Helicobacter pylori and cytomegalovirus (Ross 1999;Bittner 1998).
PATHOPHYSIOLOGY OF CEREBRAL ISCHEMIA Except for the lack of an external elastica lamina in the intracranial arteries, the morphological structure of the cerebral vessels is similar to those in other vascular beds. The arterial wall consists of three layers: the outer layer, or adventitia; the middle layer, or media; and the inner layer, or intima. The intima is a smooth monolayer of endothelial cells providing a nonthrombotic surface for blood flow. One of the major functions of the endothelium is active inhibition of coagulation and thrombosis. The brain microcirculation comprises the smallest components of the vascular system, including arterioles, capillaries, and venules. The arterioles are composed primarily of smooth muscle cells around the endothcliallincd lumen, and are the major sites of resistance to blood flow in the arterial tree. The capillary wall consists of a thin monolayer of endothelial cells. Nutrients and metabolites diffuse across the capillary bed. The venules are composed of endothelium and a fragile smooth muscle wall and function as collecting tubules. The cerebral microcirculation distributes blood to its target organ by regulating blood flow and distributing oxygen and glucose to the brain while removing by-products of metabolism. A cascade of complex biochemical events occurs seconds to minutes after cerebral ischemia. Cerebral ischemia is caused by reduced blood supply to the microcirculation. Ischemia causes impairment of brain energy metabolism, loss of aerobic glycolysis, intracellular accumulation of sodium and calcium ions, release of excitotoxic neurotransmitters, elevation of lactate levels with local acidosis, free radical production, cell swelling, overactivation of lipases and proteases, and cell death. Many neurons undergo apoptosis after focal brain ischemia (Choi 1996). Ischemic brain injury is exacerbated by leukocyte infiltration and development of brain edema. Exciting new treatments for stroke target these biochemical changes. Complete interruption of cerebral blood flow causes suppression of the electrical activity within 12-15 seconds, inhibition of synaptic excitability of cortical neurons after 2-4 minutes, and inhibition of electrical excitability after 46 minutes. Normal cerebral blood flow at rest in the normal adult brain is approximately 50-55 mL/100 g per mmute, and the cerebral metabolic rate of oxygen is 165 mmol/100 g per minute. There are certain ischemic flow thresholds in experimental focal brain ischemia. When blood flowdecreases to 18 mL/100 g per minute, the brain reaches a threshold for electrical failure. Although these neurons are not functioning normally, they do have the potential for recovery. The second level, known as the threshold of membrane failure, occurs when blood flow decreases to
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8 mIV100 g per minute. Cell death can result. These thresholds mark the upper and lower blood flow limits of the ischemic penumbra. The ischemic penumbra, or area of misery perfusion, is the area of the ischemic brain between these two flow thresholds in which there are some neurons that are functionally silent but structurally intact and potentially salvageable.
PATHOLOGY OF ISCHEMIC STROKE The pathological characteristics of ischemic stroke depend on the mechanism of stroke, the size of the obstructed artery, and the availability of collateral blood flow. There may be advanced changes of atherosclerosis visible within arteries. The surface of the brain in the area of infarction appears pale. With ischemia caused by hypotension or hemodynamic changes, the arterial border (or watershed) zones may be involved. A wedge-shaped area of infarction in the center of an arterial territory may result if there is occlusion of a main artery in the presence of collateral blood flow. In the absence of collateral blood flow, the entire territory supplied by an artery may be infarcted. With occlusion of a major artery, such as the internal carotid artery, there may be a multilobar infarction with surrounding edema. There may be evidence of flattening of the gyri and obliteration of the sulci caused by cerebral edema. A lacunar infarction, with a size of 1.5 cm or less, in subcortical areas or in the brainstem may be barely visible in the macroscopic analysis of the cut brain. Emboli to the brain tend to lodge at the junction between the cerebral cortex and the white matter. Early reperfusion of the infarct may occur when the clot lyses, leading to hemorrhagic transformation, The microscopic changes after cerebral infarction are well documented. The observed changes depend on the age of the infarction. The changes do not occur immediately and may be delayed up to 6 hours after the infarction. There is neuronal swelling initially, which is followed by shrinkage, hyperchromasia, and pyknosis. Chromatolysis appears and the nuclei become eccentric. Swelling and fragmentation of the astrocytes and endothelial swelling occur. Neutrophils infiltrate appear as early as 4 hours after the ischemia and become abundant by 36 hours. Within 48 bouts, the microglia proliferate and ingest the products of myelin breakdown and form foamy macrophages. Later, there is neovascularity with proliferation of capillaries and increased prominence of the existing capillaries. The elements in the area of necrosis are gradually reabsorbed and a cavity, consisting of glial and fibrovascalar elements, forms. In a large infarction, there are three distinct zones: an inner area of coagulativc necrosis; a middle zone of vacuolated neuropil, leukocytic infiltrates, swollen axons, and thickened capillaries; and an outer marginal zone of hyperplastic astrocytes and variable changes in nuclear staining.
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CLINICAL SYNDROMES OF CEREBRAL ISCHEMIA A number of syndromes result from ischemia involving the central nervous system (Brazis et al. 2001).
Transient Ischemic Attacks Approximately 8 0 % of ischemic strokes occur in the carorid (or anterior) circulation, and 2 0 % occur in the vertebrobasilar (or posterior) circulation. A TIA is a prognostic indicator of stroke, with one third of untreated TIA patients having a stroke within 5 years. The interval from the last TIA is an important predictor of stroke risk; of all patients who subsequently experience stroke, 2 1 % do so within 1 month and 5 1 % do so within 1 year of the last TIA. Cardiac events are the principal cause of death in patients who have had a TIA. The 5-6% annual mortality after TIA is mainly caused by myocardial infarction, similar to the 4% annual cardiac mortality in patients with stable angina pectoris. A TIA is a temporary, focal, and "nonmarching" neurological deficit of sudden onset; related to ischemia of the brain, retina, or cochlea; and lasting less than 24 hours. Yet most TIAs last only 5-20 minutes. Episodes that last longer than 1 hour are usually caused by small infarctions. The onset of symptoms is sudden, reaching maximum intensity almost immediately. To qualify as a TIA, the episode should be followed by complete recovery. TIAs involving the carotid circulation should be distinguished from those involving the vertebrobasilar circulation. Headache is a frequent symptom in patients with TIAs. The following symptoms are considered typical of TIAs in the carotid circulation: ipsilateral amaurosis fugax, contralateral sensory or motor dysfunction limited to one side of the body, aphasia, contralateral homonymous hemianopia, or any combination thereof. The following symptoms represent typical TIAs in the vertebrobasilar system: bilateral or shifting motor or sensory dysfunction, complete or partial loss of vision in the homonymous fields of both eyes, or any combination of these symptoms. Perioral numbness also occurs. Isolated diplopia, vertigo, dysarthria, and dysphagia should not be considered as being caused by a TIA, unless they occur in combination with one another, or with any of the othet symptoms just listed (Table 57A.2). Occlusive disease in the subclavian arteries or the innominate artery can give rise to extracranial steal syndromes. The most well-defined syndrome is rhe subclavian steal syndrome. In this syndrome, reversal of flow in the vertebral artery is caused by a high-grade subclavian artery stenosis or occlusion proximal to the origin of the vertebral artety from the aortic arch or innominate artery, with resultant symptoms of brainstem ischemia, usually precipitated by actively exercising the ipsilateral arm. The left side is involved most frequently. With innominate
Table S7A.2: Recognition of carotid and vertebrobasilar transient ischemic attacks Symptoms suggestive of carotid transient ischemic attacks Transient ipsilateral monocular blindness (amaurosis fugax) Contralateral body weakness or clumsiness Contralateral body sensory loss or paresthesias Aphasia with dominant hemisphere involvement Various degrees of contralateral homonymous visual field defects Dysarthria (not in isolation) Symptoms suggestive of vertebrobasilar transient ischemic attacks Usually bilateral weakness or clumsiness, but may he unilateral or shifting Bilateral, shitting, or crossed (ipsilateral face and con era lateral body) sensory loss or paresthesias Bilateral or contralateral homonymous visual field defects or binocular vision loss Two or more of the following symptoms: vertigo, diplopia, dysphagia, dysarthria, and ataxia Symptoms not acceptable as evidence of transient ischemic attack Syncope, dizziness, confusion, urinary or fecal incontinence, and generalized weakness Isolated occurrence of vertigo, diplopia, dysphagia, ataxia, tinnitus, amnesia, drop attacks, or dysarthria
artery occlusion, the origin of the right carotid is also subject to the consequences of reduced pressure. The subclavian steal syndrome can be suspected by the presence of a reduced or delayed radial pulse and diminished blood pressure in the affected arm relative to the contralateral arm. A subclavian steal may he symptomatic or asymptomatic. Many patients have angiographic evidence of reversed vertebral blood flow without ischemic symptoms. Transcranial Dopplcr sonography may detect transient retrograde basilar blood flow. Retrograde vertebral artery flow is a benign entity. Brainstem infarction is an uncommon complication of the subclavian steal syndrome. Transient global amnesia {TGA) is characterized by a reversible anregrade and retrograde memory loss, except for a total amnesia of events that occur during the attacks, and inability to learn newly acquired information. During the attacks, patients remain alert without motor or sensory impairments and often ask the same questions repeatedly. Patients are able to retain personal identity and carry on complex activities. TGA most commonly affects patients in their 50s and older. Men are affected more commonly than women. The attacks begin abruptly and without warning. A typical attack lasts several hours (mean, 3-6 hours) but seldom longer than 12 hours. Onset of TGA may follow physical exertion, sudden exposure to cold or heat, or sexual intercourse. Although a large number of conditions have been associated with transient episodes of amnesia, in most instances TGA is of primary or unknown cause. TGA has been documented in association with epilepsy, migraine, intracranial tumors, overdose of diazepam, cardiac arrhythmias secondary to digitalis intoxication, and as a complication of cerebral and coronary angiography. Many reports
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have suggested a vascular causal factor for this heterogeneous syndrome. Bilateral hippocampal and parahippocampal complex ischemia, possibly of migrainous origin, in the distribution of the posterior cerebral arteries is a potential mechanism. Acute confusional migraine in children and TGA have a number of similar features. Others have suggested an epileptic causal factor for a minority of patients. Transient amnesias have been divided into pure TGA, probable epileptic amnesia, and probable transient ischemic amnesia. In contrast to patients with TIAs, the prognosis of persons with pure TGA is benign, with no apparent increased risk for vascular endpoints. Recurrences are uncommon. Extensive evaluations are not required. Treatment with platelet antiaggregants is not indicated in most patients unless there is a suspicion for transient ischemic amnesia. The use of prophylactic calcium-channel blockers may be justified in patients with a potential migtainous causal factor.
Typically, these patients are refractoty to conventional forms of therapy (Donnan et al. 1993). Rational treatment of patients with TIAs depends on a careful history and derailed physical examination. The neurovascular examination may disclose a well-localized bruit in the mid- or upper-cervical area. Bruits arise when normal laminar blood flow is disturbed. However, the presence of a cervical bruit does not necessatily indicate undeilying carotid atherosclerosis. Correlation with angiography or ultrasound studies show only 6 0 % agreement with cervical auscultation in predicting the presence of arterial stenosis. Radiated cardiac murmurs, hyperdynamic states, nonathetosclerotic carotid arterial lesions, and venous hums can produce cervical murmurs. The absence of a bruit has little diagnostic value; the bruit may disappear when the stenosis is advanced. Convetsely, a cervical bruit may be heard contralateral to an internal carotid artery occlusion.
Drop attacks are charactetized by the sudden loss of muscle tone and strength. The attacks cause the patients to unexpectedly fall to the ground. Consciousness is preserved. Most attacks occut while standing or walking and often follow head or neck motion. Drop attacks have been considetcd a symptom of vertebrobasilar ischemia, but many of these patients have other coexistent disotdcts that could otherwise explain their symptoms. In rare instances, drop attacks may indeed be caused by ischemia of the corticospinal tract or reticular formation. However, isolated drop attacks are seldom a manifestation of vertebrobasilar occlusive disease. In most instances these attacks ate secondaty to akinetic seizures, high cervical spine or foramen magnum lesions, postural hypotension, Tumarkin's otolithic ctises (in Meniere's disease), or near syncope.
Different types of microemboli (e.g., cholesterol crystals, platelet fibrin, calcium, and so forth) can be seen in the retinal arterioles during or between attacks of transient monocular visual loss. Engorgement of conjunctival and episcleral vessels, conical edema and rubeosis irides, and anterior chamber cells flare arc indicative of an underlying ischemic oculopathy. Asymmetrical hypertensive retinal changes noted on funduscopy ate suggestive of a high-gtade carotid artery stenosis or occlusion on the side of the less severely involved retina. Venous stasis retinopathy may occut with high-grade carotid stenosis or occlusion and is characterized by diminished or absent venous pulsations, dilatated and tortuous retinal veins, peripheral microaneurysms, and blossom-shaped hemorrhages in the midperipheral retina. Corneal arcus senilis may be less obvious or absent on the side of low perfusion.
TIAs may result from atherothromboembolism that originates from ulcerated extracranial arteries, emboli of cardiac origin, occlusion of small penetrating arteries that arise from the large surface arteties of the circle of Willis, altered local blood flow (perfusion failure) caused by severe arterial stenosis, nonatherosclerotic vasculopathies, or hypercoagulable states. Pteceding TIAs occur in large numbers of patients with brain infarction. In published series of cases of stroke, TIAs occurred before 2 5 - 5 0 % of a the ro thrombotic infarcts, in 11-30% of cardiocmbolic infarcts, and in 11-14% of lacunar infarcts. Lacunar TIAs in general share the same pathogenetic mechanisms of lacunar infarcts and are associated with a substantially better prognosis than are nonlacunar TIAs. Crescendo episodes of cerebral ischemia that increase in frequency, severity, or duration may be most threatening. A small subset of ctcsccndo TIAs is the capsular warning syndrome, characterized by restricted stereotyped, repeated episodes of capsular ischemia, causing contralateral symptoms involving face, arm, and leg. When capsular infarction develops, it is usually a lacunar-type stroke and involves a single penetrating vessel. Occasionally, striatocapsular or anrcrior-choroidal artery territory infarction occurs.
Many conditions can tesemblc a TIA. Space-occupying lesions; subdural, intracerebral, or subarachnoid hemorrhage; seizures; hypoglycemia; migraine; syncope; and labyrinthine disorders are among the divctse conditions in the differential diagnosis when TIA is considered. Symptoms of a transient neurological dysfunction that resolve incompletely should lead the physician to question the diagnosis of TIA. Similarly, a migration or march of symptoms from one part of the body to another is rare during a TIA and more indicative of a focal seizure or migraine. Fortification phenomena or scintillating bright visual symptoms are suggestive of migraine. In rare instances, involuntary limb shaking movements can occur, but, in general, involuntary movements reflect convulsive activity rather than a TIA.
Carotid Artery System Syndromes Amaurosis fugax may he described as a sudden onset of a fog, haze, scum, curtain, shade, blur, cloud, or mist. A curtain or shade pattern with the loss of vision moving
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superiorly to interiorly is described only in 1 5 - 2 0 % of patients. Less commonly, a concentric vision loss, presumed to be caused by marginal perfusion, can diminish blood flow to the retina. The vision loss is sudden, often brief, and painless. The duration of vision loss is usually 1-5 minutes and rarely lasts more than .30 minutes. After an episode of amaurosis fugax, the vision is usually fully restored, although some patients may have permanent vision loss caused by a retinal infarction (see Chapters 14 and 15). The sole feature that distinguishes the middle cerebral artery (MCA) syndrome from the carotid artery syndrome is amaurosis fugax. An MCA infarction is one of the most common manifestations of cerebrovascular disease. The clinical picture with an MCA infarction is varied and depends on whether the site of the occlusion is in the stem, superior division, inferior division, or lenticulostriate branches, and whether there is good collateral blood flow. When the stem of the MCA is occluded, there is usually a large infarction with contralateral hemiplegia, conjugate eye deviation toward the side of the infarct, hemianesthesia, and homonymous hemianopia. Associated global aphasia occurs if the dominant hemisphere is involved and hemineglect with nondominant hemispheric lesions. The difference between an upper division MCA infarction and an MCA stem lesion is that the hemiparesis usually affects the face and arm more than the leg with upper division infarction. A Broca-type aphasia is more common in upper division infarcts because of the preferential involvement of the anterior branches of the upper division in occlusions. With lower division MCA syndromes, a Wernicke-type aphasia is seen with dominant hemisphere infarction and behavioral disturbances are seen with nondominant infarction. A homonymous hemianopia may be present. A lenticulostriate branch occlusion may cause a lacunar infarction with involvement of the inrernal capsule producing a syndrome of pure motor hemiparesis. These syndromes are variable and depend on the presence of collaterals or whether brain edema is present. Alexia with agraphia may occur with left-sided angular gyrus involvement. Gerstmann's syndrome, which consists of finger agnosia, acalculia, right-left disorientation, and agraphia, may be seen with dominant hemisphere parietal lesions. The aphasias with dominant hemispheric infarctions may be of the Broca, Wernicke, conduction, transcortical, or global type, depending on the site and extent of involvement. Anosognosia, the denial of hemiparesis, most commonly is associated with right hemispheric strokes. Nondominant infarction may cause hemi-inattention, tactile extinction, visual extinction, anosognosia, anosodiaphoria, apraxia, impaired prosody, and rarely acute confusion and agitated delirium. A contralateral homonymous hemianopia or contralateral inferior quadrantanopia can occur with infarctions in cither hemisphere. Anterior cerebral artery (ACA) territory infarctions are uncommon (Figure 57A.1). They occur in patients with vasospasm after subarachnoid hemorrhage caused by ACA
FIGURE 57 A.I N on enhanced axial computed tomographic scan of a 63-year-old man with left-sided weakness and abulia demonstrates a right anterior cerebral artery (ACA) territory infarction. More superior images showed the entire ACA distribution was in famed. or anterior communicating artery aneurysm. Excluding these causes, the percentage of acute cerebral infarcts that are in the ACA territory is less than 3 % . The characteristics of ACA infarction vary according to the site of involvement and the extent of collateral blood flow. Contralateral weakness involving primarily the lower extremity, and to a lesser extent, the arm, is characteristic of infarction in the territory of the hemispheric branches of the ACA. Other characteristics include abulia, akinetic mutism (with bilateral mesiofronral damage), impaired memory or emotional disturbances, transcortical motor aphasia (with dominant hemispheric lesions), deviation of the head and eyes toward the lesion, paratonia (gegenhaltcn), discriminative and proprioceptive sensory loss (primarily in the lower extremity), and sphincter incontinence. An anterior disconnection syndrome with left arm apraxia caused by involvement of the anterior corpus callosum can be seen. Pericallosal branch involvement can cause apraxia, agraphia, and tactile anomia of the left hand. Infarction of the basal branches of the ACA can cause memory disorders, anxiety, and agitation. Infarction in the territory of the medial lenticulostriate artery (artery of Heubner) causes more pronounced weakness of the face and arm without sensory loss caused by this artery's supply of portions of the anterior limb of the internal capsule. The anterior choroidal artery syndrome is often characterized by hemiparesis caused by involvement of the
ISCHEMIC CEREBROVASCULAR DISEASE
posterior limb of the internal capsule, hemisensory loss caused by involvement of the posterolateral nucleus of the thalamus or thalamocortical fibers, and hemianopia secondary to involvement of the lateral geniculate body or the gcniculocalcarine tract. The visual field defect with anterior choroidal artery syndrome infarcts is characterized by a homonymous defect in the superior and inferior visual fields that spares the horizontal meridian. In a small number of patients left spatial hemineglcct with right hemispheric infarctions and a mild language disorder with left hemispheric infarctions may occur. With bilateral infarctions in the anterior choroidal artery syndrome territory, there can be pseudobulbar mutism, and a variety of other features including facial diplegia, hemisensory loss, lethargy, neglect, and affect changes.
LACUNAR SYNDROMES Ischemic strokes resulting from small vessel or penetrating artery disease (lacunes) have unique clinical, radiological, and pathological features. Lacunar infarcts are small ischemic infarctions in the deep regions of the brain or brainstem that range in diameter from 0.5-15.0 mm. These infarctions result from occlusion of the penetrating arteries, chiefly the anterior choroidal, middle cerebral, posterior cerebral, and basilar arteries. Lacunar infarcts could also be the result of occlusion of penetrating arteries by atherosclerosis of the parent artery or microembolism. Lacunes may be single or multiple, symptomatic or asymptomatic. At least 20 lacunar syndromes have been described. Lacunar syndromes are highly predictive of lacunar infarcts, with a positive predictive value of approximately 84% to 90% (Can et al. 1997). The five best recognized syndromes are (1) pure motor hemiparesis, (2) pure sensory stroke, (3) sensory-motor stroke, (4) homolateral ataxia and crural paresis (ataxic hemiparesis), and (5) dysarthriaclumsy hand syndrome. Multiple lacunes may be associated with acquired cognitive decline. Headaches arc uncommon in patients with lacunar infarcts. Pure motor hemiparesis is often caused by an internal capsule, basis pontis, or corona radiata lacune and is characterized by a contralateral hemiparesis or hemiplegia involving the face, arm, and to a lesser extent, the leg, accompanied by mild dysarthria, particularly at onset of stroke. There should be no aphasia, apraxia, or agnosia, and there are no sensory, visual, or other higher cortical disturbances. Pure sensory stroke is often caused by a lacuna involving the ventroposterolateral nucleus of the thalamus. It is characterized by paresthesias, numbness, and a unilateral hemisensory deficit involving the face, arm, trunk, and leg. Sensory-motor stroke is often caused by a lacuna involving the internal capsule and thalamus or posterior limb of the internal capsule; large striatocapsular infarcts also can cause a similar syndrome. It is characterized by a contralateral unilateral motor deficit with a
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superimposed hemisensory deficit. Homolateral ataxia and crural paresis are often caused by a lacuna either in the contralateral posterior limb of the internal capsule or the contralateral basis pontis. It is characterized by weakness, predominantly in the lower extremity, and ipsilateral incoordination of the arm and leg. Dysarthrla-clumsy hand syndrome is often caused by a lacuna involving the deep areas of the basis pontis and is characterized by supranuclear facial weakness, dysarthria, dysphagia, loss of fine motor control of the hand, and Rabinski's sign.
Vertebrobasilar System Syndromes The areas of the cerebellum supplied by the posterior inferior cerebellar artery (PICA) are variable. There are several different patterns of PICA territory cerebellar infarctions. If the medial branch territory is affected, involving the vermis and vestibulocerebellum, the clinical findings include prominent vertigo, ataxia, and nystagmus. If the lateral cerebellar hemisphere is involved, patients can have vertigo, gait ataxia, limb dysmetria and ataxia, nausea, vomiting, conjugate or dysconjugate gaze palsies, miosis, and dysarthria. If the infarction is large, altered consciousness or confusion may occur. Hydrocephalus or herniation may develop. Although a PICA occlusion can be the cause of Wallenberg's (lateral medullary) syndrome, this syndrome is more often caused by an intracranial vertebral artery occlusion. The anterior inferior cerebellar artery (AICA) syndrome causes a ventral cerebellar infarction. The signs and symptoms include vertigo, nausea, vomiting, and nystagmus caused by involvement of the vestibular nuclei. There may be ipsilateral facial hypalgesia and thermoanesthesia and corneal hypesthesia because of involvement of the trigeminal spinal nucleus and tract. Ipsilateral deafness and facial paralysis occurs because of involvement of the lateral pontomedullary tegmentum. An ipsilateral Horner's syndrome is present because of compromise of the descending oculosympathetic fibers. Contralateral trunk and extremity hypalgesia occurs and thermoanesthesia caused by involvement of the lateral spinothalamic tract. Finally, ipsilateral ataxia and asynergia is caused by involvement of the cerebellar peduncle and cerebellum. Infarction in the territory of the superior cerebellar artery (SCA) produces a dorsal cerebellar syndrome (Hgure 57A.2). Vertigo may be present, although it is less common with SCA infarcts than with the other cerebellar syndromes. Nystagmus is caused by involvement of the medial longitudinal fasciculus and the cerebellar pathways. An ipsilateral Horner's syndrome is caused by involvement of the descending sympathetic tract. Ipsilateral ataxia and asynergia and gait ataxia are caused by involvement of the superior cerebellar peduncle, brachium pontis, superior cerebellar hemisphere, and dentate nucleus. There is an intention tremor caused by involvement of the dentate
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nucleus and superior cerebellar peduncle. Choreiform dyskinesias may be present ipsilarerally. Contra laterally, there is hearing loss caused by lateral lemniscus disruption and trunk and extremity hypalgesia and thermoanesthesia caused by spinothalamic tract involvement, Weber's syndrome is caused by infarction in the distribution of the penetrating branches of the posterior cerebral artery (PCA) affecting the cerebral peduncle, especially medially, with damage to the fascicle of cranial nerve III and the pyramidal fibers. The resultant clinical findings are contralateral hemiplegia of the face, arm, and leg caused by corticospinal and corticobulbar tract involvement and ipsilateral oculomotor paresis, including a dilated pupil. A slight variation of this syndrome is the midbrain syndrome of Foville in which the supranuclear fibers for horizontal gaze are interrupted in the medial peduncle, causing a conjugate gaze palsy to the opposite side. Bcncdikt's syndrome is caused by a lesion affecting the mesencephalic tegmentum in its ventral portion, with involvement of the red nucleus, brachium conjunctivum, and fascicle of cranial nerve III. This syndrome is caused by infarction in the distribution of the penetrating branches of the PCA to the midbrain. The clinical ma infestations are ipsilateral oculomotor paresis, usually with pupillary dilation and contralateral involuntary movements, including intention tremor, hemiathcrosis, or hemichorca. Claude's syndrome is caused by lesions that are more dorsally placed in the midbrain tegmentum than with Benedikt's syndrome. There is injury to the dorsal red nucleus, which results in more prominent cerebellar signs without the involuntary movements. Oculomotor paresis occurs (see Table 76.1 for variations of these syndromes). Nothnagel's syndrome is characterized by an ipsilateral oculomotor palsy with contralateral cerebellar ataxia. Infarctions in the distribution of the penetrating branches of the PCA to the midbrain is the cause of this syndrome. Pannaud's syndrome can result from infarctions in the midbrain territory of the PCA penetrating branches. This syndrome is characterized by supranuclear paralysis of eye elevation, defective convergence, convergence-retraction nystagmus, light-near dissociation, lid retraction, and skew deviation (see Chapter 22).
FIGURE 57A.2 A 15-year-old boy had vomiting, tinnitus, and unsteadiness. (A) Tl coronal postgadolinium magnetic resonance imaging shows enhancing lesions in the superior aspect of the left cerebellar hemisphere consistent with superior cerebellar artery infarct. (B) Anteroposterior view left vertebral artery injection shows a filling defect of the basilar apex also involving the proximal left superior cerebellar artery consistent with thromboembolus,
Top of the basilar syndrome (sec Chapter 22) is caused by infarction of the midbrain, thalamus, and portions of the temporal and occipital lobes. It is caused by occlusive vascular disease, often embolic in nature, of the rostral basilar artery. The following signs may occur: Behavioral abnormalities include somnolence, peduncular hallucinosis, memory disturbances, or agitated delirium. Ocular findings include unilateral or bilateral paralysis of upward or downward gaze; impaired convergence; pseudoabducens palsy; convergence-retraction nystagmus; abnormalities of abduction; Collier's sign, which consists of elevation and retraction of the upper eyelids; skew deviation; and oscillatory eye movements. Visual defects that may be present include hemianopia, cortical blindness, and Balint's syndrome.
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Pupillary abnormalities are variable, and may be either large or small, reactive, or fixed. Motor deficits may also occur. Although there are many named pontine syndromes, the most beneficial categorization is based on neuroanaromical divisions. Locked-in syndrome is the result of bilateral ventral pontine lesions that produce quadriplegia, aphonia, and impairment of the horizontal eye movements in some patients. Wakefulness and normal sleep-wake cycles are maintained because of sparing of the reticular formation, The patient can move his or her eyes vertically and can blink because the supranuclear ocular motor pathways lie more dorsally. In some patients with symptomatic basilar artery occlusive disease, there may be a herald hemiparesis that suggests a hemispheric lesion (Fisher 1988). However, within a few hours, there is progression to bilateral hemiplegia and cranial nerve findings associated with the locked-in syndrome. Pure motor hemiparesis and ataxiahemiparesis caused by pontine lesions are discussed with the lacunar syndromes. Occlusion of the AICA can lead to the lateral inferior pontine syndrome. Findings with this syndrome include ipsilateral facial paralysis, impaired facial sensation, paralysis of conjugate gaze to the side of the lesion, deafness, tinnitus, and ataxia. Contralateral to the lesion, there is hemibody impairment to pain and temperature, which in some instances includes the face. There may be horizontal and vertical nystagmus and oscillopsia. The medial inferior pontine syndrome is caused by occlusion of a paramedian branch of the basilar artery. With this syndrome, there is ipsilateral paralysis of conjugate gaze to the side of the lesion, abducens palsy, nystagmus, and ataxia. Contralateral to the lesion, there is hemibody impairment of tactile and proprioceptive sensation and paralysis of the face, arm, and leg. An occlusion of the AICA may lead to the total unilateral inferior pontine syndrome, a combination of the symptoms and signs seen with the lateral and medial pontine syndromes. The lateral pontomedullary syndrome can occur with occlusion of the vertebral artery. The manifestations are a combination of the medial and lateral inferior pontine syndromes. Occlusion of the paramedian branch of the midbasilar artery can lead to ipsilateral impaired sensory and motor function of the trigeminal nerve with limb ataxia, characteristics of the lateral midpontine syndrome. Ischemia of the medial midpontine region is caused by occlusion of the paramedian branch of the midbasilar artery and can lead to ipsilateral limb ataxia. Contralateral to the lesion, eye deviation and paralysis of the face, arm, and leg occur. Although there are predominant motor symptoms, variable impaired touch and proprioception may occur. The lateral superior pontine syndrome may occur with occlusion of the SCA and produces a characteristic syndrome of ipsilateral Horner's syndrome, horizontal nystagmus, paresis of conjugate gaze, occasional deafness, and severe ataxia of the limbs and gait.
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Contralateral to the lesion, there is hemibody impairment to pain and temperature, skew deviation, and impaired tactile, vibratory, and proprioceptive sensation in the leg greater than in the arm. The lateral medullary syndrome (Wallenberg's syndrome) is most often caused by occlusion of the intracranial segment of the vertebral artery (Figure 57A.3). Less commonly, it is caused by occlusion of PICA, This syndrome produces an ipsilateral Horner's syndrome; loss of pain and temperature sensation in the face; weakness of the palate, pharynx, and vocal cords; and cerebellar ataxia. Contralateral to the lesion, there is hemibody loss of pain and temperature sensation. The medial medullary (Dejerine) syndrome is less common and may be caused by occlusion of the distal vertebral artery, a branch of the vertebral artery, or the lower basilar artery. Vertebral artery dissection, dolichoectasia of the vertebrobasilar system, or embolism are less common causes of the medial medullary syndrome. The findings with this Syndrome include an ipsilateral lower motor neuron paralysis of the tongue and contralateral paralysis of the arm and leg. The face is often spared. In addition, there is contralateral hemibody loss of tactile, vibratory, and position sense. Occlusion of the intracranial vertebral artery can lead to a total unilateral medullary syndrome (of Babinski-Nageotte), a combination of medial and lateral medullary syndromes.
FIGURE 57A.3 A 74-year-old man had sudden onset of vertigo, vomiting, and gait unsteadiness. T2-weighted axial magnetic resonance imaging of the brain demonstrates an infarct in the posterolateral side of the medulla and a small cerebellar infarct in the distribution of the left posterior inferior cerebellar artery. There is poor flow void seen in the left vertebral artery.
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NEUROLOGICAL DISEASES
The manifestations with PCA territory infarctions are variable, depending on the site of the occlusion and the availability of collateral blood flow. Occlusion of the precommunal PI segment causes midbrain, thalamic, and hemispheric infarction. Occlusion of the PCA in the proximal ambient segment before branching in the thalamogeniculate pedicle causes lateral thalamic and hemispheral symptoms. Occlusions also may affect a single PCA branch, primarily rhc calcarine artery, or cause a large hemispheric infarction of the PCA territory. Unilateral infarctions in the distribution of the hemispheral branches of the PCA may produce a contralateral homonymous hemianopia caused by infarction of the striate cortex, the optic radiations, or the lateral geniculate body. There is partial or complete macular sparing if the infarction does not reach the occipital pole. The visual field defect may be limited to a quadrantanopia. A superior quadrantanopia is caused by infarction of the striate cortex inferior to the calcarine fissure or the inferior optic radiations in the ternporo-occipital lobes. An inferior quadrantanopia is the result of an infarction of the striate cortex superior to the calcarine fissure or the superior optic radiations in the parieto-occipital lobes. More complex visual changes may occur, including formed or unformed visual hallucinations, visual ami color agnosias, or prosopagnosia. Finally, some alteration of sensation with PCA hemispheral infarctions occurs, including paresthesias or altered position, pain, and temperature sensations. Infarction in the distribution of the callosal branches of the PCA involving the left occipital region and the splenium of the corpus callosum produces alexia without agraphia (Figure 57A.4). In this syndrome, patients can write, speak, and spell normally, but are unable to read words and sentences. The ability to name letters and numbers may be intact, but there can be inability to name colors, objects, and photographs. Right hemispheric PCA territory infarctions may cause contralateral visual field neglect. Amnesia may be present with PCA infarctions that involve the left medial temporal lobe or when there are bilateral mesiotemporal infarctions. In addition, an agitated delirium may occur with unilateral or bilateral penetrating mesiotemporal infarctions. Large infarctions of the left posterior temporal artery territory may produce an anomic or transcortical sensory aphasia. Infarctions in the distribution of the penetrating branches of the PCA to the thalamus can cause aphasia if the left pulvinar is involved, akinetic mutism, global amnesia, and the Dejerine-Roussy syndrome. In the latter syndrome, the patient has contralateral sensory loss to all modalities, severe dysesthesias on the involved side (thalamic pain), vasomotor disturbances, transient contralateral hemiparesis, and chorcoathetoid or ballistic movements. A number of syndromes that can result from infarctions in the distribution of the penetrating branches of the PCA to the midbrain were previously discussed with the midbrain syndromes.
FIGURE 57A.4 A 77-year-old man had alexia without agraphia, right homonymous hemianopia, and antegrade amnesia. Nonenhanced axial cranial computed tomography demonstrates an area of decreased parenchymal attenuation in the left occipitoparii-ral region.
Bilateral infarctions in the distribution of the hemispheric branches of the PCAs may cause bilateral homonymous hemianopias. Bilateral occipital or occipitoparietal infarctions can cause cortical blindness, often with denial or unawareness of blindness (Anton's syndrome). Another syndrome, Balint's syndrome, seen with bilateral occipital or parieto-occipital infarctions, consists of optic ataxia, psychic paralysis of fixation with inability to look to the peripheral field and disturbance of visual attention, and simu I tan agnosia.
Syndromes of Thalamic Infarction The main thalamic blood supply comes from the posterior communicating arteries and the perimesencephalic segment of the PCA. Thalamic infarctions typically involve one of four major vascular regions: posterolateral, anterior, paramedian, and dorsal. Posterolateral thalamic infarctions result from occlusion of the thalamogeniculate branches arising from the P2 segment of the PCA. Three common clinical syndromes may occur: pure sensory stroke, sensorimotor stroke, and the thalamic syndrome of Dcjcrine-Roussy. Anterior thalamic infarction results from occlusion of the polar or tuberothalamic artery. The main clinical manifesrations consist of neuropsychological disturbances, emotional-facial paresis, occasional hemiparcsis, and visual field deficits. Left-sided infarcts are associated with dysphasia, whereas neglect is seen primarily in patients
ISCHEMIC CEREBROVASCULAR DISEASE
with right-sided lesions. Paramedian thalamic infarctions result from occlusion of the paramedian, thalamic, and subthalamic arteries. The main clinical manifestations include the classic triad of decreased level of consciousness, memory loss, and vertical gaze abnormalities. Dorsal thalamic infarctions result from occlusion of the posterior choroidal arteries. These infarctions are characterized by the presence of homonymous quadrantanopia or horizontal sectoranopias. Involvement of the pulvinar may account for thalamic aphasia.
Watershed Ischemic Syndromes Watershed infarcts occur in the border zone between adjacent arterial perfusion beds. During or after cardiac surgery or after an episode of sustained and severe arterial hypotension after cardiac arrest, prolonged hypoxemia, or bilateral severe carotid artery disease, ischemia may occur in the watershed areas between the major circulations. Watershed infarctions also may be unilateral when there is some degree of hemodynamic failure in patients with underlying severe arterial stenosis or occlusion. Watershed infarcts also may be caused by microembolism or hyperviscosity states. Ischemia in the border zone or junctional territory of the ACA, MCA, and PCA may result in bilateral parietooccipital infarcts. There can be a variety of visual manifestations, including bilateral lower altitudinal field defects, optic ataxia, cortical blindness, and difficulty in judging size, distance, and movement. Ischemia between the territories of the ACA and MCA bilaterally may result in bibrachial cortical sensorimotor impairment (man-in-abarrel), and impaired saccadic eye movements caused by compromise of the frontal eye fields. Ischemia on the border zone regions between the MCA and PCA may cause bilateral parietotemporal infarctions. Initially there is cortical blindness that may improve, but defects such as dyslexia, dyscalculia, dysgraphia, and memory defects for verbal and nonverbal material may persist. Watershed infarcrs are also recognized between the territorial supply of the PICA, AICA, and SCA. Watershed infarctions may also involve the internal watershed region in the centrum semiovalc adjacent to, and slightly above, the body of the lateral ventricles.
DIAGNOSIS AND TREATMENT OF THREATENED ISCHEMIC STROKE An ischemic stroke develops when there is interrupted cerebral blood flow to an area of the brain. Ischemic strokes account for approximately 8 0 - 8 5 % of all strokes. Ischemic strokes may result from (1) large artery atheroscleroric disease resulting in stenosis or occlusion, (2) small vessel or penetrating artery disease (lacunes), (3) cardiogenic or
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artery-to-artery embolism, (4) nonatheioselerotic vasculopathies, (5) hypcrcoagulablc disorders, and (6) infarcts of undetermined causes. However, a rigid classification of ischemic stroke subtypes is difficult to establish because of the frequent occurrence of mixed syndromes.
LARGE ARTERY ATHEROTHROMBOTIC INFARCTIONS Large artery atherothrombotic infarctions almost always occur in patients who already have significant risk factors for cerebrovascular atherosclerosis (see Table 57A.1). A tli ero thrombosis is multifactorial, comorbidities frequently overlap, and risk factors are often additive. For example, arterial hypertension is often associated with hyperlipidemia, hyperglycemia, elevated fibrinogen levels, excessive weight, and left ventricular hypertrophy on ECG. A resting ankle-brachial index less than 0.90 is indicative of generalized atherosclerosis (Zheng et al. 1997). Persons with a stroke are at high risk for development of other vascular complications. After a stroke, rhere is a 2 5 % chance of a fatal thrombotic event in 3 years. Many of these deaths are caused by myocardial infarction. The mechanisms of large artery atherothrombotic infarction often reflect plaque complication; ulceration with artery-to-artery embolization (Figure 57A.5), or thrombosis in rhc setting of pre-existing arterial stenosis. Arteriogenic embolism is a common mechanism of cerebral ischemia. Embolism from ulcerated carotid artery atherosclerotic plaques is a common cause of cerebral infarction. In situ thrombosis occurs in the proximal carotid, distal vertebral artery, and lower or middle basilar artery (Figures 57A.6A and 57A.6B). Atherosclerotic involvement of the intracranial portion of the vertebrobasilar system frequently occurs in tandem and is the common pathological mechanism associated with the syndrome of vertebrobasilar territory infarction; this may arise in association with hypercoagulable states. Hypoperfusion secondary to hemodynamic alterations also may trigger these events. Whether the pathogenesis of stroke caused by intracranial arterial stenosis is different from that caused by extracranial aire rial disease is unsettled. In patients with risk factors for atherosclerosis, the cholesterol-rich minimally raised fatty streak may progress to a fibrous plaque rhat can evolve into a complicated plaque with intraplaque hemorrhage, extensive necrosis, calcification, and subsequent thrombosis (Figure 57A.7). The infiltrarion of the fibrous cap by foam cells may contribute to the rupture of the atherosclerotic carotid artery plaque. Atherosclerosis is often segmental and asymmetrical, and earlier lesions tend to occur in areas of low shear stress, such as the outer aspect of the carotid artery bulb. Atherosclerosis primarily affects the larger extracranial and intracranial vessels, particularly the carotid siphon, MCA stem, origin of the vertebral arteries
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NEUROLOGICAL DISEASES
FIGURE 57A..S Right common carotid angiogram shows 17% right internal carotid artery stenosis (North American Symptomatic Carotid Endarectomy Trial criteria) just superior to a large carotid ulceration. (Courtesy Vincent Mathews, MD.) (Vi), intracranial segment of the vertebral arteries (V 4 ), and basilar artery. The distribution of cerebral atherosclerosis is different in certain ethnic groups. Stenosis of major intracranial arteries is more prevalent among blacks and Asians than in whites.
SMALL VESSEL OR PENETRATING ARTERY DISEASE Lacunes usually occur in patients with long-standing arterial hypertension, current cigarette smoking, and diabetes mellitus. The most frequent sites of involvement are the putamen, basis pontis, thalamus, posterior limb of the internal capsule, and caudate nucleus. Multiple lacuna are associated strongly with arterial hypertension and diabetes mellitus. Available evidence suggests that structural
FIGURE 57A.6 (A) Nonenhanced axial computed tomographic scan shows bilateral cerebellar and pontine infarcts. (B) Anteroposterior view of vertebrobasilar angiogram shows a large filling defect on the basilar artery, consistent with partial thrombosis. (Courtesy Vincent Mathews, MD.) changes of the cerebral vasculature caused by arterial hypertension are characterized by fibrinoid angiopathy, lipohyalinosis, and microaneurysm formation. Accelerated hypertensive arteriolar damage of the small penetrating arteries is operative in a large number of patients with lacunar infarction. Microatheroma of the ostium of a penetrating artery, embolism, or changes in hemorrheology
ISCHEMIC CEREBROVASCULAR DISEASE
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be composed of platelet, fibrin, platelet-fibrin, calcium, microorganisms, or neoplastic fragments. The most common substrate for cerebral embolism in older individuals is atrial fibrillation, accounting for two thirds of emboli of cardiac origin. Other cardiac conditions with high embolic potential include acute myocardial infarction, infective endocarditis, rheumatic mitral stenosis, mechanical prosthetic heart valves, dilated cardiomyopathy, and cardiac tumors. Low or uncertain embolic risk disorders include mitral valve prolapse, mitral annulus calcification, aortic valve calcification, calcific aortic stenosis, remote myocardial infarction, left ventricular aneurysm, hypertrophic cardiomyopathy, patent foramen ovale (PFO), atrial septal aneurysm (ASA), atrial flutter, valvular strands, and Chiari network,
FIGURE 57A.7 Left carotid angiogram (lateral view) shows severe stenosis [open arrow) of origin of tlic left internal carotid artery with an intraluminal thrombus [arrow). The artery was occluded in other images. (Courtesy Vincent Mathews, MD.)
are pathophysiological^ operative in the remainder of cases. However, rhe mere association of a lacunar syndrome in a patient with arterial hypertension and diabetes is not sufficient for a diagnosis of a lacunar infarct, and other causes of ischemic stroke must be excluded, Large striatocapsular infarctions should be distinguished from lacunar infarcts, because they frequently have potential cardioembolic sources or coexistent severe carotid or MCA stenosis and often present with signs and symptoms of cortical dysfunction (Nicolai et al. 1996). Control of hypertension, prevention of microangiopathy, a better understanding of the ideal hemodynamic profile, and judicious use of platelet antiaggregants are essential in the management of patients with lacunar infarcts.
CARDIOGENIC EMBOLISM Cerebrovascular events are a serious complication of a diverse group of cardiac disorders. Cardioembolic strokes are associated with substantial morbidity and mortality. Embolism of cardiac origin accounts for approximately 15-20% of all ischemic strokes. Cardiac emboli may
Congenital heart disease is probably the most common cardiac disorder causing ischemic stroke in children. Children with congenital heart disease and a low hemoglobin concentration are at special risk for arterial strokes; those with a high hematocrit are more likely to experience cerebral venous thrombosis (Perloff 1998). Emboli from cardiac sources may be silent or cause severe neurological deficit or death. Although most types of heart disease may produce cerebral embolism, certain cardiac disorders are more likely to be associated with emboli (Table 57A.3). Cardioembolic cerebral infarcts arc often large, multiple, bilateral, and wedge shaped. Sudden, unheralded, focal neurological deficits worse at onset are often presenting manifestations. Any vascular territory may be affected. Ischemic strokes with a potential cardiac source are more often associated with Wernicke's aphasia, homonymous hemianopia without hemiparesis or hemisensory disturbances, and ideomotor apraxia. Other features suggestive of a potential cardiac source of embolism include posterior division of the MCA, ACA, or cerebellar compromise; involvement of multiple vascular territories; or a hemorrhagic component of the infarction. Reliable clinical determination of a cardioembolic source of stroke may be hampered by a variety of problems. Identification of a potential embolic cardiac source is not by itself sufficient to diagnose a brain infarct as cardioembolic because (1) many cardiac problems may coexist with cerebrovascular atherosclerosis, {2) cardiac arrhythmias may occur after arrhythmogenic lesions such as parietoinsular and brainstem infarcts, (3) computed tomographic (CT) scan differentiation between cardioembolic and atherosclerotic causes of cerebral infarction is not always reliable, and (4) cardiac changes derected by echocardiography are prevalent in control populations. An embolic stroke occurs in approximately 1% of hospitalized patients with acute myocardial infarction. Left ventricular thrombi are commonly associated with recent anterior wall transmural myocardial infarction. Echocardiography studies have demonstrated that approximately one third to one half of acute anterior myocardial infarctions, but less than 4% of acute inferior myocardial
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Table 57A.J:
Sources of cardioembolism
Acute myocardial infarction Left ventricular aneurysm Dilatated cardiomyopathy Cardiac arrhythmias Atrial fibrillation Sick sinus syndrome Valvular heart disease
Rheumatic mitral valve disease Calcific aortic stenosis Mitral annulus calcification Mitral valve prolapse Infective endocarditis Nonbacterial thrombotic endocarditis Prosthetic heart valves Filamentous strands of the mitral valve Giant Lambl's excrescences Aneurysms of the sinus of Valsalva Intracardiac tumors (atrial myxoma, rhabdomyoma, papillary fibroelastoma) Intracardiac defects with paradoxical embolism Patent foramen ovale Atrial septal aneurysm Atrial septal defect Cyanotic Congenital heart disease Eontan procedure or its modifications (cavopulmonary anastomosis) Mitochondrial encephalomyopathics (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes; myoclonic epilepsy and ragged-red fibers; Kearns-Sayre syndrome) Coronary artery bypass grafting VVI pacing Heart transplantation Artificial hearts Cardioversion for atrial fibrillation Balloon angioplasty Ventricular support devices Extracorporeal membrane oxygenator
infarctions, develop left ventricular thrombi. Almost all episodes of embolism occur within 3 months following acute myocardial infarction, with 8 5 % of emboli developing in the first 4 weeks. A decreased ejection fraction is an independent predictor of an increased risk of stroke following myocardial infarction (Loll ct al. 1997). Patients with acute myocardial infarction who receive thrombolytic therapy have a small risk of stroke. A direct comparison of tissue plasminogen activator (tPA) and streptokinase (SK) shows an excess of strokes with tPA. Myocardial infarction is rare in young adults. Although the prevalence of left ventricular thrombi in individuals with left ventricular aneurysms is high, the frequency of systemic embolism is low. Dilated or congestive cardiomyopathy may result from arterial hypertension or a variety of inflammatory, infectious, immune, metabolic, toxic, and neuromuscular disorders. The global impairment of ventricular performance predisposes to stasis and thrombus formation. Patients commonly have signs of impaired left ventricular systolic
function, and less than one hall haw-diastolic heart failure. Occasionally, patients have atrial fibrillation. A systemic embolism may be the presenting manifestation. Embolism occurs in approximately 1 8 % of patients with dilated cardiomyopathy not receiving anticoagulants. Patients with idiopathic hypertrophic subaortic stenosis may present with stroke. Thromboembolism is uncommon in patients with congestive heart failure. Mitochondrial disorders are seldom associated with dilated cardiomyopathies. Cerebral infarction is a complication of mitochondrial enccphalomyopathies (MELAS; myoclonic epilepsy and ragged-red fibers; Kearns-Sayre syndrome). Stroke in Kearns-Sayre syndrome is likely secondary to embolism. Apical aneurysms complicate Chagas' cardiomyopathy. Most cases of mitral stenosis are caused by rheumatic heart disease. Systemic emboli occur in 9-14% of patients with mitral stenosis, with 6 0 - 7 5 % having cardioembolic cerebral ischemia. Systemic embolism may be the first symptom of mitral stenosis, particularly if it is associated with atrial fibrillation. Aortic valve calcification with or without stenosis is not a risk factor for stroke (Boon et al. 1996). Cerebral embolism is a rare occurrence in patients with bicuspid aortic valves. Individuals with mitral annular calcification have twice the risk of stroke. Mitral valve prolapse affects 3^4% of adults, and when uncomplicated, does not seem to have an increased risk of stroke. Neurological ischemic events appear to occur more commonly among men older than 50 years with auscultatory findings of a systolic murmur and thick mitral valve leaflets on echocardiography. Thromboembolic phenomena complicating infective endocarditis may be systemic (left-sided endocarditis) or pulmonan (right-sided endocarditis). Vegetations are detected by transthoracic echocardiography in 5 4 - 8 7 % of patients with infective endocarditis and are associated with an increased risk of embolism (Eishi et al. 1995). Systemic emboli may occur in nearly one half of patients with nonbacterial thrombotic endocarditis, a condition characterized by the presence of multiple, small, sterile thrombotic vegetations most frequently involving the mitral and aortic valves. The risk of thromboembolism is higher with mechanical prosthetic heart valves than with biological prosthetic heart valves. Thromboemboli are more common with prosthetic heart valves in the mitral position than with prosthetic heart valves in the aortic position. The rate of systemic embolism in patients with mechanical heart valves receiving anticoagulant therapy is 4% per year in the mitral position, and 2% per year in the aortic position. Filamentous strands attached to the mitral valve appear to represent a risk for cerebral embolism, particularly in young patients, but the risk of recurrent cerebral ischemia is incompletely understood. The association of giant Lambl's excrescences or aneurysms of the sinus of Valsalva and cerebral embolism is low. Atrial fibrillation is the most common arrhythmia requiring hospitalization in the United States. The incidence of thromboembolism in patients with atrial fibrillation is
ISCHEMIC CEREBROVASCULAR DISEASE
4 - 7 . 5 % per year (Atrial Fibrillation Investigators 1994). Patients with NVAF, the leading source of cardioembolic infarctions in older adults, have a five- to sixfold increase in stroke incidence, with a cumulative risk of 3 5 % over a lifetime. Patients with rheumatic atrial fibrillation have a 17-fold increase in stroke incidence. However, individuals younger than 65 years with lone atrial fibrillation have a low embolic potential. Stroke patients with atrial fibrillation are also at high risk of death during the acute phase of stroke and during the subsequent year after stroke. A dramatic increase in the rate of atrial fibrillation occurs with age, from 0.2 cases per 1000 patients aged 30-39 years to 39 cases per 1000 patients aged 80-89 years. The proportion of strokes caused by atrial fibrillation also steadily increases, from 6.7% of all strokes in patients aged 50-59 to 36.2% in those aged 80-89. The risk of embolism is increased among patients with atrial fibrillation and hyperthyroidism, who also have an increased sensitivity to warfarin, Cerebral and systemic embolism may occur also in the setting of the sick sinus syndrome. Patients at greatest risk for embolization have bradytachyarrhythmias; left atrial spontaneous echocardiography contrast and decreased atrial ejection force increase stroke risk (Mattioli et al. 1997). Patients with sick sinus syndrome may experience cerebral ischemia or systemic embolism, even after pacemaker insertion. VVf pacing is associated with a higher risk of embolic complications than atrial or dual-chamber pacing. The risk of thromboembolism is also higher among patients in chronic atrial flutter (Wood et al. 1997; Seidl et al. 1998). Atrial myxomas are rare cardiac tumors complicated by postural syncope and systemic and embolic manifestations. Embolic complications are a presenting symptom in one third of patients with atrial myxoma. Recurrent emboli before surgery are common. Peripheral and multiple cerebral arterial aneurysms also have been diagnosed years following the initial embolic manifestations from atrial myxoma. Treatment of atrial myxomas consists of prompt surgical resection of the cardiac mass. Cardiac rhabdomyomas are associated closely with tuberous sclerosis; systemic embolism is unusual. Mitral valve papillary fibroe la stoma, an uncommon valvular tumor, is complicated rarely by stroke. A paradoxical embolism caused by a right-to-left shunt through a PFO or ASA can be responsible for stroke and other ischemic cerebral events. A PFO is present in 3 5 % of subjects between the ages of 1 and 29 years, in 2 5 % of people between ages 30 and 79, and in 2 0 % between ages 80 and 99 years. A PFO provides opportunity for right-toleft shunting during transient increases in the right atrial pressure. PFO is more common in patients with stroke than in matched controls. Patients with no identifiable cause for ischemic stroke and PFO usually have a larger PFO with more extensive right-to-left shunting than patients with stroke of determined cause. Platelet antiaggregants, oral
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anticoagulants, transcathctcr closure of the PFO, or surgical closure of the PFO have been recommended. A recent study found no difference in the time to primary endpoints between aspirin and warfarin (mean INR = 2.04) (Homma et al. 2002). ASA also might be a source of cerebral emboli. The coexistence of PFO and ASA increases the risk of embolic stroke. PFO and ASA have been associated also with mitral valve prolapse. Strokes are often severe but recurrences are uncommon. Pulmonary arteriovenous malformations occur in 15-20% of patients with Rcndu-Oslcr-Weber syndrome and can be the source of paradoxical embolism causing cerebral ischemia. Spontaneous echocardiographic contrast is associated with elevated fibrinogen levels and plasma viscosity and is a potential risk factor for cardioembolic stroke. Spontaneous cchocardiographical contrast is highly associated with previous stroke or peripheral embolism in patients with atrial fibrillation or mitral stenosis and increased left atrial size. The risk of cerebrovascular events is increased in adults with cyanotic congenital heart disease in the presence of arterial hypertension, atrial fibrillation, history of phlebotomy, and particularly with microcytosis (Perloff e t a l . 1993). The preponderance of posterior circulation ischemia following cardiac catheterization is unexplained. Stroke occurs after coronary artery bypass grafting with a frequency ranging between 1% and 5% (Figure 57A.8). Two thirds of strokes occur by the second postoperative day, and predominantly involve the cerebral hemispheres; brainstem/ cerebellar infarcts and lacunar strokes are less common. The cause of postoperative stroke is multifactorial; hypoperfusion, ventricular thrombus, and emboli are probable causal factors, although embolic causes are the most likely mechanisms. Clamp manipulation during coronary artery bypass surgery also may favor the release of aortic atheromatous debris. Epiaortic ultrasound studies demonstrate an increased stroke rate associated with an increased severity of aortic atherosclerosis. Strokes rarely relate to carotid artery stenosis. Carotid artery occlusion, but not carotid artery stenosis, increases the risk for stroke following coronary artery bypass grafting (Micklcborough et al. 1996). Thromboembolic phenomena can complicate cardiac surgery using cardiopulmonary bypass with deep hypothermia and cardiac arrest. Stroke is a potential complication of cardioversion for atrial fibrillation. Cerebral embolism may also complicate valvuloplasty; the risk is greater for aortic rather than mitral valvuloplasty. Strokes may follow heart transplantation, the use of ventricular support systems and artificial hearts, and the use of the extracorporeal membrane oxygenator. Stroke following inadvertently placed left-sided heart pacemaker leads is an unusual complication. Ischemic myelopathy is a rare complication of intra-aortic balloon pump. Aortic dissection or hematoma may lead to an occlusion of a major radicular branch or local occlusion of the artery of Adainkiewicz (see Chapter 57F),
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FIGURE 57A.8 An 80-year-old woman remained unresponsive with left-sided hemiplegia and right-sided hemiparesis after coronaryartery bypass grafting and aortic valve replacement. Noncnhanccd axial computed tomography demonstrates large left temporo-parictooccipital and right frontoparietal infarctions.
NONATHEROSCLEROTIC VASCULOPATHIES Although the majority of arterial disorders leading to stroke is caused by atherosclerosis, several nonathcrosclerotic vasculopathies can be responsible for a minority of ischemic
strokes. These vasculopathies include ccrvicocephalic arterial dissections, traumatic cerebrovascular disease, radiarion vasciiloparhy, moyamoya, fibromuscular dysplasia (FMD), and cerebral vasculitis (Tables 57A.4 and 57A.5}. Together, these uncommon conditions represent 5% of all
ISCHEMIC CEREBROVASCULAR DISEASE Table 57A.4:
Selected nonathcrosclerotic vasculopathies
Cervicocephalic arterial dissections Traumatic cerebrovascular disease Radiation-induced vasculoparhy Moyamoya disease Fibromuscular dysplasia Vasculitis Migrainous infarction
ischemic strokes. They are relatively more common in children and young adults. Cervicocephalic arterial dissections are one of the most frequent n on atherosclerotic vasculopathies causing ischemic stroke in young adults. A dissection is produced Tabic S7A.5:
Classification of cerebral vasculitides
Infectious vasculitis Bacterial, fungal, parasitic Spirochetal (syphilis, Lyme disease) Viral, rickettsial, mycobacterial Cysticercosis, free-living amebae Necrotizing vasculitides Classic polyarteritis nodosa Wegener's granulomatosis Allergic angiitis and granulomatosis (Churg-Strauss) Necrotizing systemic vasculitis-overlap syndrome Lymphomatoid granulomatosis Vasculitis associated with collagen vascular disease Systemic lupus erythematosus Rheumatoid arthritis Scleroderma Sjogren's syndrome Vasculitis associated with other systemic diseases Behcet's disease Ulcerative colitis Sarcoidosis Relapsing polychondritis Kohlmeier-Degos disease (malignant atrophic papulosis) Giant cell artcritides Takayasu's arteritis Temporal (cranial) arteritis Hypersensitivity vasculitides Henoch-Schonlein's purpura Drug-induced vasculitides Chemical vasculitides Essential mixed cryoglobulinemia Miscellaneous Vasculitis associated with neoplasia Vasculitis associated with radiation Cogan's syndrome Der m a to my o s i ti s polymyositis X-linked lymphoproliferative syndrome Thromboangiitis obliterans Kawasaki's syndrome Primary central nervous system vasculitis Source: Reprinted with permission from Biller, J. ik. Sparks, I . H. 1993, "Diagnosis and management of cerebral vasculitis," in Handbook of Cerebrovascular Diseases, ed H. P. Adams Jr., Marcel Dekker, New York.
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by subincimal penetration of blood in a cc r vie ocep ha lievessel with subsequent longitudinal extension of the intramural hematoma between its layers. Most dissections involve the extracranial segment of the internal carotid artery or extracranial vertebral arteries. Intracranial carotid and vertebrobasilar dissections are less common; intracranial dissections are usually subintimal, and may follow trivial trauma, closed head trauma, basilar skull fractute, or penetrating injuries. The recurrence rate of extracranial cervicocephalic arterial dissections is approximately 1% per year. The risk of recurrent dissections is increased in younger patients and in patients with family history of arterial dissections. Cervicocephalic artetial dissections have been reported after blunt or penetrating trauma and also are associated with FMD, Marfan's syndrome, Ehlers-Danlos syndrome type IV, pseudoxanthoma elasticum, coarctation of the aorta, Menkes' disease, or [-antitrypsin deficiency, cystic medial degeneration, reticular fiber deficiency, accumulation of mucopolysaccharides, osteogenesis imperfecta, adult polycystic kidney disease, elevated arterial elastase content (Thai et al. 1997), lentiginosis, atherosclerosis, extreme vessel tortuosity, moyamoya syndrome, homocystinuria, pharyngeal infections, sympathomimetic drug abuse, and luetic arteritis. Not infrequently, cervicocephalic arterial dissections occur spontaneously. Dissection of the cervicocephalic vessels may cause transient retinal, hemispheric, or posterior fossa ischemia, Horner's syndrome, hemicranial pain, cranial nerve palsies, cerebral infarction, or subarachnoid hemorrhage. Ischemic symptoms result from arterial occlusion or secondary embolization. In addition to a postganglionic Horner, neuro-ophthalmological manifestations of internal carotid artery dissections may also include central retinal artery occlusion, ophthalmic artery occlusion, ischemic optic neuropathy, homonymous hernia no pia, and ocular motor nerve palsies (cranial nerve ICN] III, IV, and VI). In addition to a first-order neuron Horner syndrome, other ncuro-ophthalmological manifestations of vertebrobasilar dissections include diplopia, nystagmus, oscillopsia, ocular misalignment, skew deviation, ocular motor nerve palsies (CN III, IV, and VI), lateral gaze palsy, internuclear ophthalmoplegia, and homonymous visual field defects. Cervicocephalic arterial dissections should be considered in the differential diagnosis of ischemic stroke in any young adult, particularly when traditional risk factors are absent. Diagnosis is based on artcriographical findings, although high-resolution magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), computed tomography angiography, and extracranial and transcranial Doppler ultrasound are rapidly replacing contrast angiography for the diagnosis of cervicocephalic arterial dissections, particularly in cases of carotid artery involvement (Figure 57A.9). Arteriographical features include the presence of a pearl and string sign; double-lumen sign; short, smooth, tapered
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FIGURE 57A.9 Following the intravenous administration of iodinated contrast, spiral CT images were obtained using 1.3 mm collimation and 0.5 mm image reconstruction intervals. A pseudoaneurysm of the left internal carotid artery is noted. This pseudoaneurysm measures 1.9 x 2.9 cm in greatest axial dimensions. There is calcification in the wall of the aneutysm. There is extensive mural thrombus such that the aneurysm lumen containing contrast measures 12.5 x 10.7 mm (*). The internal carotid artery is severely narrowed just proximal to its entry site into the aneutysm. occlusion; or pseudoaneurysm formation. MRI demonstrates the intramural hematoma and the false lumen of the dissected artery (Figure 57A.10), Ultrasound studies can be helpful in monitoring their course. Therapeutic interventions have included immediate anticoagulation with heparin followed by a 3- to 6-month course of warfarin; platelet atitiaggregants; or surgical correction for selected individuals with pseudoaneurysms or those who fail to respond to medical therapy. Although anticoagulants are often empirically recommended, their value in patients with extracranial cervicoccphalic arterial
FIGURE 57A.10 A 16-ycar-old boy collapsed to the ground after experiencing right eye pain and left-sided weakness. (A) Axial T2-weighted magnetic resonance imaging of the brain shows ischemic areas in the right basal ganglia and right posterior parietal region, (B) associated with a crescent sign (arrow) of high signal consistent with intraluminal blood products on the right internal carotid artery suggestive of a dissection.
dissections has not been firmly established. Anticoagulation should be withheld in patients with intracranial dissections (particularly involving the vertebrobasilar circulation) because of the risk of subarachnoid hemorrhage. Trauma is a leading cause of cerebrovascular mortality in the United States. Blunt or penetrating traumatic cerebrovascular disease may result in cervicocephalic arterial
ISCHEMIC CEREBROVASCULAR DISEASE
dissection, arterial thrombosis, arterial rupture, pscudoaneurysm formation, or development of an arteriovenous fistula. Internal carotid artery thrombosis also may follow maxillary and mandibular angle fractures. Carotid artery trauma may cause hematoma formation of the lateral neck, retinal or hemispheric ischemia, and a Horner's syndrome. Neurological deficits may be mild or devastating. Comatose patients with carotid arterial injuries with a Glasgow Coma Scale score of 8 or less do poorly regardless of management (see Chapter 5, Table 5.4). Missing the diagnosis may lead to devastating results. A thorough evaluation of the airway, oropharynx, and esophagus is needed. Arteriography is indicated in most instances, and surgical repair may be needed. Injury to the endothelial cells by high-intensity radiation may cause accelerated atherosclerotic changes, particularly in the presence of hyperlipidemia. These changes may occur months to years after completion of radiation therapy. Radiation vasculopathy correlates with radiation dose and age at time of radiation therapy. Lesions develop in locations that are unusual for atherosclerosis and may involve the extracranial or intracranial vessels. Patients who receive therapeutic radiation therapy for lymphoma, Hodgkin's disease, or thyroid carcinoma are at risk for involvement of the extracranial circulation. Follow-up ultrasound carotid and MRI studies are recommended in these patients. Radiation therapy also may cause an occlusive vasculopathy of small and large intracranial arteries following irradiation of craniopharyngiomas, germinomas, pituitary tumors, or other intracranial neoplasms. Intracranial arterial stenosis also may follow stereotactic radiosurgery. Moyamoya is a chronic progressive non-atherosclerotic, non-inflammatory, non-amyloid occlusive intracranial vasculopathy of unknown cause. Pathologically, there is fibrocellular intimal thickening and smooth muscle cell proliferation and increased elastin accumulation resulting in stenosis of the suprasellar intracranial internal carotid arteries. There is also thinning of the media, and a tortuous and often multilayered internal elastic lamina. Thrombotic lesions may be seen in major cerebral arteries. There are also numerous, perforating and anastomotic branches around the circle of Willis. Intracranial aneurysms may be seen at the circle of Willis or in the peripheral vessels (Yamamoto et al. 1997). Cases have been associated with neonatal anoxia, trauma, basilar meningitis, tuberculous meningitis, leptospirosis, cranial radiation therapy for optic pathway gliomas, neurofibromatosis type-1, tuberous sclerosis, encephalotrigeminal angiomatosis (Sturge-Weber syndrome), phakomatosis pigmentovascularis type Illb, brain tumors, FMD, polyarteritis nodosa, Marfan's syndrome, Turner's syndrome, pseudoxanthoma clasticum, hypomelanosis of Ito, Williams' syndrome, cerebral dissecting and saccular aneurysms, sickle cell disease, 0-thalassemia, Fanconi's anemia, hereditary spherocytosis, lupus anticoagulant, Sneddon's syndrome, homocystinuria, oral contraceptives,
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factor XII deficiency, type I glycogenosis, reduced form of nicotinamide-adenine dinuclcotide phosphate-coenzyme Q reductase deficiency, renal artery stenosis, Down's syndrome, Apert's syndrome, Graves' disease, coarctation of the aorta, Alagille syndrome, hyperphosphatasia, Schimke's immunosseous dysplasia, primary oxalosis, pulmonary sarcoidosis, and Hirschprung's disease. Moyamoya disease may cause TIAs, including hemodynamic paraparetic TIAs secondary to watershed paracentral lobule ischemia, headaches, seizures, movement disorders (chorea, hemidystonia, hemichorcoathetosis), mental deterioration, cerebral infarction, or intracranial hemorrhage. TIAs are often precipitated by crying, blowing, or hyperventilation. Moyamoya disease has a bimodal age distribution with peaks in the first and fourth decades of life. Childhood moyamoya is characterized by ischemic manifestations, whereas adult moyamoya disease presents with hemorrhagic manifestations. Moyamoya affects children, adolescents, and young adults most frequently. Diagnosis is based on a distinct arteriographical appearance as described by Suzuki's six angiographic stages: (1) stenosis of the carotid fork, (2) initial appearance of moyamoya vessels at the base of the brain, (3) inrensification of moyamoya vessels, (4) minimization of moyamoya vessels, (5) reduction of moyamoya vessels, and (6) disappearance of moyamoya vessels (collaterals only from external carotid arteries) (Figure .S7A.11). Moyamoya is characterized by progressive, bilateral stenosis of the distal internal carotid arteries
• 1
W^C
A
FIGURE 57A.11 Left carotid angiogram (anteroposterior view) shows occlusion of the supraclinoid internal carotid artery and innumerable moyamoya vessels. (Courtesy Vincent Mathews, MD.)
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NEUROLOGICAL DISEASES
extending to the proximal ACA and MCA, often with involvement of the circle of Willis and development of an extensive collatetal {parenchymal, leptomeningeal, and transdural) network at the base of the brain like a cloud or puff of smoke (moyamoya). Intracranial aneurysms, particularly located in the posterior circulation, may be present. The optimal treatment of ischemic moyamoya has not been determined. Platelet antiaggregants, vasodilators, calcium-channel blockers, and corticosteroids have been used with variable results. Anticoagulants are not useful. Good results have been reported with superficial temporal artery to MCA anastomosis and other indirect or combined surgical revascularization procedures. No clear superior therapy to ptevent rebleeding has been shown in the hemorrhagic type of moyamoya disease. FMD is a segmental, non-athcromatous dyspiastic, noninflammatory angiopathy affecting predominantly young and middle-aged women. Cervicocephalic HMD affects less than 1% of the population, occuts mote often in whites than in blacks, and predominantly involves the cervical carotid arteries at the level of the CI to C2 vertebral bodies. FMD of the intracranial arteries is rare and mainly limited to the intrapetrosal internal carotid artery or carotid artery siphon. The cause of FMD is unknown. Immunological and estrogenic effects on the arterial wall may be causal mechanisms. An association with ofl-antitrypsin deficiency has been reported. Four distinct histological types ate recognized: intimal fibroplasia, medial hypetplasia, medial fibroplasia, and perimedial dysplasia. Medial fibroplasia is the most frequent form of FMD, followed by perimedial dysplasia, and intimal fibroplasia. The majority of cases of FMD involves the renal arteries, followed by the carotid and iliac arteries. Some cases are familial. Most often, patients with cervicocephalic FMD are asymptomatic or present with headaches, neck pain, carotidynia, tinnitus, vettigo, asymptomatic carotid bruits, transient retinal or cerebral ischemia, cerebral infarction, or subarachnoid hemorrhage. Cervicocephalic FMD may be associated with atterial dissection. Hypertensive patients may have concomitant renal FMD, Cerebral ischemia is usually related to the underlying atterial stenosis or artetial thromboembolism. The diagnosis of cervicocephalic FMD is made on the basis of cerebral angiography. Cervicocephalic FMD occurs most often in the extracranial carotid artery and is bilateral in approximately two thirds of cases. The lesions of medial fibroplasia account for the characteristic "siting of beads" angiographical appearance seen in approximately 9 0 % of cases (Figute 57A.12). The optimal treatment of symptomatic cervicocephalic FMD has not been determined. In view of the benign natural history of this condition, platelet antiaggtegants arc recommended. Surgical intervention with angioplasty and stenting, gradual arterial dilatation, tcsection and reconstruction, or interposition grafting is seldom warranted.
FIGURE 57A.12 Lateral left carotid angiogram in a patient with FMD. Note "string of pearls" appearance at around the C2 level.
Inflammatory vasculitides can involve any size of vessel, including the precapillary arterioles and postcapillary venules. Many infectious and multisystem noninfectious inflammatory diseases cause cerebral vasculitis (see Table 57A.5). Cerebral vasculitis is a consideration in young patients with ischemic ot hemorrhagic stroke; patients with recurrent stroke; patients with stroke associated with encephalopathic featutes; and patients with stroke accompanied by fever, multifocal neurological events, mononeuritis multiplex, palpable purpura, or abnormal urinary sediment. Other manifestations of cerebral vasculitis include headaches, seizures, and cognitive deterioration. Laboratory studies typically show anemia of chronic disease, leukocytosis, and an elevated erythrocyte sedimentation tatc. The diagnosis of vasculitis usually requires confirmation by arteriography or biopsy. Overall, these disorders have a poor prognosis, but corticosteroids and alkylating agents have improved the survival rate. Intracranial vasculitis and stroke can result from meningovascular syphilis; prodromal manifestations are common before stroke. The MCA territory is most commonly affected. Spinal cord infarction may result from meningomyelitis. Other neurological manifestations in patients with secondary syphilis include headaches, meningismus, mental status changes, and ctanial nerve abnormalities. The cerebrospinal fluid (CSF) may show a modest lymphocytic pleocytosis, elevated protein content, and a positive Venerea! Disease Research Laboratory (VDRL) test result. Concurrent human immunodeficiency virus (HIV-1) infection can lead to rapid progression of early syphilis to neurosyphilis. Luetic aneurysms of the
ISCHEMIC CEREBROVASCULAR DISEASE
ascending aorta can extend to involve the origin of the great vessels and can lead to stroke. Treatment schedules for syphilis are listed in standard textbooks; patients with concurrent HIV-1 infection and meningovascular syphilis may require prolonged antibiotic treatment. Worldwide, an estimated 1 billion people arc infected with Mycobacterium tuberculosis. Neurotuberculosis affects predominantly the basilar meninges. Predisposing conditions include alcoholism, substance abuse, corticosteroid use, and HIV 1 infection. Strokes can result from tuberculous endarteritis. The exudative basilar inflammation entraps the cranial nerves at the base of the brain, most frequently the third, fourth, and sixth cranial nerves. The basilar arteriolitis most commonly involves penetrating branches of the ACA, MCA, and PCA (medial and lateral lenticulostriate, anterior choroidal, thalamoperforators, and thalamogeniculate arteries). There is usually a modest lymphocytic and mononuclear pleocytosis. The CSF protein is usually elevated, and the glucose level is depressed. In the early stages, a predominantly neutrophilic response may be noted. Smears of CSF demonstrate M. tuberculosis in 1 0 2 0 % of cases. Repeated CSF examinations increase the yield considerably. Fungal arteritis may result in aneurysms, pseudoaneurysms, thrombus formation, and cerebral infarction. Complications of acute purulent meningitis include intracranial arteritis and thrombophlebitis of the major venous sinuses and cortical veins. Intracranial arterial stenoses have been associated with a complicated clinical course. Varicella-zoster may cause a virus-induced necrotizing arteritis similar to granulomatous angiitis. Cerebral infarction is a complication of the acquired immunodeficiency syndrome (AIDS), and may result from vasculitis, meningovascular syphilis, varicella-zoster virus vasculitis, opportunistic infections, infective endocarditis, aneurysmal dilation of major cerebral arteries, nonbacterial thrombotic endocarditis, aPL antibodies, or other hypercoagulable states, hyperlipidemia resulting from protease inhibitors, and other factors such as HIV-1-related malignancy, cancer chemotherapy, and thrombotic thrombocytopenic purpura (TIP). Large artery cerebrovascular occlusions have been found in association with meningoencephalitis caused by free living amebae. Other infectious agents known to produce cerebral infarcts include Mycoplasma pneumoniae, coxsackie 9 virus, California encephalitis virus, mumps paramyxovirus, hepatitis C virus, Borrelia burgdorferi, Rickettsia typhi group, cat-scratch disease, Trichinella infection, and the larval stage (cysticercus) of Taenia solium. Cerebrovascular involvement in ncurocysticercosis is usually ischemic and is caused by chronic meningitis, arteritis, or endarteritis of small vessels (Alarcon et al. 1992). Unilateral or bilateral carotid artery occlusion can complicate necrotizing fasciitis of the parapharyngeal space. Infection with Chlamydia pneumoniae accelerates the process of atherosclerosis in animal studies; treatment with azithromycin has been shown to reduce the degree of
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atherosclerotic lesions in a rabbit model (Moazed et al. 1999; Muhlestein et al. 1998). Ischemic stroke is a complication of illicit drug use and over-thc-couutet sympathomimetic drugs. Stroke mechanisms associated with the use of illicit drugs are multifactorial, including foreign body embolization, vasculitis, vasospasm, acute onset of arterial hypertension or arterial hypotension, endothelial damage, accelerated atherosclerosis, hyper- or hypocoagulabiliry, cardiac arrhythmias, embolism from a myocardial infarction, or AIDS. The substances implicated most commonly are the amphetamines, cocaine (free-base or "crack"), phenylpropanolamine, pentazocine (Talwin) in combination with pyribenzamine ("T's" and "blues"), phencyclidine, heroin, anabolic steroids, and glue sniffing. Ischemic or hemorrhagic strokes may follow within hours of cocaine use, whether the drug is smoked, snorted, or injected (Figure 57A.13) (see Chapters 57G and 64B). The risk of intracerebral hemorrhage, especially among young women, has led to removal from the American market of phenylpropanolamine (Kernan et al. 2000). Ephedra, also called Ma Huang, widely used in weight-loss products, has been associated with high blood pressure, heart attacks, and strokes. Stroke in young athletes may also be the result of
FIGURE 57A. 13 A 41-year-old woman with a history of cocaine ahuse had acute onset of left-sided hemiplegia, left hemibody sensory deficit, and a left homonymous visual field deficit. Axial flu id-attenuated inversion recovery images of the brain demonstrates an area of infarction in the posterior limb of the right internal capsule in the distribution of the anterior choroidal artery territory. There is associated periventricular ischemia.
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FIGURE 57A.14 Lateral carotid angiogram demonstrates irregular beading appearance [arrowheads) of large and medium branches of the anterior, middle, and posterior cerebral arteries in a patient with systemic lupus erythematosus. (Courtesy Vincent Mathews, MD.)
anabolic-androgen steroid abuse and recombinant erythropoietin ("blood doping") administration. Ischemic stroke is also a complication of a variety of multisystem vasculitides. Stroke in patients with systemic lupus erythematosus may be attributable to cardiogenic embolism (nonbacterial verrucous or I.ibman-Sacks endocarditis, winch occurs in the ventricular surface of the mitral valve), aPL antibodies, underlying vasculopathy, or less often to an immune-mediated vasculitis (Figure 57A.14) (see Chapter 55A). Behcet's syndrome may involve vessels of any size. Venous thrombosis is more frequent than occlusive arterial compromise. Affected patients arc mainly of Mediterranean or East Asian origin and may have a history of iritis, uveitis, and oral, genital, and mucocutaneous ulcerations. Cerebrovascular complications include strokes, carotid aneurysm formation, and cerebral venous thrombosis, Cogan's syndrome is a rare condition characterized by nonsyphilitic interstitial keratitis, vestibular dysfunction, and deafness. Complications include aortic insufficiency and mesenteric ischemia. The angiitic form of sarcoidosis primarily affects the eyes, meninges, and cerebral arteries and veins, Kohlmeier-Degos disease or malignant atrophic papulosis is a multisystem occlusive vasculopathy characterized by cutaneous, gastrointestinal, and neurological manifestations; it may be complicated by ischemic or hemorrhagic strokes. Cerebral vasculitis may also complicate the course of children with acute poststreptococcal glomerulonephritis. The multisystem vasculitides ate described in more detail in Chapter 55A, Takayasu's arteritis is a chronic inflammatory artcriopathy of the aorta and its major branches, as well as the pulmonary artery. The cause is unknown, but an immune
mechanism is suspected. The disease, prevalent in young women of Asian, Mexican, or Native American ancestry, develops insidiously, causing stenosis, occlusion, aneurysmal dilatation, or coarctation of the involved vessels. The disease has two phases. In the acute ot ptcpulsclcss phase, nonspecific systemic manifestations are present. Patients have skin rashes, erythema nodosum, fever, myalgias, arthritis, pleuritis, carotidynia, and elevated erythrocyte sedimentation rate. Months or years later, the second or occlusive phase develops and is characterized by multiple arterial occlusions. Patients may have cervical bruits, absent carotid or radial pulses, asymmetrical blood pressure recordings, and arterial hypertension. Neurological symptoms result from central nervous system or retinal ischemia associated with stenosis or occlusion of the aortic arch and arch vessels, or arterial hypertension caused by aortic coarctation or renal artery stenosis. Visual disturbances are most often bilateral. The diagnosis can be confirmed by MR A, but the most accurate assessment still requires aortography {Figure 57A.15). Patients with active disease are treated with oral glucocorticoids; cyclophosphamide, a/athioprine, or methotrexate may be needed in special circumstances. Surgical treatment (angioplasty or bypass) of severely stenotic vessels may be required (Kerr ct al. 1999). Cranial (giant cell or temporal) arteritis is a polysymptomatic systemic large vessel arteritis with a predilection to involve carotid artery branches (see Chapter 75). Thromboangiitis obliterans, also known as Ruergcfs disease, is a rare, segmental inflammatory, oblitcrativc angiopathy of unknown cause. The condition involves small and medium arteries and veins. It is suspected in young men who smoke and have a history of superficial
ISCHEMIC CEREBROVASCULAR DISEASE
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FIGURE 57A.15 (A) Aortogram demonstrates a nonocclusive stenosis of the brachiocephalic artery. There is complete occlusion of the left subclavian artery. The left vertebra is absent or occluded. (B) The right common carotid artery shows a long segment of critical stenosis extending from C3 to C5. Continued migratory thrombophlebitis presenting with distal limb ischemia accompanied by digital gangrene. The disorder is characterized by remissions and exacerbations. Cerebral involvement is uncommon. Strokes can result from isolated angiitis of the central nervous system. Symptoms of largevessel involvement include strokelike presentations. Smallvessel involvement may be manifested as a mass lesion in the brain or multifocal encephalopathy (Figure 57A.16A and Figure 57A.16B). The erythrocyte sedimentation rate is usually normal or minimally elevated (see Chapter 57G). Migraine (see Chapters 21 and 75) affects women more often than men, and may start during childhood or adolescence. Epidemiological studies suggest a nonrandom association of both headache and migraine with stroke, particularly among young women. This rare association was limited to women younger than age 35 in a large Italian case-controlled study (Carolci ct al. 1996). The possible association between migraine headache and stroke was also evaluated by the Physician's Health Study;
physicians reporting migraine had increased risks of subsequent rotal stroke and ischemic stroke compared with those not reporting migraines (Buring et al. 1995). The International Headache Society Classification and Diagnostic Criteria require that, to establish a diagnosis of migrainous infarction, one or more migrainous aura symptoms must be present and not fully reversed within 7 days from onset, associated with neuroimaging confirmation of ischemic infarction (see Chapter 75). This definition implies that a firm diagnosis of migraine with aura has been made in the past. Also, the clinical manifestations judged to be the result of a migrainous infarction must be those typical of previous attacks for that individual, and finally, other causes of infarction, including those related to migraine therapy, need to be excluded by appropriate investigations. Headache accompanies a number of embolic or thrombotic causes of stroke, including cervicocephalic arterial dissections. Migraines also can be a prominent symptom in the aPL antibody syndrome (APAS). Symptomatic migraine
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FIGURE 57A.15, cont'd. (C) There is also a very long stenosis of the left common carotid artery. (D) A larger cervical right vertebral artery provides vigorous filling of the intracranial right internal carotid circulation.
attacks are more frequent than migraine-induced ischemic insults. The presence of headache with a stroke is therefore not sufficient to make the diagnosis of migraine as the cause of the patient's symptoms. Furthermore, patchy subcortical abnormalities on MRI in patients with migraine with aura should be interpreted with caution. In other words, migrainous infarction remains a diagnosis of exclusion. The pathogenesis of migrainous infarction is controversial. Cerebral infarcts complicating migraine are mostly cortical and involve the distribution of the PCA. The usual scenario of migrainous infarction is one of recurrent episodes of gradual buildup of unilateral throbbing headaches, associated with stereotyped visual phenomena occurring in both visual fields simultaneously, in one of which the vision loss becomes permanent. Migrainous infarctions have been subdivided as definite when all the International Headache Society criteria arc fulfilled, and possible when some, but not all criteria, are fulfilled.
Patients with migrainous infarction arc at increased risk for recurrent stroke. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial nonarteriosclerotic, nonamyloid microangiopathy characterized by migraine with auta, tccurrent subcortical ischemic strokes starting in mid-adulthood, leading to pseudobulbar palsy, cognitive decline, subcortical dementia, and early white matter hyperintensities on MRI. CADASIL is caused by simple missense mutations or small deletions in Notch 3 gene on chromosome 19ql2 encoding a transmembrane receptor Notch 3. Pathologically, there is a characteristic gtanular osmiophilic matctial in arterial walls, including dermal arteries (Kalimo et al. 2002}. A subtype of migraine, known as familial hcmiplegic migraine, characterized by transient weakness or frank paralysis during the aura, has also been mapped close to the CADASIL locus (Hutchinson et al. 1995).
ISCHEMIC CEREBROVASCULAR DISEASE
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FIGURE 57A.16 Cerebellum. (A) Within an area of recent hemorrhage there is a small blood vessel showing focal infiltration with lymphocytes and a couple of multinucleated giant cells (arrows). The lumen of the vessel is marked with an arrowhead (x 680 H&E) Cerebellum. (B) The same vessel as in A. Immunostain with CD 3 demonstrates intense perivascular infiltration with T lymphocytes (x 680).
The newer acronym, cerebral autosomal dominant adenopathy with subcortical infarcts, leukoencephalopathy, and migraine, refers to a subvariety of CADASIL characterized by the high frequency of migraine (Verin et al. 1995),
INHERITED AND MISCELLANEOUS DISORDERS Homocysrinuria, an inborn error of amino acid metabolism, is an unusual cause of stroke {Table 57A.6). Three specific enzyme deficiencies responsible for homocysrinuria have been identified: cystathionine ^-synthetase, homocysteine methyltransferasc, and methylene tetrahydrofolate reductase. The accumulation of homocysteine in the blood leads to endothelial injury and premature atherosclerosis. Patients with homocystinuria may display a marfanoid habitus, malar flush, livedo reticularis, ectopia lentis, myopia, glaucoma, optic atrophy, psychiatric abnormalities, mental retardation, spasticity, seizures, osteoporosis, and a propensity for intracranial arterial or venous
Tabic 57A.6: Inherited and miscellaneous disorders causing cerebral infarction Homocystinuria Fabry's disease Marfan's syndrome Killers-Polios' syndrome
Pseudoxanthoma clasticum Sneddon's syndrome Rendu-Osler-Weber's syndrome Neoplastic angioendotheliomatosis Susac's syndrome Eales' disease Reversible cerebral segmental vasoconstriction Hypcreosinophilic syndrome Cerebral amyloid angiopathy Coils and kinks Arterial dolichoectasia Complications of coarctation of the aorta Air, fat, amniotic fluid, bone marrow, and foreign particle embolism
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NEUROLOGICAL DISEASES
thrombosis. Death may result from pulmonary embolism, myocardial infarction, or stroke. Raised levels of plasma homocysteine may be an independent risk factor for cerebrovascular disease, coronary, and peripheral arterial occlusive disease. Elevated levels of homocysteine can be effectively reduced with the administration of folic acid, occasionally requiring the addition of pyridoxine (vitamin BJ and vitamin B12. Other agents that may reduce homocysteine include choline, betaine, estrogen, and Nacetylcysteine. Fabry's disease is an X-linkcd disorder of glycosphingolipid metabolism characterized by deficient lysosomal agalactosidase activity. As a result, deposits of ceramidc trihexosidasc accumulate in endothelial and smooth muscle cells. Patients have a painful peripheral neuropathy, renal disease, hypertension, cardiomegaly, autonomic dysfunction, and corneal opacifications. Characteristic dark-red or blue lesions that do not blanch on pressure, called angiokeratoma corporis diffusum, are found between the umbilicus and knees. Stroke and myocardial infarction are common. Female carriers may have mild disease or are asymptomatic. Marfan's syndrome is an autosomal dominant inherited connective tissue disease associated with qualitative and quantitative defects of fibrillin. Histopathological studies of aortic segments show cystic medial necrosis. This disorder is characterized by a variety of skeletal, ocular, and cardiovascular findings. Patients with Marfan's syndrome may display arachnodactyly, extreme limb length, joint laxity, pectus excavatum or carinatum, subluxation of the lens, and aortic valvular insufficiency. Marfan's syndrome is associated with a high incidence of dilatation of the aortic root. Other cardiovascular abnormalities include coarctation of the aorta, mitral valve prolapse, and mitral annulus calcification with regurgitation. Progressive dilatation of the aortic root may lead to dissection of the ascending aorta, resulting in ischemia to the brain, spinal cord, or peripheral nerves. Saccular intracranial aneurysms or dissection of the carotid artery can occur. Annual echocardiography studies arc recommended. Patients should avoid contact sports. Patients with Ehlers-Danlos' syndrome, a fairly common heritable connective tissue disorder, display hyperextensibility of the skin, hypermobile joints, and vascular fragility leading to a bleeding diathesis. Arterial complications have been reported in association with Fhlcrs-Danlos' syndrome types I, III, and IV, especially type IV. Complications include dissections, arteriovenous fistulae, and aneurysms. Other cardiovascular abnormalities in patients with type IV Ehlers-Danlos' syndrome include ventricular and atrial septal defects, aortic insufficiency, bicuspid aortic valve, mitral valve prolapse, and papillary muscle dysfunction, Arteriography carries special risks and should be avoided if possible. Patients with pseudoxanthoma elasticum, an inherited group of disorders of clastic tissue, often display loose skin
and small, raised, orange-yellowish papules resembling "plucked chicken skin" in intertriginous areas. Patients with pseudoxanthoma elasticum have a higher risk of coronary artery disease and myocardial infarction. These patients may also have arterial hypertension, angioid streaks of the retina, retinal hemorrhages, arterial occlusive disease, and arterial dissections. Women with pseudoxanthoma elasticum should avoid estrogens. Sneddon's syndrome consists of widespread livedo reticularis and ischemic cerebrovascular manifestations. A number of reports have documented a hereditary transmission and a link between Sneddon's syndrome and aPL antibodies. However, the etiopathogenesis remains unknown, although an immune mechanism is suspected. Endothelial cells could be the primary target tissue. Anticndothelial cell antibodies may be present (Frances et al. 1995). Hereditary hemorrhagic telangiectasia (Rendu-OslerWeber disease) is a familial disorder transmitted as an autosomal dominant trait. Ischemic stroke as a presenting manifestation of Rendu-Osier-Weber's disease has been reported infrequently. Paradoxical venous emboli passing through a pulmonary arteriovenous malformation can be the source of cerebral ischemia or abscess. Other potential causes leading to cerebral ischemia include air embolism and hyperviscosity secondary to polycythemia. Neoplastic angioendotheliomatosis, also called intravascular malignant lymphomatosis or angiotropic lymphoma, is a rare disease characterized by multiple small- and largevessel occlusion by neoplastic cell of lymphoid origin without an obvious primary tumor. Intravascular lymphomatosis has been reported to involve the skin, lungs, kidneys, adrenal glands, liver, pancreas, gastrointestinal tract, ovary, prostate, testicles, heart, thyroid, and parathyroid glands. Bone marrow, spleen, and lymph nodes arc usually spared. Simultaneous involvement of blood vessels throughout the body and compromise of different cerebral arterial territories is common with this disorder. Patients may present with recurrent multifocal cerebral infarctions, dementia, or myelopathy. Diagnosis requires skin, liver, renal, or brain-leptomcningeal biopsy. Combination chemotherapy has been recommended. Autologous peripheral blood stem cell transplantation after chemotherapy may be useful. Microangiopathy ot brain, retina, and inner ear (Susac's syndrome), also known as retinocochleocerebral vasculopathy, is a rare microcirculatory syndrome that affects mainly adult women (Petty et al. 1998). The syndrome is unrelated to arterial hypertension or diabetes and is characterized by arteriolar branch occlusions of the brain, retina, and inner ear, with resultant encephalopathy, vision loss, vestibular dysfunction, tinnitus, vertigo, and asymmetrical sensorineural hearing loss. CSF examination may be normal orshow mild inflammatory response. Brain biopsy may show multifocal brain microinfarcts in both gray and white matter. The causal agent is unknown but has been
ISCHEMIC U--.Rr.liKOVASa.il -\K DISKAS1-
attributed to a disturbance of coagulation, microemholism, or both. Treatment with corticosteroids, cyclophosphamide, azathioprinc, plasmapheresis, or anticoagulant therapy is empiric, but branch retinal artery occlusions and central nervous system infarctions may recur despite the treatment. Hyperbaric oxygen treatment may be an option for refractory visual symptoms. Eales' disease, commonly reported in India and the Middle East, is a rare, noninflammatory occlusive disease of the retinal vasculature characterized by repeated retinal and vitreous hemorrhages. The disorder affects mainly young men. Brain infarctions are rare. Idiopathic reversible cerebral segmental vasoconstriction is an unusual clinical angiographical syndrome characterized by recurrent headaches, and transient motor and sensory findings associated with reversible arterial narrowing and dilatation involving predominantly the arteries around the circle of Willis. The cause is unknown. The hypereosinophilic syndrome is a rare disorder caused by bone marrow overproduction of eosinophils that lodge in endothelial cells in the microcirculation primarily of heart, brain, kidney, lungs, gastrointestinal tract, and skin. Neurological complications include emboli from involved endocardium and heart valves, and neurological manifestations may result also from a hypercoagulable state with cerebral thromboses, and microcirculatory inflammation and occlusion by eosinophils. Cerebral infarction is a rare complication. Cerebral amyloid angiopathy occurs both sporadically or in rave instances as a hereditary disorder. Cerebral amyloid angiopathy is characterized by the localized deposition of amyloid in the media and adventitia of small arteries and arterioles of the cerebral cortex and meninges in the elderly. Cerebral amyloid angiopathy is more commonly associated with lobar hemorrhage than with ischemic stroke, but has been associated with an increased frequency of cerebral infarction in patients with Alzheimer's disease (Olichney et al. 1995). Biopsy of the involved cortex and leptomeninges is the only definitive way to diagnose cerebral amyloid angiopathy. Redundant length of the cervical carotid artery causes coils and kinks and other forms of tortuosity. Occasionally associated with FMD, kinks and coils of the carotid artery are an infrequent cause of cerebral ischemia. Arterial kinking seldom affects the vertebrobasilar circulation. Cerebral ischemia associated with kinking is attributable to a combination of flow reduction caused by obstruction, neck rotation, and distal embolization. Dolichoectasia is an unusual vascular disease that causes enlargement and elongation of arteries, particularly the basilar artery. This arteriopathy causes false aneurysm that leads to ischemic stroke, brainstem compression, cervicomedullary compression, cranial nerve palsies, cerebellar dysfunction, central sleep apnea, and hydrocephalus. The mechanisms of stroke arc penetrating artery occlusion, basilar artery thrombosis, or embolism from the dolichoectatic artery.
U2S
Ischemic stroke and intracranial hemorrhage, the latter caused by arterial hypertension or ruptured intracranial aneurysm, are important complications of coarctation of the aorta. Spinal cord ischemia may also complicate surgery for aortic coarctation. Neurological complications can result also from aortic rupture, infective aortitis or endarteritis, associated aortic bicuspid valve, and dissection of the aorta proximal to the coarctation. Atheromatous emboli (cholesterol emboli syndrome) may follow manipulation of an atherosclerotic aorta during catheterization or surgery. Clinical presentation may include TIAs, stroke, retinal embolism pancreatitis, renal failure, and livedo reticularis. Purple toes may occur also as a result of small cholesterol emboli lodging in the digital arteries. Pedal pulses are normal. Patients also have a low-grade fever, eosinophilia, anemia, elevated erythrocyte sedimentation rate, and elevated serum amylase, Anticoagulation may exacerbate further embolization, and its use should be discouraged. Accidental introduction of air into the systemic circulation can be a cause of cerebral or retinal ischemia. Air embolism is a dreaded complication of surgical procedures, including intracranial operations in the sitting position; open heart surgery; surgery of the lungs, pleura, sinuses, neck, and axilla; hemodialysis; thoracocentesis; arteriography; central venous catheters; and scuba diving. Symptoms include seizures and multifocal neurological findings such as cerebral edema, confusion, memory loss, and coma. CT scan may be useful in visualizing the gaseous bubbles. Treatment includes prompt resuscitative measures, placement of the patient in the left lateral position, inotropic agents, anticonvulsants, anti-edema agents, and hyperbaric oxygen. Caisson's disease can occur in persons who are scuba diving. Neurological features are caused by multiple small nitrogen emboli leading to ischemia of the brain and spinal cord; signs of spinal cord dysfunction are prominent. Hyperbaric oxygen therapy is the usual treatment. Fat embolism to the brain complicates long bone fractures, sickle cell disease, cardiopulmonary bypass, soft tissue injuries, and blood transfusions. This syndromeoccurs suddenly within hours to 3 or 4 days after injury and is characterized by dyspnea, fever, tachycardia, tachypnea, cyanosis, cutaneous petcchiae, and coagulopathy. Neurological manifestations arc confusion, disorientation, delirium, hemiparesis, aphasia, and coma. Petechia) hemorrhages may be apparent on funduscopy, conjunctivae, base of the neck, and axillary region. Vigorous respiratory supportive therapy is essential. Amniotic fluid embolism is a rare catastrophic obstetrical complication caused by the entry of amniotic fluid into the maternal bloodstream during parturition. Vigorous supportive therapy with intravenous fluids and blood replacement to treat shock, correction of respiratory distress syndrome, disseminated intravascular coagulation, and underlying fibrinolytic state are essential. Among other causes of emboli are large intracranial saccular aneurysms
1226
NEUROLOGICAL DISEASES
or extracranial false aneurysms of the internal carotid artery. Tumor emboli to the brain have been reported with osteosarcoma, atrial myxoma, and with carcinoma of the lung, breast, pharynx, or esophagus. Talc, cornstarch, and other foreign particles injected as adulterants in illicit drugs can embolize to the brain or retina. Paradoxical embolism during bone marrow infusion is an infrequent complication.
HYPERCOAGULABLE DISORDERS Alterations in hemostasis are associated with an increased risk of cerebrovascular events, particularly those of an ischemic nature and may account for a considerable number of cryptogenic strokes (Table 57A.7). These disorders account for 1% of all strokes and for 2 - 7 % of ischemic strokes in young patients (Kitchens 1994).
Primary f lypercoagulable States Inherited disorders predisposing to thrombosis especially affect the venous circulation. These disorders include AT-III deficiency, protein C and protein S deficiencies, activated protein C (APC) resistance, abnormalities of fibrinogen
Table 57A.7:
Hypercoagulahle states
Primary hypercoagulahle states Antitlirombin III deficiency Protein C deficiency Protein S deficiency Activated protein C resistance with or without factor V Leiden mutation Prothrombin G20210 mutation Afibrinogenemia Hypofibrinogenemia D ysfi b r i nogenem i a Hypoplasminogencmia Abnormal plasminogen Plasminogen activators deficiency Lupus anticoagulant and antieardiolipin antibodies Secondary hypercoagulable states Malignancy P regn a ncy/pu erpe r i u m Oral contraceptive use ( karinii liypcr^rmnilation syndrome Other hormonal treatments Nephrotic syndrome Polycythemia vera Essential thrombocythenna Paroxysmal nocturnal hemoglobinuria Diabetes mellitus Heparin-induced thrombocytopenia Homocystinuria Sickle tell disease (sickle cell anemia, sickle cell-hemoglobin C) Thrombotic thrombocytopenic purpura Chemotherapeutic agents
(dysfibrinogencmia), and abnormalities of fibrinolysis. Inherited thrombophilia should be suspected in patients with recurrent episodes of deep venous thrombosis, recurrent pulmonary emboli, family history of thrombotic events, unusual sites of venous (mesenteric, portal, or cerebral) or arterial thromboses, or in patients with thrombotic events occurring during childhood, adolescence, or early adulthood. Approximately one half of all thrombotic episodes occur spontaneously, although these patients arc at greatest risk when exposed to additional risk factors such as pregnancy, surgery, trauma, or oral contraceptive therapy. AT-III deficiency is inherited in an autosomal dominant fashion, thus affecting both sexes. There are three categories of inherited AT-III deficiency: classic or type I, characterized by decreased immunological and biological activity of AT-III; type II, characterized by low biological activity of AT-III but essentially normal immunological activity; and type III, characterized by normal AT-III activity in the absence of heparin, but reduced in heparindependent assays. Acquired AT-III deficiency may follow acute thrombosis and disseminated intravascular coagulation. It has been associated also with nephrotic syndrome, liver cirrhosis, eclampsia, various malignancies, the use of estrogens or oral contraceptives, L-asparaginase, tamoxifen, and heparin therapy. A normal level of AT-III activity obtained at the time of an acute thrombotic event is sufficient to exclude a primary deficiency. However, a low level of AT-III activity must be confirmed by repeat testing, after resolution of the thrombotic episode and discontinuation of anticoagulant therapy. Confirmation of a low plasma level of AT-III activity on repeat resting is compatible with a primary deficiency and is an indication to investigate other family members. Thrombotic episodes associated with AT-III deficiency are treated acutely with heparin with or without adjunctive AT-III concentrate. Prophylactic therapy in patients with recurrent thrombosis consists of long-term warfarin administration, keeping the therapeutic INK range between 2,0 and .i.O. Protein C deficiency is inherited in an autosomal dominant fashion. Homozygous protein C deficiency presents in infancy as purpura fulminans neonatalis. Heterozygotes are predisposed to recurrent thrombosis. Thrombotic manifestations are predominantly venous, Acquired protein C deficiency has been associated with the administration of L-asparaginase, warfarin therapy, liver disease, disseminated intravascular coagulation, postoperative state, bone marrow transplantation, and the adult respiratory distress syndrome. Testing for immunological and functional assays of protein C should be performed after oral anticoagulation has been discontinued for at least a week. Heparin does not modify the levels of protein C. Warfarin-induced skin necrosis is a serious potential complication of protein C-deficient patients at the initiation of warfarin therapy; this syndrome often occurs in association with large loading doses of warfarin. The acute
ISCHEMIC CF.REBftOVASCUI.AR DISEASE management of thrombosis associated with protein C deficiency consists of prompt administration of heparin followed by incremental doses of warfarin, starting with low doses until adequate anticoagulation is achieved. Longterm management requires the administration of warfarin. Protein S deficiency also has an autosomal dominant mode of inheritance. Protein S exists in plasma in two forms; approximately 4 0 % of the total protein S is functionally active or free, and the remaining is complexed to a binding protein. Homozygous protein S deficiency presents with venous thromboembolic disease. Heterozygotes are prone to recurrent thrombosis including cerebral venous thrombosis. Acquired protein S deficiency occurs during pregnancy, in association with acute thromboembolic episodes, disseminated intravascular coagulation, nephrotic syndrome, systemic lupus erythematosus, and with the administration of oral contraceptives, oral anticoagulants, and L-asparaginase. Testing for immunological assays of total and free protein S, and functional assay of protein S, should be confirmed after resolution of the thrombotic episode and discontinuation of oral anticoagulants. Heparin therapy is effective in the management of acute thrombotic events associated with protein S deficiency, whereas watfarin is advocated for patients with recurrent thromboembolism. Resistance to APC is one of the most common identifiable risk factors for venous thromboembolic disease, including cerebral venous thrombosis. The relation of APC resistance to arterial disease is not well established. APC resistance has been identified as 5 to 10 times more common than deficiencies of AT-III, protein C, or protein S. APC resistance also has an autosomal dominant mode of inheritance. APC resistance is associated in most patients with a single point mutation in the factor V gene (factor V Leiden), which involves the replacement of arginine 506 with glutamine 506 (Arg 506 Gin). Testing for resistance to APC must be done after discontinuation of anticoagulants. There are conflicting results about factor V Leiden gene mutation and the risk for acute cerebral arterial thromboses. The contribution of factor V Leiden or prothrombin G20210A to ischemic stroke in the young is less clear. Conversely, both factor V Leiden and prothrombin G20020A mutations are associated with an increased risk for cerebral venous thrombosis (Ludemann et al. 1998; Peuner et al. 1998; Cushman et al. 1998). In the Physicians' Health Study, no association between factor V Leiden or prothrombin G20210A and ischemic stroke was found (Ridker et al. 1995). Abnormalities of fibrinogen account for approximately 1% of all inherited thrombotic disorders. Fibrinogen crosslinks platelets during thrombosis and is an important component of atherosclerotic plaques. High concentrations of fibrinogen increase the risk for stroke and myocardial infarction. Afibrinogenemia is probably transmitted as an autosomal recessive trait; complications include umbilical cord bleeding, gastrointestinal hemorrhage, and
1227
intracranial hemorrhage. Hypofibnnogenemia represents the heterozygous lorm of afibrinogenemia; bleeding is rare. Dysfibrinogcnemia reflects a qualitative disorder in the fibrinogen molecule and may be associared with hemorrhagic or thrombotic episodes. Hereditary dysfibrinogcnemia is inherited in an autosomal dominant fashion. Decreased concentrations of fibrinogen are associated with disseminated intravascular coagulation, liver failure, snake bite, treatment with t.-asparaginase, Ancrod, fibrinolytic drugs, and valproate. Treatment consists of infusions of cryoprecipitate. Decreased levels of plasminogen (hypoplasminogcnemia), qualitative abnormalities in the plasminogen molecule (dysplasminogencmias), and defective release of plasminogen activators occur in families with recurrent thrombotic events. Cerebral venous thrombosis occurs with disorders of plasminogen. Prophylactic therapy in patients with recurrent thrombosis consists of lifelong anticoagulation. Lupus anticoagulants and anticardiolipin (aCL) antibodies are known collectively as antipbvspbolipid antibodies and have a pathogenetic role in arterial and venous thrombosis. Ischemic stroke is the most common arterial thrombotic event in patients with APAS. APAS associates the presence of aPL antibodies in high titers with recurrent arterial or venous thromboses, feral loss, and livedo reticularis. Several aPL antibodies have been described in immunoglobulin (Ig)G, IgA, or IgM isorypes: aCL, antiphosphatidylcthanolaminc (aPL), antiphosphatidylserine, and antiphosphatidykholinc. Affinity-purified aCLs do not bind to cardiolipin in the absence of seium or plasma. The component required for aCL binding is £2-gIycoprotein 1 (/32GP1). It is the 02-GPl -dependent aCL of the IgG isotype that has been significantly associated with sttokes and myocardial infarcts (Brey et al. 2001). Other stroke studies have reported an association with aPE (GonzalesPortillo et al. 2001). APL antibodies arc present in patients with systemic lupus erythematosus and related autoimmune disorders, Sneddon's syndrome, acute and chronic infections (including HIV-1), neoplasias, inflammatory bowel disease, administration of certain drugs, early onset severe preeclampsia, liver transplantation, and also in individuals without demonstrable underlying disorders. A distinct group of patients has a primary APAS; its association with ischemic cerebrovascular disease is rare. APL antibodies arc associated with recurrent fetal loss, a prolongation of the activated partial thromboplastin time (aPTT) that does not correct on 1 to 1 mixing with normal plasma, thrombocytopenia, a false-positive VDRL test result, and livedo reticularis. They may also be associated with cerebral and ocular ischemia, cerebral venous thrombosis, migraine, vascular dementia, chorea, transverse myelopathy, myocardial infarction, peripheral arterial thromboembolism, venous thrombosis, pulmonary embolism, and Degos' disease. Multiple cerebral infarctions are
1228
NEUROLOGICAL DISEASES
common in patients with aPL antibodies; a subset of patients may present with vascular dementia (Figure 57A. 17). Still another group may have an acute or progressive thrombotic ischemic encephalopathy. Pathological studies of cerebral arteries involved in association with aPL antibodies demonstrate the presence of a chronic thrombotic microangiopathy, but no evidence of vasculitis. Patients with a PI. antibodies have an increased frequency of mitral and aortic vegetations. There are findings resembling verrucous endocarditis (Libman-Sacks endocarditis). Left ventricular thrombus formation is a rare occurrence, Treatment for arterial thrombosis associated with aPL
antibodies is not well established. One casc-conttolled study found that high-intensity warfarin (INR > 3.0), with or without aspirin, was more effective in preventing thrombotic recurrences than low-intensity warfarin, with or without aspirin, or aspirin alone (Khamashta et al. 1995). Guidelines published in the United Kingdom have recommended an INR target of 3,5 (British Committee for Standards in Hematology 1998) or 2.5 (Greaves et al. 2000). In the Warfarin Aspirin Recurrent Stroke Study (WARSS), warfarin (median INR = 2.09) did not provide additional benefit over aspirin in preventing recurrent ischemic stroke among ischemic stroke patients who were
FIGURE 57A.17 A 44-year-old man with elevated anticardiolipin antibodies had a branch retinal vein occlusion in the left eye, progressive balance problems, poor memory, and an overall decline in cognitive functioning, Echocardiography showed thickened mitral valve without significant stenosis, T2-weighted axial magnetic resonance imaging of the brain demonstrates confluent hyperintensities in the periventricular region and basal ganglia consistent with ischemia. There are also bilateral hyperintensities in the cerebellum consistent with infarcts. Cortical ischemic changes are also present bilaterally in the occipital lobes and in the right frontal lobe.
ISCHEMIC CEREBROVASCULAR DISEASE
1229
manifestations produce a diffuse encephalopathy secondary to disseminated microinfarcts. Other patients with malignancy and cerebral infarction may have cerebral venous occlusive disease caused by thrombi, tumor invasion, or stroke associated with chemotherapy. In addition, cancer-en ha need arhcrothrombosis, neoplastic angioendotheliomatosis, arterial compression by tumor, occlusive vascular disease secondary to irradiation, intercurrent angiitis, and arterial rupture also may be responsible for cerebral infarction in some patients. Treatment consists of management of the underlying malignancy. Anticoagulants and platelet antiaggregants are used with variable success.
FIGURE 57A.17,
cont'd.
aPl. antibody-positive at baseline (Levine et al. 2002). Pregnant patients are often treated with prednisone and low-dose aspirin.
Secondary Hypercoagulable States Strokes may complicate the clinical course of malignancies. In rare instances, stroke may be the initial manifestation of cancer. Cerebral infarction mostly complicates lymphomas, catcinomas, and solid tumors. Cerebral hemorrhages are more common with leukemia. Hypercoagulability is not an uncommon finding in patients with malignancy, especially with mucin-producing carcinomas of the pancreas, gastrointestinal tract, and lung; myeloproliferative disorders; acute promyelocytic leukemia; and brain tumors. Mucinous adenocarcinomas of the gastrointestinal tract, lung, and ovary may produce infarcts from widespread cerebral arterial occlusions by mucin. The cause of the hypercoagulable state is often multifactorial. The pathophysiology is believed to be a state of low-grade disseminated intravascular coagulation and secondary fibrinolysis, but with the balance shifted toward clotting. Atherosclerosis is still the leading cause of infarction in patients with malignancy. Cerebral infarction in patients with malignancy also may be caused by tumor emboli, bone marrow embolization, emboli originating from mural thrombi, or emboli arising from marantic vegetations associated with nonbacterial thrombotic endocarditis. Many patients with nonbacterial thrombotic endocarditis have associated disseminated inttavascular coagulation, which may cause capillary occlusion of multiple organs, especially the lungs, kidneys, gastrointestinal tract, heart, and brain. Neurological
The postpartum period is a hypcrcoagulable state. Characteristically, arterial causes of stroke are more common during pregnancy, whereas venous causes of stroke are more common during the puerperium (sec Chapter 87). Oral contraceptives cause alterations of the vessel wall with intimal hyperplasia. They also increase blood viscosity. (here arc decreased levels of protein S, AT-III activity, and plasminogen activator content in women taking oral contraceptives. There also may be an increase in the levels of fibrinogen, factors VII and X. Oral contraceptive therapy may enhance arrerial hypertension. Women taking oral contraceptives have an estimated ninefold increased risk of thrombotic stroke. This risk is increased by prolonged use, high dosage of the estrogen component, cigarette smoking, concomitant diabetes, arterial hypertension, hyperlipidcmia, and age older than 35 years. Current users of oral contraceptives are at increased risk of stroke. One study showed that oral contraceptives containing 30-40 ^g of estrogen are associated with a one third reduced risk compared with preparations containing 50 ng. The occurrence of intracranial venous thrombosis as a complication of oral contraceptives is well recognized. A patient on oral contraceptives occasionally presents with stroke caused by paradoxical embolism associated with deep venous thrombosis. Oral contraceptives also increase the risk of subarachnoid hemorrhage. Oral contraceptives probably should be avoided in women with arterial hypertension. They should also be avoided in the first 2 weeks after delivery. Women older than 35 years of age who smoke cigarettes probably should be advised to choose a different contraceptive method. As part of primary stroke prevention efforts, women who smoke should not use oral contraceptives. The ovarian hypersrimularion syndrome occurs in women after induction of ovulation with clomiphene, human menopausal gonadotropin, human follicle-stimulating hormone extracted from human pituitary, and human chorionic gonadotropin. Evidence of body fluid shifts and hypercoagulability exist with this syndrome, reflected in thromboembolic events. Stroke is a rare but serious consequence of severe ovarian hyperstimillation syndrome. Thromboembolic events are a feared complication of hormone treatment in ttansscxuals. Cerebral infarction has
1230
NEUROLOGICAL DISEASES
occurred as a side effect of exogenous estrogen in a male-tofemale transsexual. Likewise, TIAs and cerebral infarction may follow the administration of anabolic steroids for the treatment of hypogonadism and hypoplastic anemias. Cerebral ischemia has occurred also following the use of human recombinant erythropoietin in the treatment of anemia of patients on hemodialysis. The nephrotic syndrome may be accompanied by venous and arterial thromboses, including cerebral arterial and venous occlusive disease. Ischemic stroke can be the presenting manifestation. The mechanism by which nephrotic syndrome causes hypercoagulability is multifactorial and includes elevated levels of fibrinogen, raised levels of factors V, VII, VIII, and X, thrombocytosis, enhanced platelet aggregation, and reduced levels of AT-III and protein S. The exact role of hyperlipidemia, corticosteroids, and diuretic use is uncertain. Nephrotic syndrome should be considered as a contributing mechanism in any patient with ischemic stroke and pre-existing renal disease. A urinalysis is the initial clue to the diagnosis. The presence of severe proteinuria and a low serum albumin should prompt consideration of a hypercoagulable state. Treatment of thromboembolism associated with nephrotic syndrome consists of anticoagulants until remission of the renal condition. Polycythemia vera and primary or essential rhrombocythemia are typically disorders of middle-aged or elderly patients. Polycythemia vera is characterized by increased red blood cell mass and normal arterial oxygen saturation. Patients have ruddy cyanosis, painful pruritus, hypertension, splenomegaly, elevated hemoglobin, high hematocrit value, thrombocytosis, leukocytosis, and elevated serum B12 levels. Typically, the bone marrow is hypercellular. Secondary polycythemia may occur in association with cerebral hemangioblastoma, hepatoma, hypernephroma, uterine fibroids, benign renal cysts, carbon monoxide exposure, and administtation of androgens. Cerebral blood flow is reduced, and cerebral hemorrhage, and arterial or venous thrombosis, can complicate the condition. The majority of the intracranial events are thrombotic in origin, the larger cerebral arteries being the most frequently involved. The risk of stroke parallels the hemoglobin level: The higher the hemoglobin and hematocrit values, the greater the risk of stroke. Headaches, dizziness, vertigo, tinnitus, visual disturbances, carotid and vertebrobasilar TIAs, chorea, and fluctuating cognitive impairment are we 11-recognized features of patients with polycythemia vera. Spinal cord infarction is a rare complication. Cautious lowering of the hematocrit is a reasonable therapeutic approach. Because of the potential risk of hemorrhagic intracranial complications, aspirin therapy should be used cautiously. Cerebral thrombotic and hemorrhagic complications are not uncommon in primary or essential thrombocythemia. Patients may have splenomegaly, mucocutaneous hemorrhagic diathesis, persistently elevated platelet count, usually
in excess of 1 million per pi, giant platelets, and a bone marrow megakaryocyte hyperplasia. Neurological complications are common. Headaches, dizziness, amaurosis fugax, and TIAs of the brain are relatively frequent. Cerebral arterial thrombosis caused by platelet-fibrin thrombi is a rare but serious complication of essential thrombocythemia. Papilledema secondary to cerebral venous thrombosis may be a complication in patients whose platelet levels have not been controlled. Cerebral infarctions also have been reported in patients with secondary thrombocythemia caused by iron deficiency anemia. Iron deficiency anemia with or without thrombocytosis also has been implicated as a cause of intraluminal thrombus of the carotid artery, intracranial venous thrombosis, and intracranial hemorrhage (Hartficld et al. 1997), Thrombocytosis is common after splenectomy, but does not seem to catty an inctcascd thromboembolic risk. However, reactive thrombocytosis following cardiopulmonary bypass surgery may be involved in the cause of stroke in the late recovery period after surgery. The role of rebound thrombocytosis in ischemic stroke among heavy alcohol drinkers is uncertain. Treatment of primary thrombocythemia includes hydroxyurea, plateletpheresis, recombinant interferon-a, and aspirin. Vigorous correction of the anemia is indicated for those patients with thrombocytosis associated with iron deficiency anemia, Paroxysmal nocturnal hemoglobinuria is an acquired clonal stem cell disorder characterized by severe hemolytic anemia and hemosiderinuria. A feared complication is cerebral venous thrombosis. Thrombosis of major cerebral veins or dural sinuses and portal vein thrombosis are the most frequent causes of death. Acute thrombotic episodes involving the cerebral veins may be treated with thrombolytic agents, unless contraindicated, or anticoagulant therapy. High-dose cyclophosphamide and granulocytecolony stimulating factor are being studied for the treatment of paroxysmal nocturnal hemoglobinuria. Diabetes is a well-established risk factor for ischemic stroke. Diabetes associated with arterial hypertension or hyperlipidemia adds significantly to stroke risk. There are a variety of platelet, theological, coagulation, and fibrinolytic abnormalities thai may play a role in the pathogenesis ol stroke in diabetic patients. Numerous hemorrheological disturbances appear to affect the development of diabetic microvascular disease and may contribute to cerebrovascular ischemic events. Hemorrheological alterations producing increased blood viscosity may include increased fibrinogen values, increased hematocrit, elevated factors V and VII, increased platelet aggregation, increased platelet adhesion, increased release of /i-thromboglobulin, decreased red blood cell deformability, and decreased fibrinolytic activity. Heparin-induced thrombocytopenia can cause high morbidity and mortality from thrombotic complications. Heparin therapy may induce two types of thrombocytopenia. The most frequently observed is type I heparin-induced
ISCHEMIC CEREBROVASCULAR DISEASE
thrombocytopenia, which is a mild and benign condition with platelet counts around 100,000 per pi. This thrombocytopenia tends to occur early and resolve spontaneously. Complications are rare. Type II heparin-induccd thrombocytopenia is a major, albeit infrequent (< 3% with unfractionated heparin and < 1% with low-molecular weight heparins), adverse side effect of heparin therapy with a delayed onset (5-15 days after heparin administration). An immune-mediated disorder characterized by increased levels of platelet-associated IgG and IgM, it increases the risk for venous and arterial thrombotic complications involving the brain, heart, and limbs. Fatalities arc high, and hemorrhagic complications are rare. Unlike drug-induced immune TTP, petechiae are not seen in cases of heparin-induced thrombocytopenia with thrombosis. Prevention is paramount, requiring an optimal reduction of the time of exposure to heparin to less than 5 days when possible, and daily platelet counts during heparin administration. Treatment requires immediate discontinuation of heparin. If anticoagulant therapy is still needed, the use of danaparoid, recombinant hirudin or argatroban should be considered. Elevated plasma homocysteine levels are an independent risk factor for atherosclerotic disease. Patients with high plasma homocysteine levels have a greater likelihood of occlusive disease of the extracranial carotid arteries, cerebral arteries, peripheral vascular and coronary beds when compared with the general population. Diagnosis of hyperhomo cy stein cmia may be made by demonstrating elevated basal plasma levels of homocysteine or raised levels after methionine loading. Reduction of homocysteine levels in plasma requires the supplementation of folate, vitamin B1.7), a prolonged aPTT or use of heparin in the previous 48 hours, platelet count less than 100,000 pet j.iL, another stroke or serious head injury in the previous 3 months, major surgery within the previous 14 days, arterial puncture at a noncompressible site within the previous 7 days, or pretreatment SBP greater than 185 mm Hg or DBP greatet than 110 mm Hg. The use of intravenous rt-PA for Alteplasc Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke trial was terminated early because of non statistical efficacy at interim analysis (Clatk et al. 1999). Favorable outcome at 3 months was 4 2 . 3 % for those treated with tPA versus 38.9% for those treated with placebo. Mortality at 3 months was 11.0% for tPA-treated patients versus 6.9% fot those patients receiving placebo. Symptomatic intracranial hemorrhage occurred in 7.0% of tPA-treated patients. The Second European-Australasian Acute Stroke Study investigators recently assessed the safety and efficacy of intravenous alteplasc {0.9 mg/kg of body weight) administered within 6 hours of ischemic stroke onset and failed to confitm a statistical benefit for alteplasc; symptomatic intracranial hemorrhage occurred in 8.8% of altcplasctreated paricnts and in 3.4% of placebo-treated patients (Hacke et al. 1998). An earlier study, using a dose of TPA of 1.1 mg/kg, also failed to demonstrate therapeutic efficacy among 620 patients treated within 6 hours from ischemic stroke onset (Hacke et a I. 1995). Favorable outcome at 3 months was 35.7% for those treated with tPA vctsus 24.3% for those receiving placebo. Mortality at 3 months was 22.4% for tPA-treated patients vetsus 15.8% for those treated with placebo (Clark et al. 1999; Hacke et al. 1998). Thrombolysis-related intracranial hemorrhages are usually large volume lobar bleeds, often multiple, with blood/fluid levels; intraventricular and subarachnoid extension is not uncommon. The rate of symptomatic intracranial hemorthage in several phase IV series of tPA in the community setting was similar to that seen in the NINDS
Trial (Chiu et al. 1998; Albers et al. 2000). Protocol violations have been associated with higher rates of symptomatic intracranial hemorrhages (Katzan et al. 2000; Buchan et al. 2000). In spite of a consistently lower frequency of intracerebral hemorrhage with the use of SK rather than tPA, in patients with acute myocardial infarction, current data do not support the use of intravenous SK, 1.5 million units, in acute ischemic stroke. Recombinant ptoutokinase (r-pro-UK) was tested in the Proutokinase in Acute Cerebral Thromboembolism II trial. In this multicenter, phase III, randomized, controlled trial, 180 patients with angiographically proven occlusion of the MCA (Ml or M2 MCA occlusion) wete given local intra-arterial pro-UK within 6 hours of symptom onset. Of the treated patients, 4 0 % were functionally independent, compared with 2 5 % of the placebo group patients 3 months after treatment {p — .04). The efficacy of treatment seemed to fall off after approximately 5 hours. Treated patients, however, also encountered a higher risk of intracranial hemorrhage with neurological detetioration within 24 hours of treatment (10% versus 2% in the control group; p = .06) (Furlan et al. 1999). The potential therapeutic benefit of intra-arterial thrombolysis and of the combination of thrombolytic and ncuroprotectant agents is being studied. Whether the combined use of intravenous and intra-arterial t-PA in acute ischemic stroke is safe or effective has yet to be determined. Mechanical thromboaspiration with newer catheter techniques is being actively explotcd. The following seem to be predictors of favorable outcome with intravenous thrombolytic therapy for acute ischemic stroke: treatment within 90 minutes of symptom onset, normal baseline CT scan, milder baseline stroke severity, no history of diabetes mellitus, notmal prctrcatment blood glucose level, and normal pretreatment blood pressure. The following seem to portend a less favorable outcome and/or increased risk for cerebral hemorrhage; extended area of low attenuation with mass effect or low attenuation on one third or more of the MCA territory on pretreatment CT scan; advanced age; prior head injury; diabetes mellitus; marked elevation of the blood pressure before, during, and after treatment; hypertension requiring postrandomization antihypertensive treatment; severe pretreatment neurological deficits; and protocol violations according to the NINDS study protocol (Kocnnecke H-C 2002). Although no strict age cutoff exists for administering thrombolytics for ischemic stroke, physicians need to balance the increased risk of hemorrhage in patients aged 75 and older with potential benefit.
Defibtinogciiating Agents Ancrod, an enzyme extracted from the venom of the Malayan pit viper, lowers fibrinogen and blood viscosity,
IS< :i UMir CEREBROVASCULAR DISEASE Table 57A.9: Current status of thrombolytic therapy of cerebral ischemia Therapy Thrombolytic therapy Streptokinase tPA r-prourokinase Hemorheological therapy Hcmodilution Pentoxifylline Ancrod
Conclusion Negative Positive (within 3 hr of stroke onset; intravenous use) Positive (within 6 hr of stroke onset; intra-arterial use)* Negative Negative Positive (within 3 hr of stroke onset; intravenous use)*
"Currently, neither r-prourokinase nor Ancrod is available or approved by the U.S. Food and Drug Administration for use in acute ischemic stroke. tPA = tissue plasminogen activator.
inhibits erythrocyte aggregation, indirectly stimulates thrombolysis, and possibly causes local vasodilatation. It also has a weak anticoagulant effect at high dosages. Its potential as a treatment for ischemic stroke was shown to be beneficial when initiated within 3 hours of stroke onset in the multicentcr Stroke Treatment with Ancrod Trial (Sherman et al. 2000). The positive results of this study were not replicated in a European Trial. Currently, neither r-pro-UK nor Ancrod are available or approved by the U.S. Food and Drug Administration for use in acute ischemic stroke. Hemorheologic therapy with isovolemic, hypovolemic, or hypervolemic hcmodilution has been ineffective (Table 57A.9).
Neuroprotective Agents Despite widespread interest in neuroprotective drug therapy and positive results in experimental animals, no neuroprotective agent has been approved to date by the U.S. Food and Drug Administration for acute ischemic stroke. Almost 120 controlled clinical trials involving more than 21,000 subjects, and investigating more than 50 neuroprotective interventions, have yielded negative results. New agents (spinal tap agents, oxygenated fluorocarbon nutrient emulsions, a-amino-3-hydroxy-5-merhyl-4-isoxazole propionic acid antagonists, and potassium channel openers) have been proposed. Intracellular adhesion molecules (ICAMs) arc molecules to which leukocytes adhere and which facilitate migration of leukocytes through the endothelium. Some of these molecules are expressed in the cerebral vasculature during ischemia. Neutrophils in particular can contribute to tissue injury by obstructing capillaries and possibly by liberating cytotoxic products. Prevention of neutrophil adhesion by infusion of monoclonal antibodies directed at ICAMs
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improved neurological outcome in animal models of transient ischemia, but clinical trials yielded negative results. The sudden decrease in blood flow after ischemia provokes a cascade of events eventually leading to cell death. These events include the release of excitatory amino acids (F.AAs) with secondary opening of ion channels, which leads to an increase in intracellular calcium concentration, activation of enzymes, and generation of free radicals. Several agents have been shown in vitro and in animal studies to interfere at various steps of this cascade, thus potentially protecting the cells from ischemia. Cerebroselectivc calcium-channel blockers such as nimodipine have been tested in acute stroke, but the benefits for patients with acute ischemic stroke remain unproven. Endogenous EAA neurotransmitters play a major role in the pathogenesis of cerebral ischemia. In animals, EAA antagonists reduce the size of an infarct after occlusion of a maior artery. From preliminary studies, some of these compounds appear to be safe in humans, but their efficacy has not been demonstrated, and several clinical trials yielded negative tesults. Optimal protective regimens may necessitate blockading of both N-methyl-u-aspartate (NMDA) and non-NMDA receptors. Free radicals produced during ischemia can degrade polyunsaturated lipids, which arc building blocks of cellular membranes, by means of lipid peroxidation. The central nervous system appears particularly susceptible to free radical injury. The 21 aminosteroid compounds inhibit lipid peroxidation by scavenging free radicals. Tirilazad is one such compound that decreases damage secondary to global ischemia in experimental animal models, but its clinical application in the treatment of patients with ischemic stroke has not been established. Neurotrophins are factors known to promote cell growth in certain neuronal populations. Studies have shown that some of these factors given intraventricular^ to animals during ischemia reduce infarct size. The mechanism of action is still unknown but could be related to interaction with EAAs. Calpains are cytosomal enzymes that are normally quiescent but become activated by increases in intracellular calcium concentration. These enzymes have many proteins as their targets, and thus their activation can cause considerable damage. In experimental models of stroke in animals, intra-arterial infusion of calpain inhibitors given after onset of ischemia significantly reduced infarct size compared with controls. The value of calpain inhibitors in humans has not been established. The value of intravenous magnesium (which is an NMDA antagonist) is under investigation. Treatments with gangliosides, barbiturates, prostacyclin, opiate antagonists, aminophylline, ^-adrenergic receptor blockers, vasopressor therapy, naftidrofuryl, clometbiazole, inhibitors of leukocyte adhesion, fosphenytoin, lubeluzole, basic fibroblast growth factor, and citicolinc have been ineffective (Table 57A.10).
1240
NEUROLOGICAL DISEASES
Tabic 57A.10: Current status of neuroprotection of cerebral ischemia: results of selected therapies Ni modi pi tie Tirilazad Excitatory amino acid antagonists Neurotrophins Calpain inhibitors Other agents Gangliosides Barbiturates Prostacyclin Opiate antagonists Aminophylline /(-Adrenergic receptor blockers Vasopressor therapy Anti-ICA.M antibodies Lubcluzole Fosphcnytoin Enlimomab Basic fibroblast growth factor Naftidrofuryl Magnesium (intravenous) Glyceryl trinitrate Astrocyte inhibitors (ONO-2506) Serotonin agonists (repinotan)
Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Under investigation Under investigation Under investigation Under investigation
ICAM = intracellular adhesion molecule.
Surgical Therapy Symptomatic
Carotid Artery Stenosis
Stroke is often caused by atherosclerotic lesions of the carotid artery bifurcation; approximately 15% of ischemic strokes are caused by extracranial internal carotid artery stenosis. Carotid atherosclerosis develops in areas of low vessel-wall shear stress, most commonly the carotid bulb. In addition to the degree of carotid artery stenosis, plaque structure has been postulated as a critical factor in defining stroke risk. Ulcers found during CEA have been associated with cerebral artery microemboli detected by transcranial Doppler (Sitzer et al. 1995). Echoluccnt carotid artery plaques may also be associated with an increased risk of stroke. CEA, by removing the atherosclerotic plaque, restores cerebral blood flow and reduces the risk of cerebral ischemia, Results from three major prospective contemporary studies provide compelling evidence of the benefit of CEA performed by experienced surgeons in improving the chance of stroke-free survival in high-risk symptomatic patients. Timely surgical intervention in selected patients with hemispheric TTAs, amaurosis fugax, or completed nondisabling carotid terrirory strokes within the previous 6 months, and with 7 0 - 9 9 % diameter-reducing carotid stenosis, can significantly reduce the risk of recurrent cerebral ischemia or death. Other factors that increase the risk of ipsilateral stroke are hemispheric (rather than retinal) site of ischemia, ulcerative nature of the stenosis, presence of contralateral carotid artery occlusion, and vascular risk factors. Benefits of CEA are similar for men
and women. Advanced age by itself should not be considered a contraindication for properly selected patients with symptomatic high-grade carotid artery stenosis. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) confirmed the effectiveness of CEA for preventing stroke in 659 symptomatic patients with TIAs or minor strokes with high-grade (70-99%) diameter-reducing carotid artery stenosis. A uniform and strict technique measured carotid artery stenosis from an arteriogram. For different endpoints, absolute risk reductions in favor of surgery were 17.0% for ipsilateral stroke; 15.0% for all strokes; 16.5% for the combined outcomes of all strokes and death; 10.6% for major ipsilateral stroke; 9.4% for all major strokes; and 1 0 . 1 % for major stroke and death. CEA was also beneficial and not more dangerous in symptomatic patients with atheromatous carotid artery pseudo-occlusion (carotid string sign). Longer term outcome was also better for surgically treated patients despite an occluded contralateral carotid artery. Morbidity and mortality of early CEA were similar to that of delayed surgery. The European Carotid Surgery Trial (ECST) also indicated the benefit from CEA compared with medical therapy in patients with mild carotid territory ischemic events associated with a diameter-reducing proximal internal carotid stenosis between 7 0 % and 9 9 % . The cumulative risk of any ipsilateral stroke at 3 years was 10.3% for the surgical group and 16.8% for the medical group. The ECST trial used different criteria than NASCET for measurement of carotid artery stenosis on angiography. A diameter-reducing carotid artery stenosis of 7 0 - 9 9 % by NASCET criteria is equivalent to a stenosis of 8 2 - 9 9 % by ECST methodology; likewise a stenosis of 7 0 - 9 9 % by ECST criteria is equivalent to a stenosis of 5 0 - 9 9 % by NASCET criteria (Rothwell et al. 1994). These methodological differences were more important with mild carotid artery stenosis. The Veterans Administration Trial of Carotid Endarterecromy in Symptomatic Carotid Stenosis was terminated early because of the positive results of NASCET and ECST. The Veterans Administration study also showed that CEA improved outcome in selected symptomatic patients with high-grade extracranial carotid artery stenosis. Among symptomatic patients with less than 3 0 % stenosis, results from the ECST trial favor the use of medical therapy with platelet antiaggrcgants. The utility of CEA for symptomatic patients with 3 0 6 9 % carotid artery stenosis has recently been determined. Results were analyzed separately for those patients with 3 0 - 4 9 % and those with 5 0 - 6 9 % stenosis. Analysis from 1599 patients suggests that CEA is not indicated in most of these patients (European Carotid Surgery Tria lists' Collaborative Group 1996). With a low surgical risk, CEA also provides modest benefit in symptomatic patients with carotid artery stenosis of 5 0 - 6 9 % (Barnett et al. 1998), especially among men with hemispheric ischemia who are not diabetic. CEA
ISCHEMIC CEREBROVASCULAR DISEASE
provides no benefit if the stenosis is less than 5 0 % (50% by NASCET criteria is equal to 7 5 % stenosis by ECST criteria). The benefit of CEA is highly dependent on surgical risk. Mortality and morbidity caused by CEA are significantly lower for asymptomatic patients. The acceptable level of surgical risk varies with the indication for carotid artery surgery. Maximal acceptable limits of surgical risks for combined perioperative neurological morbidity and mortality are 3% for asymptomatic patients, 5% for patients with TIAs, 7% for patients with stroke, and 10% for patients with recurrent stenosis. Whether selected patients should undergo CEA on the basis of duplex scanning alone (without cerebral angiography), or duplex scanning complemented by MRA remains controversial. Carotid artery angioplasty and s ten ting may offer an alternative treatment to CEA, particularly in patients with internal carotid artery stenosis that is in an anatomically high location in the neck, carotid artery restenosis following prior CEA, radiation-induced carotid artery stenosis, and among certain high-risk patients with serious medical comorbidities. Carotid artery angioplasty and stenting should still be regarded as experimental. Results from randomized trials are needed before these techniques can be recommended. The Carotid Revascularization Endarterectomy versus Stent Trial is currently comparing the efficacy of CEA and carotid artery stenting among good-risk symptomatic patients with stenosis of more than 5 0 % . Asymptomatic
Carotid Artery Stenosis
Asymptomatic carotid artery atherosclerosis is prevalent in the general population, especially in the elderly. Compared with symptomatic stenosis, asymptomatic carotid artery stenosis is associated with a relatively low risk of ipsilateral cerebral infarction. Data from four randomized clinical trials concerning the efficacy of CEA in patients with asymptomatic carotid artery stenosis are now available. The study by Clagett and colleagues was a fairly small study that followed only 57 asymptomatic patients with cervical bruits and abnormal ocular pneumoplcthysmography; only 29 were truly randomized to aspirin therapy or CEA. More unfavorable outcomes were noted in those patients undergoing CEA and the authors concluded that most asymptomatic patients with cervical bruits and abnormal ocular pneumopathy sinography are appropriately managed without CEA (Clagett et al. 1984), The Carotid Artery Surgery Asymptomatic Narrowing Operations versus Aspirin trial enrolled asymptomatic patients with 5 0 - 9 0 % carotid artery stenosis. Patients with greater than 9 0 % carotid artery stenosis were excluded on the basis of presumed surgical benefit. Overall, the trial showed no difference between the medically and surgically treated groups. The Mayo Asymptomatic Carotid Endarterectomy Trial (Mayo, 1992) was terminated early because of higher rates of myocardial infarction and TIAs in the surgical group.
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Patients in the surgical group did not receive aspirin, probably explaining those results. The Veterans Affairs Asymptomatic Carotid Endarterectomy Trial evaluated 444 asymptomatic patients with angiographicslly proven carotid stenosis of 5 0 - 9 9 % . The study showed n relative risk reduction in the incidence of ipsilateral neurological events in favor of surgery when both TIA and stroke were included as composite end points. However, when ipsilateral stroke was considered alone, only a nonsignificant trend favoring surgery was noted. For the combined outcome of stroke and death, no significant differences were found between the two treatment arms (Hobson et al. 1993). The fifth randomized clinical trial, the Asymptomatic Carotid Atherosclerosis Study (ACAS), found that CEA combined with aspirin and risk-factor reduction is superior to aspirin and risk-factor reduction alone in preventing ipsilateral stroke in patients younger than 80 years who had greater than 6 0 % asymptomatic carotid artery stenosis. The ACAS angiographieal methods were similar to NASCET. All patients randomized to the surgical arm of the study had a catheter angiogram but it was not mandatory in the medically treated patients. The aggregate morbidity and mortality of the ACAS participating surgeons were extremely low. Based on a 5-year projection, ACAS showed that CEA reduced the absolute risk of stroke by 5.9% (which corresponds to an absolute risk reduction of only 1% per year), and the relative risk of stroke and death by 5 3 % . The surgical benefit incorporated a perioperative stroke and death rate of 2 . 3 % including a permanent artcriographical complication rate of 1.2%. It is also important to note that all patients with a 60—99% stenosis were analyzed together in this study. In spite of these results, controversy surrounds the selection of asymptomatic patients for CEA. Based on the low risk of stroke for all deciles until 8 0 - 8 9 % carotid artery stenosis demonstrated by the European Carotid Artery Surgery Trialists (The European Carotid Surgery Trialists 1 Collaborative Group 1995), some experts recommend surgery only when the degree of stenosis is greater than 80%, provided that the operation is performed by an experienced surgeon with a complication rate (combined artcriographical and surgical) of 3% or less. The value of impaired cerebral vasomotor reactivity using intravenous administration of acetazolamide as a predictor of stroke risk in patients with asymptomatic carotid artery stenosis is controversial. The necessity for widespread screening of patients with asymptomatic carotid artery stenosis is not supported by available data. Although concomitant CEA and coronary artery bypass grafting can be achieved with acceptably low operative risk, the best management for symptomatic carotid stenosis patients with coexisting severe carotid and coronary artery disease is still unknown. The risk seems to be low for asymptomatic carotid stenosis patients, and the available data do not justify preoperative prophylactic CEA in patients requiring coronary angioplasty.
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NEUROLOGICAL DISEASES
GENERAL MANAGEMENT OF ACUTE ISCHEMIC STROKE Rapid diagnosis of stroke and initiation of treatment are important to maximize recovery, prevent recurrence of stroke, and prevent complications. Patients with an acute stroke should be admitted to the hospital for emergency evaluation and treatment, preferably in a stroke unit or intensive care unit where close medical and nursing observation is available. Treatment of unselected acute stroke patients in specialized stroke units correlated with a lower mortality, reduced length of hospital stay, reduced frequency of discharge to a nursing home, and potentially reduced cost (see Chapter 54). Development of a stroke team is advantageous to expedite emergency care. Emergency care involves attention to the protect ion ol the airway to avoid obstruction, hypoventilation, and aspiration pneumonia. Pulse oximetry or arterial blood gases may be indicated. Supplemental oxygen and ventilatory assistance should be added if needed. Mild hypothermia protects the brain from ischemic injury; mild hyperthermia worsens ischemic outcome. Prevention of pulmonary complications is necessary in (lie bedridden patient or in the patient with impaired oropharyngeal function. The mortality from pneumonia is as high as 1 5 - 2 5 % in stroke patients. Aspiration was documented by videofluoroscopical modified barium swallow examination in more than one third of patients with brainstem strokes, in one fourth with bilateral hemispheric, and in one tenth of patients with unilateral hemispheric strokes. It is important to place a temporary enteral feeding tube if there is evidence of oropharyngeal dysfunction to minimize the risk of aspiration. Patients with oropharyngeal dysfunction, even if it appears to be mild, should receive nothing by mouth until evaluation by an experienced speech pathologist and until appropriate swallowing studies arc completed. Good pulmonary toilet is needed. The next step is assessment of the circulation. This involves evaluation of cardiac function and blood pressure. Because of the high frequency of cardiac dysfunction associated with stroke, cardiac monitoring is recommended for the first 24—48 hours after stroke. An immediate ECG should be obtained. Concomitant cerebral and myocardial ischemia can occur in approximately 3% of cases. Ischemic stroke can be complicated by a variety of cardiac arrhythmias. If ischemic F.CG changes occur, serial creatine kinase and lactate dehydrogenase isoenzymes are indicated. In patients with stroke, the blood pressure should be monitored frequently or even continuously for the first 4 8 72 hours. It is not unusual for the blood pressure to be transiently elevated after a stroke. One study showed that pharmacological elevation of SBP to a mean of 156 mm Hg appeared to be safe and may improve neurological symptoms in some patients with thrombotic stroke (Rordorf et al. 1997). Within a few days, the blood pressure may return to prestroke levels. Whether transient
elevations should be treated is controversial, it is important not to overtreat the blood pressure and cause hypotension. The most important objective is to maintain adequate cerebral blood flow in the presence of impaired autoregulation. If urgent lowering of the blood pressure is indicated, intravenous labetalol can be given (e.g., 10 mg over 1-2 minutes, repeated or doubled every 10-20 minutes until the desired response has been achieved or a maximum dosage of 300 mg has been administered). Contraindications to the use of labetalol include congestive heart failure, asthma, second- or third-degree heart block, or cocaine use. The use of immediate release preparations of nifedipine should be strongly discouraged, because they lower the blood pressure in an unpredictable and sometimes dramatic fashion, and have caused major cerehral infarcts. Immediately after the patient's arrival in the emergency room, blood should be sent for appropriate studies including a complete blood cell count, PT (INR), aPTT, and a general chemistry screen. A focused neurological examination should be performed to assess neurological stability and to determine the extent of infarction. General signs that point toward a large infarction are forced eye deviation, hemiplegia, and altered consciousness. A National Institutes of Health Stroke Scale value of greater than 15 is another general indicator of a large infarction. Once stability of the airway, breathing, and circulation is determined and a focused neurological examination is performed to assess neurological stability, the patient should be sent immediately for an emergent cranial CT scan without contrast. This can point the way to treat the patient with tPA, or to avoid anticoagulants in patients with intracranial bleeds. Attention should be directed not only to the treatment of the stroke, but also to the prevention of complications. A variety of neurological and medical complications can arise after a stroke. During the first week after an acute cerebral infarction, the most common cause of deterioration is development of brain edema. Brain edema begins to develop within the first several hours after an ischemic event. The edema reaches its peak 72-120 hours after the stroke. Ischemic edema is initially cytotoxic and later vasogenic. Cytotoxic edema involves predominantly the gray matter, whereas vasogenic edema involves predominantly the white matter. Those at the greatest risk for development of edema are younger patients and those with large infarctions, often caused by large artery occlusions. There is no specific pharmacological agent that has been proven effective against ischemic cerebral edema. Traditional treatment of increased intracranial pressure associated with acute ischemic stroke is shown in Table 57A.11. For cerebellar strokes with edema and herniation, posterior fossa decompression may be life saving. Ventriculostomy may also be performed, but has the risk of upward herniation of the cerebellum and brainstem. In the second through the fourth weeks, pneumonia is the most common cause of non-neurological death. Many cases
ISCHEMIC CEREBROVASCULAR DISEASE Table 57A.11: Medical management guidelines for elevated intracranial pressure in patients with acute ischemic stroke Correction of factors exacerbating increased intracranial pressure Hyperearbia Hypoxia Hyperthermia Acidosis Hypotension Hypovolemia Positional Avoidance of head and neck positions compressing jugular veins Avoidance of flat supine position; elevation of head of the bed 15-30 degrees Medical therapy Endotracheal intubation and mechanical ventilation, if Glasgow Coma Scale l the spina' cord Chant; er al. 2002). Radiation therapy is beneficial to patients with residual symptomatic tumor after operation, at recurrence, or with aggressive histology (Scbild et al. 1998). Low-grade tumors, especially those located within the spinal cord, require only involved field radiation. Craniospinal irradiation is needed if leptomeningcal spread occurs. The benefits of prophylactic craniospinal irradiation for high-grade ependymoma are unclear. Local failure tends to herald leptomeningcal spread. Chemotherapy for ependymoma includes carboplatin, PCV, combination chemotherapy with cisplatin, lomustine, and vincristine, or alternating cycles of cisplatin/etoposide and cyclophosphamide/ vincristine (Chamberlain 2002). Siibependymoma Subependymomas are benign tumors in proximity to the ventricles. Not uncommonly, their dereccion as calcific masses is incidental, and therapy is onl\ indicated v. hen symptoms ensue. The fourth ventricle is the most common location, followed by the septum pellucidum and the lateral ventricles. The tumor is well demarcated and surgical removal is curative. Subtornlly resected tumors should be followed with serial MRI studies. Symptomatic residual tumors and those that show progressive growth should be irradiated.
MANAGEMENT OF PRIMARY NERVOUS SYSTEM TUMORS IN ADULTS Choroid Plexus Tumors Choroid Plexus Papilloma and Carcinoma Choroid plexus papillomas are tumors of childhood. In adults they account for only 0.5% of all intracranial neoplasms. The tumor is located in the fourth ventricle, the lateral ventricles, or the cerebellopontine angle. Patients most commonly present with deficits of the eighth cranial nerve, signs of cerebellar dysfunction, or overproduction of CSF. Total resection is accomplished in fewer than half of cases. Frequently the tumor is attached to lower cranial nerves. Thus morbidity of surgical intervention is significant. In one small series, transient worsening ot neurological deficits occurred in up to 2 5 % of cases, and postoperative mortality approached 2(i%. Preoperative selective microembolization has been used. There is no role for adjuvant treatment modalities at diagnosis because long-term survival follows even subtotal resection. At progression or recurrence, treatment with conventional external beam radiation ot SRS is of benefit. Obstructive hydrocephalus, a frequent complication of choroid plexus papilloma, is relieved by tumor removal, and shunt procedures are only indicated in a few cases (Tacconi et al. 1996). Choroid plexus carcinoma in adults is the subject of case reports only. Adjuvant treatment after surgical removal includes irradiation and chemotherapy. Therapeutic efficacy has been shown for lomustinc.
Neuronal and Mixed Neuronal-Glial Tumors Ganglioglioma
and
Gangliocytoma
Gangliogliomas contain two cell populations: gangliocytes and mature glial elements derived from precursor cells that can differentiate into both elements. Although commonly benign, anaplastic changes develop in 4 - 3 2 % of cases. Gross total resection results in survival ranging from 7 to 17 years. Thus adjuvant irradiation is not indicated. Radiation therapy is provided to tumors that are incompletely resected or those with anaplastic progression. These have a worse prognosis with an overall survival of 3 years or less (Hakim ct al. 1997). Chemotherapy is used with the assumption that the astrocytic component will respond. For the anaplastic glial component, regimens are identical to the ones used for high-grade gliomas. Central
Neurocytoma
Central neurocytoma, a neuronal tumor, occurs in young adults in proximity to the supratentorial ventricular system. The tumor arises from the fornix, septum pellucidum, or the walls of the lateral ventricles. A benign tumor, surgical removal is performed by operations
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through the corpus callosum or cortex with attendant memory and cognitive problems, which are transient, Fewer than 5 0 % of patients experience cure; for the remainder there is bleeding or adherence of tumor to adjacent structures. However, long-term tumor control can be achieved with partial resection. Instances of anaplasia or dissemination along CSF pathways are rare. Thus radiation therapy is recommended for tumors with a high proliferative index or growth. For tumors smaller than 3 cm, SRS may be beneficial. Adjuvant chemotherapy benefits a minority of patients treated with a combination of cisplatin, etoposide, and cyclophosphamide (Schild et al, 1997; Brandes ct al. 2000).
Pineal Parenchymal Tumors Although a variety of tumors appear in the region of the pineal gland or the subarachnoid space surrounding it, cells of "pineal" origin can form tumors: pineocytoma, pineal parenchymal tumors of intermediate grade, and pineobi asroma. The more malignant tumors are seen in younger patients; more than 9 0 % of patients with pineoblastoma are younger than age 2 3 , whereas in patients older than the age of 40 years, one third of the masses are tumors of low or intermediate grade (Chang et al. 2000). There is uncertainty regarding the role of surgery. CT- or MR-based stereotactic biopsies are performed in manycenters. Tertiary neurosurgical hospitals advocate complete tumor resection. Radiation therapy to the pineal region and the craniospinal axis is provided to patients with highgrade neoplasms, residual tumor after surgery, and subarachnoid dissemination. Chemotherapy is used in the setting of pineoblastoma or parenchyma) tumors that are disseminated at onset or at recurrence. Commonly, preirradiation chemotherapy reduces tumor size. As with other neuroblasts tumors (esthesioneuroblastoma, mcdullobla stoma, PNET), platinum-based compounds are used, usually in combination with etoposide, alkylating agents (CCNU, PCZ, cyclophosphamide), or vincristine. Longterm responders are reported, but estimates of survival are based on literature reviews or small retrospective institutional series.
Peripheral Neuroblastic Tumors Esthesioneuroblastoma Esthesioneuroblastoma arises from the neuroepithelium of the upper nasal cavity. From there it invades the neurocramum through the cribriform plate, compresses the frontal lobes of the brain, and may infiltrate the brain parenchyma or subarachnoid spaces. A standardized therapeutic approach has not been established. Frequently, gross total resection via a craniofacial approach is followed by
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NEUROLOGICAL DISEASES
adjuvant external beam radiation therapy unless the tumor is excised completely or is low grade (Eich ct a I. 2001). Because gratifying responses are seen with chemotherapy, patients with disseminated or recurrent disease and those with high-grade tumors are treated with combinations such as cisplatin-etoposide, cyclophosphamide-vincristinedoxorubicin, or alternating cycles of cisplatin-etoposide and cyclophosphamide-vincristine (McElroy et al. 1998). Advocates of radiation and chemotherapy prior to surgery cite decreased tumor burden and facilitation of gross total removal with decreased morbidity as benefits of this approach. Others recommend chemotherapy with cisplatin and etoposide after biopsy, followed by radiosurgery and postradiation chemotherapy. Patients with low-grade tumors have progression-free survival exceeding 10 years, in comparison with less than 3 years for those with more aggressive tumors. Not uncommon are late local recurrences or metastases to cervical lymph nodes. When the tumor invades through the dura into the subarachnoid space, intrathecal methotrexate, cytosine-arabinosidc, or thio-TEPA may be used. Radiation is administered to symptomatic or nodular leptomeningeal recurrences,
Embryonal Tumors Medulloblastoma Medulloblastomas in adults are rare neoplasms. The majority of patients present before 40 years of age. Unlike childhood tumors, these are prone to the cerebellar hemispheres, less commonly in contiguity with the fourth ventricle. As a result, dissemination into the CSF is seen in fewer than one third of cases. In general, the natural history is less aggressive: Extraneural metastases have been reported in fewer than 150 patients, and then most frequently to bone (Chan et al. 2000). Multidisciplinary management is critical for the successful treatment of these tumors. Resection, craniospinal radiation, and adjuvant chemotherapy results in 10-year survival rates of 56%. Obstructive hydrocephalus is a frequent complication of medulloblastoma. Ventrieulo-pcritoncal shunting is provided to symptomatic patients with occlusion of the fourth ventricle and dilatation of lateral ventricles. Often a filter is placed into the distal end of the shunt tubing to reduce the risk of peritoneal dissemination of tumor. Resection is followed by evaluation of CSF and lumbar spine for tumor spread, and craniospinal irradiation (posterior fossa 56 Gy, whole-brain 36 Gy, and spine 30-36 Gy). Chemotherapy benefits high-risk patients with significant residual tumor, brainstem infiltration, or leptomeningeal metastasis. Commonly used drugs cither prior to or following irradiation include cisplatin, cyclophosphamide, nitrosoureas, and etoposide. The Pediatric Oncology Group pioneered the use of alternating cycles of cisplatin (90 mg/m 2 on day 1 or
20 mg/m on days 1-5) and etoposide (100 mg/m on days 1-5) with cyclophosphamide (between 450 and 1580 mg/m on days 1 and 2) and vincristine (1.5 mg/m day 1). Rational administration of these drugs provides for their use before irradiation because craniospinal irradiation limits bone marrow reserve and the incidence of leukoencephalopathic complications is higher when chemotherapy follows radiation. However, radiation therapy should not be delayed by extended periods of myclosuppression from chemotherapy. Whether to offer prophylactic chemotherapy to low-risk patients is uncertain. Ultimately this issue will he addressed by formal study, but drugs are easily provided at diagnosis, and even "low-risk" patients are seldom cured, with relapse occurring years after initial diagnosis. Treatment of tumor recurrence after multimodality therapy is extremely difficult. Re-resection or SRS may be offered to selected patients. Alkylating agents are effective, and high-dose chemotherapy followed by stem cell rescue may benefit young patients. Supratentorial
Primitive
Neuroectodermal
Tumors
Supratentorial PNETs arc rarer than medulloblastomas. Well-delineated tumors with minimal residual tumor after surgery have a favorable prognosis. Surgical resection establishes the diagnosis and reduces the tumor burden. Adjuvant therapy consists of fractionated external beam radiation to the primary site and the craniospinal axis. However, because many of these masses are sensitive to chemotherapy, many centers have begun to treat high-risk patients with low-dose radiation in conjunction with chemotherapy. Drugs used include the PCV combination, cisplatin-etoposide alone, or alternating with cyclophosphamide-vincristine. Toxicity to bone marrow, gastrointestinal tract, and kidney accompanies the latter regimen, and thus these agents are provided prior to radiation therapy. Survival may exceed 5 years, but many patients succumb to their disease within a few years. Whether intrathecal chemotherapy with ara-C, methotrexate, or thio-TEPA confers any benefit to the patient with leptomcninge.il spread is uncertain. Treatment failure usually occurs locally. At recurrence, re-resection and salvage chemotherapy can be offered.
Tumors of Cranial and Peripheral Nerves Schwannoma
and
Neurofibroma
Schwannomas and neurofibromas are benign tumors of the peripheral nerve sheath. Intracranial schwannomas arise commonly from the sensory branches of cranial nerves such as the acoustic or trigeminal nerves. However, these rarely occur within the parenchyma of cortex or medulla. Schwannomas most commonly affect the vestibular division of the eighth cranial nerve and may result in hearing
MANAGEMENT OF PRIMARY NERVOUS SYSTEM TUMORS IN Al HUTS
loss, vertigo, and facial numbness. However, the majority arc without symptoms and thus arc undetected. Small and stable asymptomatic tumors arc commonly followed with serial MRI scans on an annual basis. Symptomatic tumors are treated with microsurgical resection or SRS. Surgical risks include postoperative CSF leak, facial and trigeminal neuropathy, and deafness. These risks are directly related to tumor size (Kaylie et al. 2001}. The use of proton radiosurgery or fractionated SRT achieves tumor "control" without disappearance in more than 9 0 % of patients, with hearing complications in approximately 2 0 % (Harsh et al. 2002). Only a small fraction of schwannomas undergo malignant degeneration. Malignant Peripheral Nerve Sheath Tumor Malignant peripheral nerve sheath tumor (MPNST) is a rare neoplasm of peripheral nerves, including cranial nerves. Wide surgical excision is the treatment of choice, Average extent of resection depends on tumor location and ranges from 2 0 % in paraspinal nerve root and plexus masses to nearly 100% in tumors of the distal extremities. Radiation therapy is provided for residua! disease in the form of external beam radiation alone or in combination with brachytherapy (iridium-192) or intraoperative high energy electron irradiation. Although amputation has been historically offered, these approaches have improved limbsparing control. Twenty to forty percent of patients are treated with adjuvant chemotherapy at diagnosis (MESNA, doxorubicin [Adriamycin], ifosfamide, and dacarbazine, or single-drug regimens such as high-dose methotrexate). No • link/.! trials have been published and chemotherapy does not have a role in the initial treatment of completely resected MPNST. Treatment failure in half the patients is local within 3 years, but late local recurrences at 25 years have been described. The median survival exceeds 2-5 years. Tumor size, extent of surgery, and age at diagnosis are predictors of survival.
Meningeal Tumors Meningioma Meningiomas are the most common nonglial intracranial tumors. These tumors have been found incidentally in 2 0 % of autopsy series and affect women more than men. Management depends on location, coexistent motbidities, and the patient's age and health (Chamberlain 2001). Incidentally found asymptomatic meningiomas lacking mass effect or compression of a venous sinus can be followed conservatively with serial MRI evaluations. Many meningiomas will not grow over years, sparing older adult patients the need for craniotomy (Black et al. 1998). However, when seizures occur (20% risk), tumors grow
1417
(approximately one third of patients), or focal signs emerge, surgical resection can be curative, especially in meningiomas overlying the hemispheres. Although highly vascularized, preoperative embolization is usually not necessary. Technically more challenging are tumors invading dural venous sinuses, tumors arising from the dura overlying the medial portions of the sphenoid bone or other parts of the skull base, meningioma en plaque, posterior fossa meningiomas, and the rare intraventricular meningiomas. Complete surgical removal may not be possible in these situations and may be complicated by infection, CSF leakage, cerebral venous thrombosis, or cranial neuropathies. Less aggressive surgery in association with stereotactic radiation reduces treatment morbidity and may improve progress ion-free survival (Villavicencio et al. 2001). At recurrence or tumor progression, conventional external beam irradiation or SRS are the major treatment options. Atypical (6%) and malignant meningiomas (2%) account for a small fraction of all meningiomas, but these tumors recur in spite of surgical resection and irradiation. Although meningiomas express estrogen and progesterone receptors, clinical trials with tamoxifen or progesterone receptor antagonists such as mifepristone (RU-486) have been disappointing. Some authors have reported partial responses or stable disease in patients with recurrent or malignant meningioma who receive hydroxyurea, alpha interferon, or drug regimens such as cyclophosphamide/ doxorubicin vincristine, ifosfamide/MESNA, or doxorubicin dacarbazine. Hemangiopericytoma Intracranial hemangiopericytoma, often confused with meningioma on imaging studies, is a rare meningeal neoplasm. Its high rate of local recurrence and predisposition to metastases to bone and liver make it unique in mcningeal-based neoplasms. Leptomcningeal spread has been described as have recurrences beyond 5 years of diagnosis. Gross total resection emphasizes removal of surrounding normal dura or brain. Radiation therapy (fractionated to 48-60 Gy) reduces the local recurrence rate and prolongs the progression-free and overall survival (Rastin et al. 1992). Unfortunately, as with meningioma and schwannoma, tumor shrinkage cannot be expected until years after therapy. At tumor recurrence, options include surgical resection, conventional external beam radiation, and SRS. Chemotherapy may benefit the patient with systemic metastases or local therapy-refractory disease, but data are not available (Galams et al. 1998). Most protocols use doxorubicin in combination with cyclophosphamide, ifosfamide, cisplatin, and/or dacarbazine. Partial responses or stable disease for several months have been observed with these regimens. Up to 9 0 % of tumors recur locally or systcmically within 9 years of initial manifestation.
1418
NEUROLOGICAL DISEASES
Extraneural recurrence is predictive of worsened prognosis. Median survival after first tecurrcnce is between 4 and 5 years, but with aggressive management, long-term survival is possible.
Ncuraxis Tumors Derived from the Hematopoietic System I'rimary Central Nervous System Lymphoma Non-AIDS Related Disease. PCNSI, is a highly aggressive tumor. Left untreated, most patients succumb within 6 months. As with most brain malignancies, young age (younger than 60) conveys improved prognosis. Unfavorable prognostic factors include older age, low performance status, multiple brain lesions, evidence of leptomeningeal dissemination, lack of radiographic complete response to treatment, and elevated serum lactate dehydrogenase level. Methotrexate-based chemotherapy given in high doses (above 3.5 g/m1) followed by leucovorin rescue has been shown to be the single most effective treatment for PCNSI,. Its introduction, either alone or in combination before radiation therapy, has resulted in response rates of 7 0 - 9 5 % and survival durations in excess of 3 years. The treatment produces no alopecia, minimal to modest myelotoxicity, and is compatible with normal cognitive function. Other potentially efficacious agents include ara-C, rhio-TEPA, cyclophosphamide, ifosfamide, BCNU, PCV, CCNU, PCZ, temozolomide, and topotecan. Polychemotherapy tcgimens include inelkolitwalc. K.Z-, .i:id vn\ i ist ire with radiation therapy, and postradiation ara-C. Virtually all regimens share response rates and durations of response that are comparable to those provided by methotrexate monotherapy. However, combination regimens are associated with highet tisks of myelotoxicity and radiation-containing regimens increase the likelihood of clinically significant neurotoxicity, especially in older adult patients. Intraarterial administration of chemotherapy preceded by disruption of the BBB with manmtol is effective, but requires two-vessel angiography and general anesthesia with each treatment. The administration of intrathecal or intraocular chemotherapy is of uncettain benefit. High-dose intravenous methotrexate results in cytotoxic drug levels within the CSF and in the aqueous and vitteous humor of the eyes. However, high tumor burden within CSF may be associated with methotrexate resistance and thus intrathecal chemotherapy may postpone the need for craniospinal irradiation. WBRT is now commonly deferred until the time of recurrence, given the high incidence of neurotoxicity, especially in patients older than the age of 60. Above doses of 35-45 Gy, escalation provides no survival benefit. Failures of radiation therapy occur within months and within the radiation field. Similarly, surgical resection provides no survival benefit and thus only biopsy is performed to establish the diagnosis.
In spite of major progress, there is still a need for refinement of therapy. This reflects several noteworthy features of the current natutal histoty: Most patients relapse, systemic dissemination is encountered in up to 8%, and the underlying hematogenous origin of the tumor is uncertain. At the time of recurrence there is likely benefit for retreatment. We have successfully used methotrexate at the time of relapse even in prior methotrexate recipients. Anecdotal responses at the time of relapse have also been reported with the use ci topotecan, NIU\II:LI1> (a chimerit antibody targeting CD20), temozolomide, PCV, or cytosine-arabinoside/etoposide, as well as intensive chemotherapy supported by autologous or allogeneic peripheral blood stem cell transplantation, WBRT is an option for patients who either fail or are not candidates for salvage chemothctapy. Meningeal or ocular relapse can be treated with radiation and chemotherapy (intrathecal or intravitreal). AIDS-Related PCNSL. Patients with the acquited immunodeficiency syndrome (AIDS) develop PCNSL in the advanced stage of their disease. A severely compromised immune system and concomitant opportunistic infections frequently preclude chemotherapy. Thus WBRT has been the standard treatment for PCNSI. in AIDS patients. This approach has been associated with poor and nondurable responses. A subset of patients with low HIV burden and high CD4 T-cell counts are eligible to receive chemotherapy, The introduction of highly aggressive antiretroviral therapy has increased the patients in this category while reducing the incidence ot brain lymphoma.
Germ Cell Tumors Germ cell tumors of the CNS are rare adult tumors (less than 0 . 1 % of primary brain tumors) occurring commonly before the age ol 20 years. Nine times more common in Asia, the most common germ cell tumor occurring within the CNS is germinoma, which shares a common histology with testicular seminoma and ovarian dysgerminoma. Less common are nongerminomatous germ cell tumors (teratoma, embtyonal carcinoma, yolk sac tumor [endodermal sinus tumorl, choriocarcinoma, and mixed germ cell tumors). The entire group has a proclivity for the sellar and suprasellar region, walls of the third ventricle, and the pineal gland. Surgical access u difficult and often limits intervention to biopsy or empiric radiation/chemotherapy. The latter approach is usually avoided, given the high incidence of mixed neoplasms. Treatment planning depends on careful analysis of resected tissue, often with evaluation of serologic and CSF levels of ,8-human chorionic gonadotropin, a-fetoprotein and placental alkaline phosphatase. The major determinants of outcome are local tumor control and histological subtype. Treatment schedules are still being optimized.
MANAGEMENT OF PRIMARY NERVOUS SYSTEM TUMORS IN ADUITS
Germinoma Germinomas are infiltrative tumors with a tendency to subependymal and leptomeningeal spread. Traditionally, treatment has included surgical resection or biopsy followed by radiation therapy. The radiation is provided to the ventricular system, with craniospinal irradiation reserved for patients with cy to pathological or radiographic evidence of leptomeningeal spread. Preirradiation chemotherapy is given to high-risk patiencs to achieve complete responses and allows significant reduction of radiation dose (Matsutani et al, 1998; Sawamura et a I. 1998). The most commonly used agents are cisplatin, etoposide, and cyclophosphamide. Long-term survivors of radiation exceed 15 years with hypothalamic/pituitary neuroendocrine morbidities. Nongerminomatous
Germ
Ceil
Tumors
Gtoss total resection prolongs survival but is achieved in less than half the cases. Each of the nongerminomatous germ cell tumors is approached differently (Schild et al. 1996). Mature or immature teratomas are operated on and then u u ' i u ' invu!u'd held i.iLh.Ltic i:i ihcrap\ v, n:i i.\40 mg/L are toxic. Levels >25 mg/L can Idiosyncratic irreversible marrow aplasia (1:30,000 patients) is the most feared complication. 'Also causes neuromuscular blockade—caution in myasthenia gravis, respiratory failure, and postoperatively when curare has been u • CNS toxicity includes seizures ( 2 - 8 % of patients).
1482
NEUROLOGICAL DISEASES
Current antibiotic recommendations, when culture results reveal a specific pathogen, are listed in columns five and six of Table 59A.2, Because bacteria! meningitis develops in an immunologically privileged site lacking a lymphatic system, bactericidal, rather than bacteriostatic, antibiotics that rapidly achieve adequate CSF levels should be selected. Therefore, antibiotic selection and reevaluation arc made in the context of several general pharmacological principles. Meningeal inflammation increases permeability of the blood-brain barrier to /^-lactam antibiotics from 0 . 5 2.0% to 5-10% of serum concentration. For more lipidsoluble antibiotics, such as chloramphenicol, rifampin (RIF), and trimethoprim/sulfamethoxazole (TMP/SMX), CSF levels reach 3 0 - 4 0 % of serum concentrations even without meningeal inflammation. The low pFI of infected CSF impairs aminoglycoside activity, and increased CSF protein reduces the concentrations of active free drug for the ^-lactams, which are highly protein bound. Antibiotics used in meningitis, their relevant properties, and specific indications appear in summary form in Table 59A.2. Optimal duration of therapy is not known for bacterial meningitis. Parenteral antibiotics are administered for 7-10 days for meningococcal and H, influenzae meningitis, 10-14 days for pneumococcus, and longer courses of 14-21 days for L, monocytogenes and Group R streptococci, and 21 days for gram-negative bacilli other than H. influenzae (Quagliarello and Scheld 1997). Treatment of bacterial meningitis sometimes extends to include family, medical personnel, and other contacts who may require che mo prophylaxis (vide infra). In many instances, proven or suspected bacterial meningitis requires notification of public health authorities to ensure accurate surveillance.
Adjunctive Therapy Despite the availability of bactericidal antimicrobial therapy, the morbidity and mortality from bacterial meningitis remain unacceptably high. Recent studies have focused on the pathogenesis and pathophysiology of tissue injury in bacterial meningitis because the simple introduction of powerful antimicrobial agents may not improve the situation. Experimental evidence from animal models supports a role for inflammatory cytokines in the pathophysiology of bacterial meningitis (Scheld et al. 2002), The proinflammatory cytokines, interleukin 1 and 6, and TNF-a, produced by CSF leukocytes in response to a bacterial stimulus, whether whole organism, component, or toxin, mediate CNS inflammation, cerebral edema, cerebrovascular dysregulation, and brain injury in these models. Corticosteroids have a beneficial effect by inhibiting the synthesis of proinflammatory cytokines at the level of messenger RNA (mRNA) and by decreasing CSF outflow resistance and stabilizing the blood-brain barrier; therefore, their use in bacterial meningitis has been proposed. The available
evidence on adjunctive dexamethasone therapy confirms a benefit for H. influenzae type b meningitis in reducing audiological sequelae and suggests a benefit in reducing audiological and neurological sequelae in pneumococcal meningitis in children. Adjunctive dexamethasone therapy, recommended in children over 3 months of age and many adults (Tunkel and Scheld 2002) with bacterial meningitis, should be started intravenously at the same time as, or shortly before, the first dose of antibiotic as 0.15 mg/kg body weight and administered every 6 hours for 2 to 4 days (Mclntyre et al. 1997; de Cans and Van de Beek 2002}. The rationale for giving dexamethasone before antibiotic therapy is that dexamethasone inhibits the production of TNF-a (mRNA level) if administered to macrophages and microglia before they are activated by bacterial cell wall components. Dexamethasone is unable to regulate TNF-a production once mRNA induction occurs. Advantage of corticosteroid therapy for meningitis, especially pneumococcal, in adults is not as clear as in children with H. influenzae. In a single 1989 study, dexamethasone, 12 mg intravenously every 12 hours for 3 days, was beneficial in patients with pneumococcal meningitis. Flowever, with increasing pneumococcal resistance to antibiotics, the effect of corticosteroids on CSF antibiotic penetration would influence the recommendations for management of pneumococcal meningitis. For example, experimental evidence in animal models of meningitis shows that concurrent corticosteroid administration reduces vancomycin penetration into CSF. As a result, currently recommended treatment of pneumococcal meningitis in adults receiving adjuvant dexamethasone, pending antibiotic sensitivities, consists of ceftriaxone plus RIF. In treating penicillin-resistant pneumococcal meningitis, a second CSF study in 24-48 hours is recommended to document bacteriological improvement, because adjuvant dexamethasone may mask clinical signs of poor antibiotic response (Quagliarello and Scheld 1997). Other adjunctive treatment may be useful in critically ill patients with bacterial meningitis. Patients with increased 1CP may benefit from the insertion of an ICP monitoring device and vigorous treatment of raised ICP. To avoid status epilepticus, seizures should be treated promptly with appropriate agents, such as lorazepam or diazepam and phenytoin. Treatment of shock and disseminated intravascular coagulation may be necessary. Plasma exchange has proved life saving in some patients with fulminant mcningococcemia, but this treatment must be considered experimental.
Complications Focal cerebral signs such as hemiparesis usually imply arteritis, septic venous thrombophlebitis, ot cerebritis. Meningeal inflammatory processes in bacterial meningitis can cause cranial neuropathies. Cranial nerve VI palsy and a
BACTERIAL INFECTIONS deteriorating level of consciousness within the first 48 hours usually indicate an increase in ICP. Subdural effusions may develop in children, particularly with H. influenzae or other gram-negative meningitis. Indications for tapping and culturing a subdural effusion include persistent fever, rapidly enlarging head circumference in the absence of hydrocephalus, or focal neurological signs related to the effusion. Subdural effusions are aspirated under CT guidance. Sterile effusions often resolve spontaneously; subdural empyemas require more aggressive neurosurgical management (Bleck 2002). Depending on clinical circumstances, hydrocephalus may require intervention with serial LPs (if communicating) or external ventricular drainage. Obstructive hydrocephalus may be monitored expectantly with serial CTs.
SOME SPECIFIC PATHOGENS AND PUBLIC HEALTH ISSUES Pneumococcus Meningitis occurs in approximately 4% of patients with invasive S. pneumoniae. Associated conditions include otitis media, skull fractures, alcoholism, and sickle cell disease. Pneumovax, the pneumococcal vaccine composed of polysaccharides of 23 pneumococcal types, is recommended for patients with surgical or functional asplenia (such as sickle cell disease) and chronic illnesses. Of all blood culture isolates of pneumococci in the United States, 88% are contained in the 23-vaIent vaccine. Rare pneumococcal meningitis cases have been classified as apurulent by the absence of CSF pleocytosis. Turbid CSF, masses of pneumococci, elevated protein, fewer than 100 cells/jiL, and low CSF glucose are characteristic. Within 24 hours after initiating antibiotic treatment, CSF cell counts can increase to more than 2000 cells/uL and the pneumococci disappear from the CSF. Penicillin G and ampicillin are equally effective in treating meningitis caused by penicillin-sensitive strains of S, pneumoniae. For patients with S. pneumoniae resistant to both penicillin and ampicillin, treatment is by ceftriaxone combined with vancomycin. Consideration should be given to using intraventricular vancomycin in patients not responding to intravenous vancomycin. Intraventricular vancomycin is safe and is not associated with increased seizure activity.
Meningococcus N. meningitidis infection may manifest as fever and bacteremia without sepsis, meningococcemia without meningitis, or meningitis with or without meningococcemia (Ferguson et al. 2002). Meningitis occurs in an estimated 4 8 % of cases of invasive disease. Penicillin G is the antibiotic of choice for meningococcal meningitis; ampicillin
1483
may also be used. Rare NT. meningitidis isolates produce ^-lactamase or have altered penicillin-binding proteins. In the event of poor initial response to penicillin or ampicillin, isolates should be tested for sensitivities and therapy changed to ceftriaxone or cefotaxime. Treatment of systemic infection may not eliminate nasopharyngeal carriage. During widespread outbreaks or epidemics, when up to 1% of the population may be affected, a single injection of long-acting oily preparation of chloramphenicol (Tifomycine) at a dose of 3 g intramuscularly has been used successfully, Current commercial vaccines include the quadrivalent vaccine with activity against serogroups A, C, Y, and W135. Protective antibodies persist for up to 5 years in adults, but only 1-2 years in children younger than 4 years. Vaccination is recommended for patients with complement deficiency or asplenia, as well as military recruits and travelers to hyperendemic or epidemic areas in Africa, Asia, and South America. Most vaccinations arc given during outbreaks. A vaccine against serogroup B has been developed in Cuba and used in some areas of South America. Prophylaxis for meningococcal meningitis is recommended for the index case and all household members and medical personnel who may have had close contact with infected patients. A 2-day course of oral rifampin (RIF) is given in doses of 600 mg every 12 hours for adults, 10 mg/kg every 12 hours for children 1 month to 12 years old, and 5 mg/kg every 12 hours for infants younger than 1 month of age. Alternatives include ceftriaxone intramuscularly, recommended for pregnant and lactating women or children younger than 2 years (250 mg for adults, 125 mg for children), or minocycline or ciprofloxacin. Haemophilus
Influenzae
Meningitis complicates approximately 10% of H. influenzae infections, often in the setting of a paramemngeal ear or nose infection or basal skull fracture. The H. influenzae type b conjugate vaccine series is administered at 2, 4, and 12-18 months of age. Chemoprophylaxis with oral RIF is recommended for all household members under 4 years of age. The doses are the same as for meningococcal prophylaxis, but treatment is given for 4 days. Listeria
Monocytogenes
Listeria, a common meningeal pathogen in immunosuppressed hosts and neonates, also causes meningitis in the normal host. Meningitis develops in 3 6 % of cases of invasive listeriosis. Ampicillin plus gentamicin is recommended for patients of all ages with Listeria meningitis, because neither ampicillin nor penicillin is bactericidal for Listeria in vitro, and third-generation cephalosporins are inactive against Listeria. TMP/SMX may be used in penicillin-allergic patients. Listeria cerebritis or rhombencephalitis is a distinct nonmeningitic syndrome, which presents as headache,
14S4
NEUROLOGICAL DISEASES
fever, nausea, and vomiting, followed by cranial nerve palsies, decreased consciousness, seizures, and focal deficits. The CSF may contain few or no WBCs. CSF Gram stain and culture results are negative, but blood culture results are positive. Listeria cerebritis requires 6 weeks of treatment.
Nosocomial Agents Increasing numbers of nosocom hilly acquired mlections, including meningitis, are encountered in hospitalized sick patients. Gram-negative bacteria of the Enterobacteriaceae family (E. colt, K. pneumoniae), Pseudomonas species, and gram-positive cocci (staphylococci, pneumococci) frequently cause hospital-acquired meningitis. Members of the genus Acinetobacter, especially multircsistant strains of A. baumannii, increasingly cause nosocomial pneumonia, bacteremia, and meningitis in the intensive care units (ICU). Associated systemic features include petechial rash in 3 0 % of patients and Waterhouse-Friderichsen syndrome in some cases. Acinetobacter and meningococcus thus share clinical, as well as microbiological, features, leading to diagnostic confusion. Acinetobacter are rod-shaped gramnegative organisms during rapid growth and coccoid in the stationary stage. Most A. baumannii are now resistant to ampicillin, carbenicillin, cefotaxime, chloramphenicol, gentamicin, and other aminoglycosides. Imipenem, carbenicillin plus an aminoglycoside, and amoxiciilin-clavulanic acid are treatment alternatives.
Brain Abscess Brain abscess is a focal suppurative process of brain parenchyma, accounting for an estimated 1 in 10,000 general hospital admissions. Brain abscesses develop most frequently by spread from a contiguous infected cranial site, such as ear, sinus, or teeth. Other predisposing causes include open head trauma, previous neurosurgical procedures, and craniofacial osteomyelitis. Hematogenous spread from a remote source also can cause brain abscesses, particularly in the setting of congenital heart disease with right-to-left shunt or pulmonary disorders such as lung abscess, bronchiectasis, or arteriovenous fistula. Metastatic, or blood-borne abscesses, are usually found at gray and white matter junctions, in the distribution of the middle cerebral artery, and are often multiple. However, 2 0 % of abscesses are occult, without an additional source of infection (Anderson 1993). Classifying brain abscesses by likely entry point of infection allows physicians to predict likely pathogens and choose appropriate empiric therapy (Lu et al. 2002). Frontal abscesses arise most often from paranasal sinus infection, temporal or cerebellar abscesses from an otogenic source, and multiple abscesses from a remote site.
Experimental evidence suggests that bacteria require a damaged brain, such as the microscopic or macroscopic area of necrosis resulting from septic thrombophlebitis, emboli, or hypoxemia, to establish infection. The predilection of metastatic abscesses for gray-white matter junctions, for example, may be a consequence of the fluctuations in blood supply to those areas. Once infection is established, the abscess passes through the stages of cerebritis, central necrosis, capsule development, and maturity over a period of approximately 2 weeks or so. Clinical Features Patients with brain abscess present with signs and symptoms of an expanding mass lesion, with progressive headache, altered mentation, focal deficit, or seizures. About one half of patients develop nausea and vomiting. Approximately the same proportion has fever, and hence the diagnosis should not be excluded based on normal temperatute alone. Acute worsening of headache and nuchal pain, together with an increase in temperature, can signify rupture of the abscess into the subarachnoid space, with consequent pyogenic meningitis, a serious event. Diagnosis Neuroimaging studies reveal one or more ring-enhancing masses with surrounding edema (Figure 59A.2). The ring of enhancement may be thicker near the cortex and thinner near the ventricle; large abscesses tend to have thin, enhancing rings of relatively uniform thickness. Associated sinus or ear infection also may be identified by cranial imaging, though dedicated sinus or temporal bone CT may be necessary, in order to better visualize the primary site of infection. An early lesion in the cerebritis stage appears as a nonenhancing focal low-density area on CT scan or hypointensity on magnetic resonance imaging (MRf). Air within a brain mass, in the absence of recent neurosurgical procedures, suggests an abscess. An indium-labeled leukocyte scintillation scan demonstrating an active inflammatory focus may complement CT or MRI studies. Peripheral leukocytosis may be mild or absent and should not be relied on for considering the diagnosis. Because of the risk of herniation or precipitating rupture, LP is contra indicated in suspected or proven brain abscesses. CSF reveals only nonspecific findings of elevated protein and lymphocytic pleocytosis with normal glucose and rarely yields positive culture results unless the abscess has ruptured into the subarachnoid space. Pathogens Occurring as mixed infections 3 0 - 6 0 % of the time, brain abscess pathogens vary with the clinical setting. In immunocompetent patients the most commonly encountered aerobic organisms arc the a-hcmolytic and nonhemolytic
BACTER1AL INFECTIONS
14S.S
FIGURE 59A.2 Brain abscess. Postgadolinium axial T1W-MRI showing multiple ring-enhancing lesions (some multiloculated, arrow, A) with surrounding edema best seen in T2W sequence (B) and with associated intralesional diffusion restriction (DW-MRI, C). Prominent lactate (arrow) and inverted peak at 0.9 ppm (arrowhead) in single voxel from the lesion {H1 spectroscopy, D and E) are typical of bacterial abscess. (Courtesy Dr. S. Ouanounou.) Continued streptococci (such as S. milleri), S. aureus, and Enterabacteriaceae. Other important pathogens include anaerobes such as Bacteroides., Fusobacterium, Peptostreptococcus, and Propionibacterium; gram-negative bacteria such as Eikenella, Actinobacitlus, and Haemophilus; and enteric gram-negative bacteria such as E. colt, Klebsiella, and Pseudomonas. Several important associations include 5. milleri or pneumococcus with a sinus source; Bacteroides, Enterobacter, Proteus, streptococci, or Pseudomonas with an ear source; anaerobic streptococci with pulmonary infections; Actinomyces with dental procedures; and S. aureus in patients with head trauma, recent neurosurgical procedures, or cranial osteomyelitis. Various other bacteria may occasionally be found in brain abscesses, including Clostridium spp. after trauma and wound contamination by soil, C. diversus in neonates, Salmonella spp., .S. moniliformis (the agent of rat-bite fever), and Brucella spp. Except for pneumococcus and H. influenzae, typical bacterial meningitis pathogens irif requently cause brain abscess (Case Records 1993).
(TB) prevalence. Amcbae, toxoplasmosis, cysticcrcosis, or other helminths, including schistosomal species, Paragonimus, trichinosis, sparganosis, and echinococcosis, cause parasitic cerebral abscesses. P. boydii fungal abscess may follow a near-drowning episode by 2-4 weeks. In immunocompromised patients with T-ccll or mononuclear phagocyte defects, causes of brain abscesses include L. monocytogenes, N. asteroides, G, terrae (an environmental actinomycete), Mycobacterium spp., and parasites such as Toxoplasma, Acanthamoeba, Cryptococcus, and T. cruzi. In HIV-infected patients, polymicrobial pyogenic abscesses with S. bovis, Fusobacterium, Peptostreptococcus, and group Gl streptococcus have been reported, along with abscesses with unusual combinations of organisms, such as Candida and staphylococci (Maniglia et al. 1997). Neutrophil abnormalities lead to an increased incidence of Enterobacteriaceae and Pseudomonas abscesses and fungal abscesses caused by Aspergillus, Mucor, or Candida; and Strongyloides.
Geography and immune status are other important determinants of brain abscess microbiology and its differential diagnosis. Tuberculomas frequently cause space-occupying lesions in countries with high tuberculosis
Differential
Diagnosis
In the febrile patient with headache, altered mentation, and laterali/.ing findings, the differential diagnosis includes
1486
NEUROLOGICAL DISEASES
FIGURE 59A.2, cont'd. (Courtesy Dr. S. Ouanounou.)
BACTERIAL INFECTIONS
other infectious etiologies, such as subdural empyema, epidural abscess, viral encephalitis, bacterial or acute aseptic meningitis, septic thrombophlebitis, and endocarditis with septic embolism or mycotic aneurysm rupture. When fever is low grade or absent, primary or metastatic brain tumor is also a consideration. Occasionally, demyelinating lesions presenting as focal deficits or seizures appear as ring-enhancing masses on neuroimaging studies. Resolving cerebral hemorrhages also appear as ringenhancing lesions on neuroimaging studies, particularly brain CT. Brainstem infection with L. monocytogenes or P. acnes may produce brainstem encephalitis (rhombencephalitis) that clinically mimics brainstem abscess. Treatment Successful treatment of brain abscess requires antibiotics in all patients and surgery in many cases. Antibiotics must not only penetrate brain tissue, but also reach the abscess cavity and retain activity at its characteristically low p H . For years, standard brain abscess therapy combined highdose penicillin (24 million U per day intravenously) with chloramphenicol (1 g every 6 hours). Because metronidazole (1 g loading dose, followed by 500 mg every 6 hours) provides excellent anaerobic coverage and penetrates well into brain abscesses, it has replaced chloramphenicol, which carries the additional risk of aplastic anemia. Hence, empiric antibiotic therapy for brain abscess usually includes metronidazole and either penicillin or a third-generation cephalosporin (cefotaxime, ceftriaxone, or ceftazidime), which covers the streptococci and aero-to let ant anaerobes resistant to metronidazole. Following head trauma or neurosurgical procedures, when S. aureus is a concern, an antistaphylococcal penicillin (nafcillin, methic.illin) or vancomycin is added. Current recommendations for empiric therapy, based on location of abscess and inferred source of infection, are metronidazole with either penicillin or a third-generation cephalosporin for frontal abscesses; penicillin, metronidazole, and ceftazidime for temporal or cerebellar abscesses; nafcillin, metronidazole, and cefotaxime for multiple (metastatic) abscesses; nafcillin and cefotaxime for penetrating wounds; and vancomycin and ceftazidime for postoperative abscesses {Mathisen and Johnson 1997). Intravenous treatment must continue for 6-8 weeks and may be followed by oral therapy for 2 - 3 months. Surgical excision may shorten the time course of intravenous therapy by 1 or 2 weeks. Optimal therapy usually requires neurosurgical intervention. Although controversy continues as to whether aspiration under stereotactic CT guidance or total excision yields better results, excision is recommended for gascontaining, multiloculated, or fungal abscesses. Patients for whom medical management alone may be the better choice include those with multiple, deep, or dominant hemisphere abscesses; simultaneous meningitis or ependymitis;
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abscesses measuring less than 3 cm; or abscesses that shrink after antimicrobial therapy. Surgery is not performed in the cerebritis stage until a capsule forms. Ear, nose, sinus, and dental infections should be evaluated and treated by the appropriate surgical specialists. Adjunctive medical therapy for medical or surgical cases includes corticosteroids for mass effect, hyperosmolar agents for worsening cerebral edema and raised ICP, and prophylactic or symptomatic anticonvulsants. Decreased mortality from brain abscesses over the last two decades, from more than 5 0 % to less than 10%, reflects improvements in neuroimaging and neurosurgical techniques. One half of survivors recover completely. Rapid disease progression before hospitalization and altered consciousness at the time of admission portend poor outcome. Intraventricular rupture of a brain abscess is associated with mortality exceeding 8 0 % . After treatment, patients are followed with neuroimaging studies at monthly intervals for approximately 6 months or until contrast enhancement disappears. Persistent contrast enhancement predicts recurrence in up to 2 0 % of patients. Seizures occur in 2 5 - 5 0 % of patients during their early period of hospitalization, and anticonvulsants initiated during hospitalization are continued for 6-12 months. When administered prophy tactically, anticonvulsants are continued for a minimum of 3 months after surgery.
Subdural Empyema Subdural empyema is a collection of pus between the dura and arachnoid. It develops most commonly as a consequence of ear or sinus infection. Other causes include cranial osteomyelitis, penetrating head trauma or neurosurgery, infection of subdural effusions in childhood meningitis, and hematogenous spread from a remote source. Purulent material tracks over the brain surface of the hemispheres (Figure 59A.3), along the falx, or adjacent to the primary focus. Posterior fossa involvement is unusual; spinal subdural empyemas are rare and always meta static. Clinical
features
Patients typically present acutely with prominent headache, fever, stiff neck, seizures, focal neurological deficit, and rapid clinical deterioration. The diagnosis should be considered in all patients with meningeal signs and deficits indicating extensive, unilateral hemispheric dysfunction or in patients with sinusitis who develop meningeal signs. A parafalcine collection would be indicated by leg weakness, paraparesis, or sphincter disturbance. Children younger than 5 years may develop subdural empyemas after H. influenzae or gram-negative bacterial meningitis and present with irritability, poor feeding, and increasing head circumference. Radicular pain and signs of cord
1488
NEUROLOGICAL DISEASES
B FIGURE 59A..1 Subdural empyema. (A) Contrast-enhanced computed tomographic scan showing right frontal sinus infection (short arrow) that has spread to the right subdural space [long arrow) and forehead [arrowhead), (B) In a second patient, the contrast-enhanced computed tomographic scan shows an extra-axial fluid collection and midline shift disproportionately greater than the size of the subdural collection, compression in the absence of vertebral tenderness suggest spinal subdural empyema. Diagnosis Because there are similarities between subdural empyema and bacterial brain abscess with regard to pathogenesis and clinical presentation, the disorders share many aspects of diagnosis and management. Bacterial pathogens for both disorders are similar, although subdural empyemas are less often mixed. Neuroimaging studies help establish the diagnosis, but may underestimate the size of the empyema. In infants, the diagnosis may be made by subdural taps. The empyema fluid is usually too turbid to tran si Humiliate. Spinal cases are examined by M R ! or myelography. Treatment Because subdural empyema progresses rapidly, combined medical and surgical management should proceed emergcntly (Bleck 2002), Untreated, subdural empyemas are uniformly fatal. Whether craniotomy or burr hole aspiration is the better surgical treatment remains controversial. Burr holes work well for early cases, but pus may reaccumulate. Craniotomy is recommended in posterior fossa cases or if cranial osteomyelitis coexists. Otitis or sinusitis may require simultaneous surgical therapy. Empyema fluid should be cultured, and antibiotic treatment is continued for at least 3 weeks. In as many as one
fourth of cases, no organism can be cultured from pus (Anderson 1993). Overall mortality is 1 4 - 1 8 % . Rapid disease progression before hospitalization and depressed level of consciousness at admission arc associated with poor prognosis. Mortality is 7 5 % in comatose patients. An estimated 4 2 % of survivors develop seizures within 16 months.
Cranial Epidural Abscess Cranial epidural abscess, an infection in the space between dura and skull (Figure 59A.4), begins as cranial osteomyelitis complicating ear, sinus, or orbital infection and nasopharyngeal malignancy. Diagnosis, urgent management, and prognosis are similar to subdural empyema. Because S. aureus is a frequent cause, particularly after trauma or surgery, antibiotics should cover staphylococcus as well as the aerobes, anaerobes, and gram-negative organisms encountered in brain abscesses and subdural empyemas. Brain abscess, subdural empyema, and epidural abscess may occur simultaneously in the same patient.
Septic Venous Sinus Thrombosis Septic thrombosis of cerebral veins or venous sinuses may complicate meningitis or epidural or subdural abscesses or develop during the intracranial spread of infection from extracranial veins. Once established, infection and clot
BACTERIAL INFECTIONS
1489
papilledema, and clinical involvement of the third, fourth, sixth, and ophthalmic division of the fifth cranial nerves. Lateral (transverse) sinus thrombosis is accompanied by papilledema, extension to the jugular bulb with involvement of cranial nerves IX, X, and XI and extension to petrosal sinuses with involvement of cranial nerves V and VI. Sagittal sinus thrombosis is associated with papilledema, focal or generalized seizures, leg weakness, aphasia, or cortical sensory deficits. Diagnosis CT scan or MRI may demonstrate the primary infection or clot within the sinus. Clot within the sinus may appear as hyperdensity in the sinus on noncontrast CT, but may be missed by MRI, because acute thrombus may appear hypointense on T2-weighted images. MR venography or cerebral angiography with venous phase studies may be necessary to confirm the diagnosis. Treatment
FIGURE 59A.4 Epidural abscess associated with frontal sinus disease. Postgadolinium axial T1W-MR1 showing thiek-wallcd enhancing epidural collection close to the inner table of the frontal bone {arrowheads) with adjacent soft tissue swelling. (Courtesy Dr. S. Ouanounou.)
Treatment is directed towatd the primary infection. As with subdural and epidural empyema, empirical therapy is directed at gram-positive organisms, including staphylococci, aerobic gram-negative bacilli, and anaerobes. Anticoagulants are generally contraindicated because venous cerebral infarcts aire often hemorrhagic. However, they may help prevent clot propagation, particularly in early cases. Polycythemia, if present, is treated with volume expansion.
Spinal Epidural Abscess spread through the venous system, aided by the absence of valves in intracranial veins. Fortunately, antibiotics have rendered this grim complication of facial, sinus, ear, dental infection, or bacterial meningitis itself less common. The most common bacterial pathogens depend on the source of initial infection; with sinusitis they arc staphylococcus, aerobic and microaerophilic streptococci, gram-negative E. coli, and/or anaerobes, whereas .S. aureus predominates when facial infection is the source. Otitis media or mastoiditis may be complicated by the development of the lateral sinus thrombosis. Clinical Features Thrombosis may develop in the cavernous, superior sagittal, or lateral sinuses, depending on the site of primary infection. Specific presenting features vary with the site involved and include headache, altered mentation, seizures, cranial neuropathies, fluctuating focal deficits, nonartcrial distribution strokes, and increased ICP. Cavernous sinus thrombosis is indicated by ipsilatcral proptosis and facial edema, retinal vein engorgement, retinal hemorrhages or
Spinal epidural abscess follows infection elsewhere in the body in most cases. Infection develops in the epidural space by direct extension of vertebral osteomyelitis or soft tissue infections (retroperitoneal, mediastinal, perinephric, psoas, or paraspinal abscess) following penetrating trauma or decubitus ulcers or by hematogenous spread from skin or parenteral drug use. Rarely, back or abdominal surgery, LP, or epidural anesthesia has been contributory. Clinical Features Localized back pain and radicular pain are common early symptoms, frequently overshadowed by rapid evolution of paraparesis or quadriparesis. The thoracic spine is involved in 5 0 - 8 0 % of cases, lumbar in 1 7 - 3 8 % , and cervical in 10-25%. Diagnosis The combination of fever, back pain with local spine tenderness, and radiculopathy or myelopathy mandates
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NEUROLOGICAL DISEASES
Treatment Once MRI or myelography has established the diagnosis, utgent surgical decompression and antibiotic thetapy are needed. Antibiotics to cover S. aureus and gram-negative bacilli are administered, pending definitive identification by cultures of blood or intraoperative specimens. S. aureus is the most common pathogen, detected in 5 0 - 9 0 % of cases, followed by streptococci and gram-negative enteric bacilli in 1 0 - 2 0 % of cases. Other pathogens include M. tuberculosis, Salmonella, Listeria, Brucella, Actinomyces spp,, Nocardia, fungi {cryptococcosis, aspergillosis, mucormycosis, coccidioidomycosis, blastomycosis), and parasites (cysticercosis, echinococcosis, schistosomiasis). Corticosteroids are frequently administered preoperative^and postoperatively during the first week of treatment. Antibiotic treatment continues for 3-4 weeks in uncomplicated spinal epidural abscess and for 6-8 weeks if osteomyelitis is apparent. Prognosis for recovery is good if surgery is performed in the early stages. Neurological recovery is often dismal if surgery is performed more than 24 hours after the onset of paralysis.
Shunt Infections
FfGURE 59A.5 Spinal epidural abscess. Postgadolinium sagittal T1W-MRI of lumbar spine demonstrating enhancing epidural collection [arrowheads] with irregularity of the adjacent verrebral endplates suggesting discitis, osteomyelitis, and associated epidural abscess. (Courtesy Dr. S. Ouanounou.)
emergent evaluation. Peripheral WBC count and erythrocyte sedimentation tate are usually, but not always, elevated. The diagnosis depends on MRI or myelography, if MR! is not available. MRI is the test of choice because it is noninvasive and provides images of the cord and epidural space in sagittal and transverse planes, as well as direct visualization of inflammatory tissue (Figure 59A.5). LP risks spinal herniation or spreading infection to the subarachnoid space should the needle pass through the abscess. Even so, because outcome depends so heavily on early diagnosis, myelography should be performed in suspected cases when MRI cannot be obtained emergently. Blood culture results ate often positive and cotrelate well with abscess pathogens. Differential diagnosis includes transverse myelitis, spinal osteomyelitis, or less commonly, spinal subdural empyema, epidural hematoma or metastases, primary spinal tumots, spinal artery syndromes, and discitis. More chronic cases may resemble the hypertrophic spinal pachymeningitis (progressive dural fibrosis with motor root compression) associated with TB or syphilis.
S. epidermidis causes most infections of external ventricular catheters, ICP monitors, shunt devices, and Ommaya reservoirs, followed by .S. aureus. Infection, often within 2 weeks of installation, is signaled by fever, shunt malfunction, and wound infection (Figure 59A.6). Signs of meningitis may be absent, but CSF pleocytosis is present, Although CSF cell counts may be gteater in ventricular compared with lumbar CSF, both should be examined and cultured. Because most infections are hospital acquired, the organism should be assumed to be methiciilin resistant, and initial treatment is with vancomycin, combined with a third-generation cephalosporin and often an aminoglycoside, to cover gram-negative bacilli. Intraventricular vancomycin and aminoglycoside may be necessary, along with removal of the shunt (Kim and Pons 1994),
MYCOBACTERIAL DISEASES Tuberculosis Although TB most commonly involves the lungs, it can produce disease in nearly every organ system. Approximately 1% of TB infections arc complicated by neurological disease such as tuberculous meningitis, tuberculoma, or tuberculous involvement of the spine with myelopathy (Pott's disease). The TB bacilli are obligate aerobic organisms infecting humans and other animals. Two main species ate recognized, M. tuberculosis and M. bovis. Other less common species include M. africanum
BACTERIAL INFECTIONS
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Pathogenesis Neurological TB may develop during primary infection (Tung et al. 2002) or reactivate as a consequence of immunosuppression. TB meningitis develops most commonly after a two-stage process. Tubercle bacilli spread hematogenously from the lung or other organs fotm tubercles (Rich focus) in the brain parenchyma, and at a later stage, rupture into the subarachnoid or ventricular space. In other instances, meningitis may arise in the course of miliary TB or from parameningeal infection. Inflammatory exudate spreads along the subarachnoid space and pial vessels to the brain. Pott's disease, or spinal TB, develops when hematogenous spread of tubercle bacilli to the spine causes vertebral osteomyelitis, adjacent joint space infection, and subsequent paravertebral abscess. Tuberculosis
FIGURE 59A.6 Ependymitis secondary to shunt infection. Gadolinium-enhanced axial Tl-weighted magnetic resonance image showing abnormal contrast enhancement of ependymal lining of dilatated lateral ventricles (arrowheads); swollen, infected contrast-enhancing craniotomy site; and dural enhancement (long arrow) after removal of shunt.
in West and Central Africa and M. ulcerans. The atypical or nontuberculous mycobacteria, M. avium-intracellulare, arc widely distributed saprophytes and cause multisystem infections, including meningitis, in immunocompromised patients.
Epidemiology
and
Current
Trends
TB is the most important infectious disease in the world, with an estimated one third of the population infected with the TB bacillus. As is the case for other infections introduced to new, susceptible populations, TB occurs in epidemic waves. Unfortunately, this wave is taking 300 years to pass and has not yet crested in many countries of Asia and Africa. Each year an estimated 8 million individuals around the world develop active TB. Approximately 70,000 of these patients worldwide and 4000 patients in the United States acquire TB meningitis. The majority of these individuals develop a subacute meningitis that if left untreated soon produces severe brain damage. HIV infection in recent decades has been associated with an increasing numbers of new cases and with a higher risk of extrapulmonary TB.
Meningitis
Clinical Features. TB meningitis typically follows a subacute course with low-grade fever, headache, and intermittent nausea and vomiting, followed by more severe headache, neck stiffness, altered mentation, and cranial (usually III, but also II, VII, and VIII) nerve palsies. Untreated disease progresses with more pronounced meningeal signs, seizures, and focal neurological deficits, including hemiparesis, increasing drowsiness, and signs of increased ICP. Other presentations of tuberculous meningitis include acute meningitis, behavioral or intellectual disturbances without meningeal signs, encephalopathy, seizures, isolated cranial neuropathies, stroke, increased ICP, and recurrent serous or aseptic meningitis. Overall, meningeal signs are present in approximately 7 0 % of cases, cranial nerve palsy in 2 5 % , and focal neurological findings in 1 6 - 1 8 % . Purified protein derivative (PPD) testing is positive in 5 0 % and active chest infection in some of the patients. Diagnosis. Identifying tubercle bacilli on CSF acid-fast bacilli (AFB) smear or culture establishes the diagnosis. Serial LPs and centrifugation of specimens increases the yield of the AFB smear, a test that is diagnostic in only 1 0 - 3 0 % of cases. CSF culture results arc positive for M. tuberculosis in 4 5 - 7 0 % of patients but may take 6-8 weeks to become positive. Because a negative CSF AFB smear result does not rule out TB meningitis and the culture may not yield organisms for weeks, a presumptive diagnosis is often made based on other clinical criteria so that empiric anti-TB therapy can be started as early as possible. CSF examination demonstrates normal or elevated opening pressure, elevated protein {80^400 mg/dL), low glucose (5 cells/mm ) Reactive CSF VDRL test (CSF without blood contamination) Positive CSF FTA-ABS test (highly sensitive but less specific) No single test will diagnose all cases of neurosyphilis Treatment recommendations Penicillin G 18-24 million U/d (3-4 million U q 4hr IV for 10 to 14 days), or Procaine Penicillin 2.4 million U/d 1M plus probenecid 500 g PO qjd for 10-14 days, or Ceftriaxone 2 vjA IM or IV for L0-.I4 d;n-s, plus hen/,athin;: penicillin 2.4 million U IM, one dose at 2 weeks Follow-up monitoring If CSF pleocytosis, repeat CSF every month until cell count is normal If CSF cell count has not decreased after 6 months, or if CSF is not normal after 2 years, consider retrcatment Source: Adapted from Rompalo, A. N. 2002, "Neurosyphilis," in Current Therapy in Neurologic Disease, 6th ed., eds R. T. Johnson, J. W. Griffin, & J. C. McArther, Mosby, Philadelphia.
BACTERIAL INACTIONS and neurological forms. Early neurological manifestations of tertiary neurosyphilis include pure meningeal or meningovascular disease, with a 5- to 10-year latency from primary infection, and parenchymal forms, which occur 10-30 years after initial infection. General paresis refers ro parenchymal cerebral involvement and tabes dorsalis to syphilitic myeloneuropathy. Syphilitic gummas, granulomas that presenr as space-occupying lesions in brain or cord, may occur at any stage of disseminated disease. Neurosyphilis spans all stages of disseminated disease. Meningeal, meningovascular, and parenchymal syndromes are perhaps best viewed as a continuum of disease, rather than as discrete disorders. Syphilitic meningitis, meningovascular syphilis, general paresis, and tabes are different clinical expressions of rhe same fundamental pathological events, specifically meningeal invasion, obliterative endarteritis, and parenchymal invasion. Especially in the antibiotic era, symptomatic neurosyphilis may present, not as one classic syndrome, but as mixed, subtle, or incomplete disease (Cintron and Pachner 1994). All of the neurological complications of syphilis have been reported in HIV disease, which may accelerate the onset and progression of neurosyphilis. Syphilitic meningitis typically occurs earlier than other forms of neurosyphilis and is often asymptomatic. Rare complications of acute syphilitic meningitis include hydrocephalus, myelitis, or lumbosacral radiculitis. Meningovascular syphilis usually occurs 4 - 7 years after primary infection (range, 6 months to 12 years). In addition to stroke, involvement of large and small cerebral vessels also causes headache, vertigo, insomnia, and psychiatric or personality disorders. General paresis, the encephalitic form of neurosyphilis, typically presents as progressive dementia beginning 15-20 years after original infection (tange, 3-30 years). The clinical picture also may include delusional or apathetic states, dysatthria, myoclonus, intention tremor, seizures, hyper-reflcxia, and Argyll Robertson pupils {small, irregular pupils that constrict with accommodation but not light). Disease manifestations may be remembered using the mnemonic paresis: personality, effect, reflexes, eye, sensorium, intellect, and speech. Tabes dorsalis, the spinal form of syphilis, develops approximately 15-20 years after the original infection (range, 5-50 years). Tabes is characterized by lightning pains, autonomic dysfunction (urinary incontinence), and sensory ataxia. Affected patients have normal strength and lack reflexes in the legs; a positive Romberg's sign accompanies impaired proprioception. Pupils are abnormal in more than 9 0 % of cases, with Argyll Robertson pupils observed in approximately one half. Other associated features include optic atrophy, ophthalmoplegia, ptosis, gastric or other visceral crises (pharyngeal, laryngeal, genitourinary, intestinal, rectal), impotence, fecal incontinence, and pain and temperature loss leading to trophic
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changes such as Gharcot's (neuropathic) joints and perforating foot ulcers. Syphilitic inflammatory diseases of rhe eye include uveitis, chorioretinitis, and vasculitis. Each may accompany acute syphilitic meningitis or present as an isolated complication of secondary syphilis. Optic attophy evolves over months to years and may coexist with other forms of neurosyphilis, particularly tabes. Optic nerve degeneration usually begins peripherally and extends to the center of the nerve, producing progressive constriction of the visual fields with ptesetved acuity. Syphilitic otitis, an unusual manifestation, presents as unexplained hearing loss or vestibular abnormalities, with positive treponemal serology. At birth, congenitally infected infants may show signs of serous nasal discharge (snuffles), rash, condylomas, hepatosplenomegaly, or osteochondritis. If left untreated, the classic stigmata of Hutchinson's teeth, saddle nose, interstitial keratitis, saber shins, mental retardation, hearing loss, and hydrocephalus develop. Diagnosis Syphilis can be diagnosed by demonstration of spirochetes in lesions of primary, secondary, or early congenital syphilis. More commonly, however, treponemal and nontreponemal serologic tests are used to make the diagnosis. Treponemal tests include fluorescent treponemal antibody absorption, microhemagglutination assay, fluorescent treponemal antibody-absorption double staining, hemagglutination treponemal test for syphilis, and T, pallidum immobilization. Treponemal test results become positive 3—4 weeks after inoculation and usually remain positive for life. Nontreponemal or reagin tests detect antibodies to membrane lipids of T, pallidum, using antigens such as cardiolipin, lecithin, or cholesterol, and include the Venereal Disease Research Laboratory (VDRL) test and rapid plasma reagin test. More sensitive but less specific than treponemal serologies, nontreponemal test results become positive 5-6 weeks after exposure and usually become negative in the year following adequate treatment. Patients with classic neurosyphilis syndromes require serum serologies and CSF examination. Because syphilitic eye disease often is associated with neurosyphilis, patients with syphilis and oculat manifestations should also undergo LP. The Centers for Disease Control and Prevention (CDC) recommends CSF examination for all patients with syphilis who have neurological or ophthalmic symptoms and signs or active tertiary disease (aortitis, gumma, iritis) or have failed therapy (see Table 59A.4). In addition, the CDC advises that HIV-infected patients with late latent syphilis or latent syphilis of unknown duration undergo LP prior to treatment (Centers for Disease Control 1998; Pao et al. 2002). The diagnosis of neurosyphilis depends on clinical evidence, CSF findings, and serology. CSF mononuclear pleocytosis (>5 cells per pi) and elevated protein support the
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NEUROLOGICAL DISEASES
diagnosis of neurosyphilis. CSF-VDRL is very specific; it is more sensitive in meningovascular syphilis and general paresis than in asymptomatic neurosyphilis and tabes. False-positive CSF-VDRL may occur if blood contaminates CSF, as occurs with traumatic LP. Intrathecal T. pallidum antibody production, oligoclonal antibodies, IgM antibodies, or PCR-amplificd products may increase sensitivity of CSF examination (Cinque et al. 1997), Serum VDRL may be negative in up to 2 5 % of patients with late neurosyphilis, but specific treponemal tests remain reactive. The CSF of patients with tabes may show less-pronounced inflammatory changes than other forms of neurosyphilis. False-positive treponemal tests occur in Lyme borreliosis, nonvencreal treponematoses, genital herpes simplex, pregnancy, lupus, alcoholic cirrhosis, scleroderma, and mixed connective tissue disease. Transient false-positive reactions to nontreponemal tests can result from mycoplasma or enterovirus infection, mononucleosis, pregnancy, parenteral drug use, advanced TB, scarlet fever, subacute bacterial endocarditis, viral pneumonia, brucellosis, rat-bite fever, relapsing fever, leptospirosis, measles, mumps, lymphogranuloma venereum, malaria, trypanosomiasis, and varicella. Chronic false-positive reactions may be caused by malaria, leprosy, lupus, other connective tissue disorders, parenteral drug use, Hashimoto's thyroiditis, rheumatoid arthritis, reticuloendothelial malignancy, and advanced age. The differential diagnosis of neurosyphilis includes other inflammatory meningovascular or CNS granulomatous diseases, such as TB or cryptococcal meningitis, brucellosis, Lyme disease, CNS sarcoid, and cerebral vasculitides. Treatment Diagnosis and treatment of neurosyphilis is summarized in Table 59A.4. Optimal treatment of neurosyphilis is aqueous penicillin G at doses of 18-24 million units per day intravenously {3-4 million units every 4 hours) for 10-14 days. The alternative, procaine benzyl penicillin, 2.4 million units intramuscularly daily, with probenecid, 500 mg orally four times daily, both for 10-14 days, has been associated with treatment failures. In penicillin-allergic patients, alternatives include oral doxycycline, 200 mg twice daily for 4 weeks, or skin testing to confirm allergy and consideration of desensitization. A patient with a positive serum treponemal antibody test result and neurological disease compatible with neurosyphilis should be treated with penicillin in doses adequate for neurosyphilis, even in the absence of CSF confirmation. Because of sequestration of spirochetes in the inner ear and poor antibiotic penetration to that area, syphilitic otitis may require a longer duration of thetapy, from 6 weeks to 3 months. Patients with documented neurosyphilis should be followed after therapy. Clinical symptoms or signs of syphilis should prompt consideration of retreatment, as should fourfold increase of serum titers or failure of CSF titers greater than 1 to 32 to decrease at least fourfold by
12-24 months. If pleocytosis was present, LP should be performed every 6 months until cell count normalizes. Patients in whom CSF cell count does not decrease after 6 months, or in whom CSF does not return to normal after 2 years, may require retreatment. Complications
of and
Response
to
Treatment
Jatisch-Herxheimer reactions most frequently complicate treatment in patients with early syphilis. Clinical features of this systemic response to release of heat-stable pyrogens from spirochetes include rigors, fever, hypotension, and leukopenia. The response to treatment varies according to the chronicity of the neurological damage. In meningovascular syphilis, signs that remain 6 months after treatment usually persist indefinitely. Treatment of general paresis may improve the cognitive or psychiatric disease in relatively early cases or arrest disease progression in approximately one half of advanced cases. Residual symptoms of tabes continue after the CSF has normalized and require symptomatic treatment of joint deformities with orthotics, visceral crises with atropine, and pain with anticonvulsants or amitriptyline. Pretreatment optic atrophy and extensive perioptic meningeal infiltrate may presage progressive vision loss during treatment. Adequatetreatment of a mother with syphilis before the sixteenth week of gestation prevents congenital syphilis.
Lyme Disease (Borreliosis) Lyme disease, a systemic disease with dermatological, rheumatological, neurological, and cardiac manifestations, is caused by Borrelia burgdorferi and transmitted by the hard-shelled deer ticks: Ixodes dammini in the eastern United States, Ixodes pacificus in the western United States, and Ixodes ricinus in Europe. Clinical Features The existence of both early and late neurological manifestations, diagnostic uncertainty, and potential for relapse despite therapy have fueled continuing debate over the spectrum of Lyme-related neurological disease. Best agreement exists for the early neurological syndromes, which include lymphocytic meningitis, cranial neuropathy (commonly unilateral or bilateral Bell's palsy), and painful radiculoneuritis, which can occur alone or in combination. Optic neuritis, mononeuritis multiplex, and Guillain-Barre syndrome are other infrequent manifestations of early neurological involvement. Neurological complications of more advanced Lyme disease include encephalomyelitis, with predominant white matter involvement and peripheral neuropathy. Lymphocytic meningitis is usually acute, but may cause chronic or relapsing meningitis and communicating hydrocephalus. Radiculoneuritis, beginning as
BACTERIAL INFECTIONS
a painful limb disorder, may continue with exacerbations and remissions for up to 6 months. Encephalopathy with memory or cognitive abnormalities, confusional states, accelerated dementia, and normal CSF study results may occur. Other psychiatric or fatigue syndromes appear less likely to be causally related to Lyme disease (Steere 2001). The most common form of neuroborreliosis in Europe, radiculoneuritis {lymphocytic mcningoradiculitis, Bannwarth's syndrome), is rare in the United States. The meningitic forms of borreliosis may resemble CNS lymphoma, because the CSF may contain atypical lymphocytes. The differential diagnosis of Borrelia encephalomyelitis includes a first episode of multiple sclerosis. Bites from uninfected ticks may produce similar neuropathies (GarciaMonco and Benach 1995). Several systemic disorders support the diagnosis of Lyme borreliosis. Dermatotogical manifestations include erythema chronicum migrans, a painless expanding macular lesion present shortly after initial infection in approximately two thirds of patients, and acrodermatitis chronicum atrophicans, a bluish-red discoloration of the legs that occurs after the first year of infection. Other extraneural features include Borrelia lymphocytoma, occurring 6-12 months after infection, recurrent monoarthritis or polyarthritis, and second- or third-degree cardiac conduction block. Diagnosis The best clinical marker for the disease is the erythema chronicum migrans rash that occurs in 6 0 - 8 0 % of patients. The diagnosis of active neuroborreliosis is made by the presence of consistent history, signs, and symptoms, together with CSF pleocytosis, serum anti-B. burgdorferi antibodies, and evidence of intrathecal antibody production. Serologic testing by ELISA is performed as an initial screen, followed by Western blot confirmation. Culture of organisms and PCR testing of CSF are also available. Treatment Borreliosis is treated with parenteral antibiotics if there is evidence that infection has crossed the blood-brain barrier. Ceftriaxone (2 g once daily intravenously) or penicillin (3-4 million units intravenously every 3-A hours) for 2 - 4 weeks are first-line drugs. Tetracycline and chloramphenicol are alternatives in penicillin- or cephalosporin-allergic patients. Jarisch-Merxheimcr reactions may occur within 2 hours of initiating therapy. Mepta/inol, a drug with mixed opiate agonist and antagonist properties, may mitigate the attack. Routine use of corticosteroids is not indicated. Recommendations for the use of corticosteroids in neuroborreliosis generally have been limited to patients tteatcd aggressively with intravenous antibiotics with evidence of severe inflammation that fails to improve with time. CSF examination should be performed toward the end of the 2- to 4-week treatment course to assess the need for
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continuing treatment and again 6 months after the conclusion of therapy. Intrathecal antibody production may persist for years following successful treatment and in isolation does not indicate active disease. Patients in whom CSF pleocytosis fails to resolve within 6 months, however, should be retreated. Peripheral or cranial nerve involvement without CSF abnormalities may he treated with oral agents, either doxycycline, 100 mg twice daily for 14-21 days, or amoxicillin, 500 mg every 8 hours for 10-21 days.
Relapsing Fever The term relapsing fever applies to two distinct borrelial diseases, louse-borne relapsing fever and tick-borne relapsing fever. Both are characterized by episodic fever and spirochetcmia, systemic symptoms, and variable presence of neurological complications. The human body louse transmits .0, recurrentis and soft ticks of the genus Ornithodoros transmit other Borrelia spp., including B. duttoni. Clinical
features
Overcrowding and poor hygiene predispose to louse-borne relapsing fever. Clinical featutes may he mild, but sevete febrile illness with mortality reaching 4 0 % in epidemic situations also is seen. Hepatosplenomegaly, jaundice, respiratory symptoms (cough and dyspnea), and myocarditis ate more common than in the tick-borne syndrome, and neurological manifestations, including meningitis, meningoencephalitis, cerebral hemorrhage, or neuropathy, develop in approximately 3 0 % of patients. Neurological syndromes associated with tick-borne relapsing fever appear at the end of the first bout of fever or with relapses. Cranial neuritis is the most common neurological manifestation of tick-borne disease, with facial weakness affecting up to 2 2 % of patients. Lymphocytic meningitis, subarachnoid hemorrhage, encephalitis, transient or permanent focal deficits, iritis, iridocyclitis, optic atrophy, and sciatic neuralgias also have been described. Diagnosis Demonstrating borreliae in the peripheral blood of febrile patients using darkfield microscopy and Wright's or Gicmsa's stained blood smears establish the diagnosis. Proteus OX-K agglutinin titers are elevated in relapsing fever. Nervous system disease is accompanied by CSF lymphocytic pleocytosis and elevated protein. Spirochetes may be detected in CSF by smear or animal inoculation in approximately 1 2 % of patients with CNS signs. In the westetn United States, the diffetential diagnosis of tickborne relapsing fever includes Colorado tick fever and Rocky Mountain spotted fever.
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NEUROLOGICAL DISEASES
Treatment Louse-borne relapsing fever is treated with a single oral dose (500 mg) of tetracycline; erythromycin in the same dose is also effective. Tick-borne relapsing fever is treated with oral tetracycline or erythromycin, 500 mg every 6 hours for 5-10 days.
Leptospirosis Many wild and domestic animals carry Leptospira interrogans. Leptospirosis is a worldwide zoonotic infection transmitted direct!;- to humans by contact with urine of infected rodents or domestic animals or indirectly via water or soil contaminated by infected urine. The severity of disease varies widely; jaundice, hemorrhage, and renal failure develop in severe cases. Approximately 15% of patients develop signs and symptoms of meningitis, and many more have lymphocytic CSF. Clinical Features The illness often follows a biphasie course. The first bacteremic phase is characterized by fever, headache, myalgias, nausea, vomiting, and abdominal pain. Dissemination of the organism in the acute phase leads to meningeal invasion, during which leptospirae may be cultured from blood and CSF but not urine. A second immune phase develops in the second week, once the patient has mounted an antibody response to the organism. This stage is characterized by more severe systemic illness, with meningitis, uveitis, rash, and in severe cases, hepatorenal and hemorrhagic syndromes. Eighty percent to 9 0 % of patients have CSF abnormalities consistent with aseptic meningitis. CSF examination reveals lymphocytic pleoeytosis, elevated protein, and normal glucose levels, but the leptospirae have been cleared from the CSF by tins stage. CSF pressure is usually normal, yet LP may improve the headache. Moresevere forms of illness are accompanied by conjunctival suffusion, myositis with rhabdomyolysis, meningoencephalitis, or myelitis. In Weil's disease, the most severe form, hepatorenal dysfunction and myocarditis accompany depressed consciousness and, occasionally, intracerebral hemorrhage. Cerebral arteritis is an unusual late complication, and a form of moyamoya disease has been thought to occur as a result of obstruction of the internal carotid arteries near the circle of Willis. Mononeuritis multiplex and Guillain-Barre syndrome have been reported. Invasion of the eyes by leptospirae during the acute phase may produce uveitis weeks or months after recovery.
Organisms can be isolated from blood or CSF during the first 10 days of illness and from urine during the first month of illness. Serological test results, based on macroscopic or microscopic agglutination procedures, arc positive after the first week. Treatment Severe leptospirosis is treated with penicillin G, 1.5 million units intravenously every 6 hours for at least 7 days. 1 esssevere cases are treated with doxycycline, 100 mg twice daily for 5-7 days.
RICKETTSIAE AND RELATED ORGANISMS Rickettsiae are obligate parasites that appear microscopically as coccobacilli. The major ones are maintained in nature by a cycle involving an animal reservoir, an insect vector (lice, fleas, mites, and ticks), and humans. Q fever is an exception and is probably contracted by inhalation. In the early twentieth century, the rickettsial diseases, epidemic typhus in particular, were common and of grave health concerns. In Eastern Europe, between 1915 and 1922, there were an estimated 30 million cases of typhus, with 3 million deaths. Now, as a result of insect control and antibiotic therapy, the rickettsial diseases are uncommon. In the United States these diseases are quite rare, bur they are important because up to one third of patients have neurological manifestations, mainly headache and meningoencephalitis. Rocky Mountain spotted fever is the commonest form in the United States, with about 200 cases each year. All rickettsial diseases share the clinical triad of high fever, skin rash, and headache, with meningoencephalitis developing during the second week of illness in some cases. Rickettsiae infect small blood vessels throughout the body causing endothelial wall inflammation and proliferation, thrombosis, and perivascular inflammation. The vasculitis is most prominent in skin, heart, skeletal muscle, kidney, and CNS.
Lpidemic (Louse-Borne) Typhus K. prowazekii is transmitted by the human body louse from person to person, causing epidemic louse-borne typhus. A nonhuman reservoir, the southern flying squirrel in the eastern and south-central United States, has been recognized as an alternative source of infection, but the vector insect is not known. Clinical Features
Diagnosis Jaundice, renal failure, and elevated serum creatine kinase (CK) following a febrile illness suggest the diagnosis.
The illness begins within 12 days of a louse bite with abrupt fever, headache, limb pain, nausea, vomiting, facial swelling, and rash (Sexron and Kaye 2002), The rash
BACTERIAL INFECTIONS
appears first in the axillae and upper trunk, spreading to become confluent and hemorrhagic, but sparing the face, palms, and soles. Vacant, placid expressions or agitation are described during the high, unremitting fever, whereas meningitis or meningoencephalitis with focal neurological deficits, delirium, or coma accompany severe disease and complicate up to 5 0 % of cases. Tinnitus, hyperacusis, deafness, dysphagia, and midbrain stroke syndromes are recognized consequences of brainstem microinfarction. Transverse myelitis, hcraiparesis, painful peripheral neuropathy, akinetic mutism, and psychiatric disturbances have been reported in survivors. Systemic complications include vascular occlusions and gangrene, myocarditis, shock, and secondary infections. Diagnosis The combination of a cold weather environment, crowded conditions, and infrequent bathing and changing of clothes provides an ideal setting for louse-borne typhus. Clinical suspicion and serological demonstration of heterophilc antibodies to Proteus mirabilis OX-19 and OX-2 strains, the Weil-Felix reaction, assist in diagnosis. CSF may show modest elevations in protein and lymphocyte count, with normal glucose. Specialized laboratories can make a diagnosis by organism isolation, agglutination or EI .ISA serologic tests, or PCR amplification. Treatment Early and specific treatment is indicated to avoid a potentially fatal outcome. Effective therapies include oral or intravenous chloramphenicol, 500 mg every 6 hours intravenously for 7 days; oral or intravenous tetracycline, 500 mg every 6 hours intravenously for 7 days; or doxycycline in a single oral dose of 200 mg for adults. Relapses arc retreated with the same regimen. Formaldehydeinactivated R. prowazekii vaccine is recommended for persons with potential occupational exposure.
Rocky Mountain Spotted Fever Rocky Mountain spotted fever, a tick-borne infection caused by R. rickettsii, is the most virulent of the spotted fevers, with fatality of 2 0 % when treatment is delayed. Rocky Mountain spotted fever is present in the northwestern and eastern United States, Canada, Mexico, Colombia, and Brazil. Seasonality is predicted by activity of local ixodid tick species, including Dermacentor andersoni (wood tick) and Dermacentor variabilis in the western United States, Amblyomma americanum (lonestar tick) in the southern United States, Rhipicephalus sanguineus in Mexico, and Amblyomma cajennense in Brax.il and Colombia. Other forms of tick typhus, some in geographically overlapping areas, include Rickettsia
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japonica in japan, Rickettsia australis in Australia, Mediterranean spotted fever (Rickettsia conorii) in Asia, Africa, and the Mediterranean, and Siberian tick typhus (R. siberica). Clinical Features The illness begins with fever, headache, myalgia, and gastrointestinal symptoms 2-14 days after the tick bite. The rash appears first around the wrist and ankles from days 3-5 of the illness and spreads to the soles of the feet and forearms. Petechial and ecehymotic rashes, indicating microcirculatory injury, may foreshadow gangrene of the digits or rhabdomyolysis. Other complications include renal failure and pulmonary edema. CNS manifestations accompany severe cases. Meningitis or meningoencephalitis with microinfarcts causes focal neurological deficits, transient deafness, depressed consciousness, or coma. CSF examination reveals elevated protein and lymphocytic or polymorphonuclear plcocytosis in approximately 3 0 % of patients, with low glucose in fewer than 1 0 % . Electroencephalography shows diffuse abnormalities, which may persist into convalescence. Flame-shaped hemorrhages, venous engorgement, or arterial occlusion on ophthalmoscopic examination, indicate retinal vasculitis. Diagnosis R. rickettsii can be demonstrated by direct immunofluorescence or immunoperoxidase staining of skin biopsy in patients with rash. Other laboratory tests may indicate anemia, thrombocytopenia, coagulopathy, hyponatremia, and muscle tissue breakdown. Serology retrospectively confirms the diagnosis. Rocky Mountain spotted fever and the other rickettsial diseases should be distinguished from other causes of meningoencephalitis with rash, insect exposure, or recurrent fever by tests specific for the alternative diagnoses: from meningococccmia by blood and CSF culture, viral hemorrhagic fevers or hemorrhagic measles by serology, relapsing fever and tularemia by blood culture, typhoid fever by blood or bone marrow culture, leptospirosis by clinical or laboratory evidence of myositis and hepatitis, Lyme disease by serology, malaria by blood films, secondary syphilis by serology, toxic shock syndrome by blood wound or vaginal culture, and thrombocytopenic purpuras and immune-mediated vasculitis by serological markers of collagen-vascular disease, Treatment Treatment is with oral or intravenous tetracycline ( 2 5 50 mg per kg per day) or chloramphenicol (50-75 mg per kg per day) in four divided doses or oral doxycycline, 100 mg twice a day for 7 days and continued for 2 days once the patient has become afebrile.
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Other Rickettsial Diseases Murine typhus is caused by R. typhi. The organism is harbored by rats worldwide and transmitted to humans by flea bites. Early disease is characterized by fever, headache, myalgia, nausea, and truncal rash in 1 8 % of patients. Neurological symptoms, including confusion, drowsiness, seizures, and ataxia, and focal deficits may occur. Diagnosis is based on clinical suspicion, and the Weil-Felix reaction is the same as for louse-borne typhus. Treatment is with chloramphenicol, tetracycline, or doxyeycline. Scrub typhus is a febrile disease in East and Southeast Asia with headache, painful adenopathy, eschars, and trunk and thigh rash. R. tsutsugamushi, the causative agent, is transmitted by the bite of larval-stage trombiculid mites (chiggers). Meningoencephalitis or myocarditis accompanies severe cases. Specific serological or PCR tests arc used for diagnosis when available. Treatment is with a single oral dose of doxyeycline, 200 mg for adults and 100 mg for children. Q fever, an acute or chronic febrile illness that occurs worldwide, is caused by Coxiella burnetii. Cattle, sheep, and goats are the animal reservoirs. C. burnetii, though in the rickettsial family, differs from the other rickettsial infections by the aerosol route of transmission, absence of rash, and lack of cross-reacting antibodies to Proteus OX species. Characteristic clinical syndromes include atypical pneumonias or hepatitis. Also seen are endocarditis, vertebral osteomyelitis, and neurological syndromes, including aseptic meningitis and encephalitis. Diagnosis depends on ELISA or indirect fluorescent antibody serologic tests. Rarely, C. burnetii has been isolated from the CSF. Early, uncomplicated Q fever is treated with chloramphenicol, tetracycline, or doxyeycline. Endocarditis requires therapy with RIF and TMP/SMX or tetracycline. A formalinized vaccine is available for individuals with potential occupational exposure.
Ehrlichiosis Ehrlichioses are tick-borne zoonotic infections caused by an intra leukocytic bacterium closely related to Rickettsiae. First recognized as a canine pathogen, two species of Ehrlichia have been associated with human disease, including a summertime meningitis, in the United States, and a third species with a mononucleosis-like illness in Japan. In the United States, incidence peaks from spring through autumn. Patients presenr with fever, headache, myalgia, rash, and history of tick bite. Occasionally, meningitis is the sole clinical manifestation. Renal failure, disseminated intravascular coagulation, cardiomegaly, opportunistic infection, seizures, encephalopathy, or coma are among the serious complications in some cases (Fishbein et al. 1994). Most patients have varying degrees of leukopenia, thrombocytopenia or anemia, and mild to moderate hepatic enzyme abnormalities. Diagnosis depends on epidemiolog-
ical and clinical features, plus a high index of suspicion. Acute and convalescent sera confirm the diagnosis. PCRbased tests are available for early confirmation of acute infection. Treatment is with oral or intravenous doxyeycline, 100 mg twice daily, for 7 days. Bartonella Oroya fever and verruga peruana are two forms of the same disease, bartonellosis, caused by Bartonella hacilliformis. These two clinical forms were linked to bartoncllosis by the fatal self-inoculation experiment of the Peruvian medical student, Daniel Carrion, who, with the help of a colleague, injected himself with material from verruga peruana cutaneous lesions and contracted Oroya fever. Bartonellosis also is referred to as Carrion's disease. Oroya fever is associated with encephalitis and cerebral venous thromboses, and verruga peruana with intracranial nodules. These diseases occur in river valleys along the western slopes of the Andes in Peru, Ecuador, and Colombia at altitudes of 2000-8000 feet. Sandfly bite transmits the disorder. B. hacilliformis can be seen in red blood cells in the acute febrile stage and in smears from verruga. The differential diagnosis for Oroya fever includes malaria, typhus, and typhoid. The verruga stage resembles yaws or secondarysyphilis. Chloramphenicol (4 g daily in divided doses) for at least 7 days is the drug of first choice. Penicillin, tetracycline, streptomycin, and eotrimoxazole are alternatives.
ZOONOSIS PATHOGENS AND RELATED ORGANISMS Brucellosis Brucellosis, a zoonosis caused by several Brucella species (B. melitensis, B. abortus, and B. suis), is a multisystem illness characterized by fever, frequent bone and joint disease (arthritis, sacroiliitis, spondylitis, osteomyelitis), and respiratory, gastrointestinal, cardiac, or neurological disease. Normally a disease of domestic and wild animals, Brucellosis is transmitted to humans by ingestion of infected unpasteurized milk, by aerosol spread, or by contact with infected animals or animal products. The disease exists worldwide, but is especially prevalent in Mediterranean regions, the Middle East, the Indian subcontinent, and Latin America. In the United States, the disease is rare, with less than 100 cases being reported annually since 1990. Early complaints may include fatigue, sensations of malodorous sweat or abnormal taste, and symptoms of deptession. Untreated, an undulant fever pattern emerges in 2- to 4-week cycles. Meningitis can be the presenting manifestation, or it may occur late in disease. Acute or chronic meningitis, encephalitis, meningovascular disease, multifocal white matter disease, intracerebral or epidural abscess, subdural empyema, intracranial hypertension,
HACTERIAI- INFECTIONS
ruptured mycotic aneurysms, hydrocephalus, papilledema, cranial neuropathies, psychosis, parkinsonism, radiculopathies (usually lumbosacral) or myelopathy, peripheral neuropathies, and myositis have been reported. Endocarditis occurs in approximately 2% of cases. Brucellosis figures in the differential diagnosis of nearly any neurological disease in endemic areas. Definitivediagnosis depends on isolation of brucellae from blood, bone marrow, or other tissues. Because the organism is difficult to culture, diagnosis usually depends on (1) positive Brucella agglutination or FLISA test results with high titers of antibody in blood and CSF; (2) abnormal CSF with a lymphocytic pleocytosis, elevated protein, and low to normal glucose; and (3) response to therapy. Uncomplicated brucellosis is treated with oral doxycyclinc, 200 rng daily, with streptomycin, 1 g intramuscularly daily, for 12 weeks, or another amino glycoside for the first 4 weeks, then followed by RIF (10-15 mg/kg per day) for an additional 4-8 weeks. Neurobrucellosis, endocarditis, and skeletal and other severe organ involvement are treated with three-drug therapy with doxycycline, an aminoglycoside, and RIF for at least 12 weeks. Children under 8 years of age are treated with trimethoprim/sulfamethoxazole (TMP-SMX) in combination with an aminoglycoside and RIF. Adjunctive corticosteroid therapy has been used for concurrent vasculitic or demyelinatiug disease.
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CSF Gram stain and culture. Treatment of the primary infection is with streptomycin, 30 mg/kg per day intramuscularly in two divided doses for 10 days. Meningitis is treated with intravenous chloramphenicol, 25 mg/kg initially, followed by 60 mg/kg per day in four divided doses for 10 days, either alone or in combination with streptomycin.
Tularemia Tularemia (rabbit fever, deer fly fever, Ohara's disease, yatobyo) is an infectious disease of rodents caused by Francisella tularensis. Tularemia is transmitted to humans by insect bite, handling infected animals, ingesting infected meat or water, or inhaling contaminated aerosols or dust. F. tularensis causes an acute febrile illness; classic forms include ulceroglandular, oculoglandular, pneumonic, pharyngeal, abdominal, or typhoidal (septicemic) disease. Dissemination may lead to meningitis or encephalitis with mononuclear pleocytosis, elevated protein, and low glucose. Encephalitis and Guillain-Barre syndrome accompanying the pneumonic and pleuritic form have been reported also. Clinical suspicion and serological studies aid in the diagnosis; culture and isolation of F. tularensis are difficult. Streptomycin, 1 g intramuscularly daily for 10-14 days, treats the infection. Gentamicin is an alternative.
Anthrax Anthrax, caused by the gram-positive sporulating bacillus, Bacillus anthracis, is usually a disease of herbivores, acquired from contact with soil-containing spores. Less commonl\. anthrax causes hemorrhagic meningitis in humans after exposure to infected animals or their products. The three main forms of disease are cutaneous, respiratory, and gastrointestinal (Swartz 2001). Meningitis is seen in less than 5% of cases. For a diagnosis of anthrax meningitis, there should be a primary site of infection, such as a malignant pustule or pulmonary syndrome, plus CSF and blood containing B. anthracis. Treatment is with penicillin G, 4 million units cvety 4 - 6 hours for 7-10 days.
Pasteurellosis Pasteurellae, primarily animal pathogens carried in the nasopharynx or gastrointestinal tract of many domestic and wild mammals and birds worldwide, are rare causes of meningitis or brain abscess in humans during disseminated infections. Human Pasleurella infections, usually P. multocida, are either focal soft tissue infection after an animal bite, respiratory infection, or bacteremia. Diagnosis is by demonstration or culture of the organism from wound, sputum, or CSF, and treatment is with penicillin.
Glanders Plague Plague, caused by Yersinia pestis, is a zoonotic infection of wild rodents, transmitted by the bites of infected fleas to humans, an accidental host. Meningitis is an unusual manifestation of plague, usually complicating bubonic plague, particularly if buboes are located in the axilla. Human infection takes the clinical forms of febrile lymphadenitis (bubonic plague), septicemic, pneumonic, or meningeal plague. Most meningitis cases follow inadequately treated bubonic plague by 9-15 days, but primary plague meningitis also occurs. Y. pestis can be found on
Glanders, primarily an equine infection by Pseudomonas mallei, occasionally produces human disease consisting of suppurative infections, lymphadenopathy, and pulmonary disease. Meningitis or brain abscesses occur in up to one fourth of patients. A history of contact with horses, mules, or donkeys is typical, and transmission occurs through contamination of broken skin or mucosal surfaces by draining ulcers of an infected animal. Diagnosis is by microscopic examination of exudates. A 3-week course of sulfadiazine, 100 mg/kg daily in divided doses, is recommended.
1504 NEUROLOGIC At. DISEASES Melioidosis Melioidosis, caused by the ubiquitous soil saprophyte Fseudomonas pseudomallei, is a glanderslike infectious disease of animals and humans, with meningitis or brain abscess sometimes complicating disseminated forms (Woods et al. 1932). A role for a neurological toxin in the development of aseptic meningitis or brainstem encephalitis, bulbar and respiratory weakness, and peripheral motor neuropathy of Guillain-Barrc type, in the absence of direct CNS infection, has been suggested but not proven. The diagnosis should be considered in patients with a radiological pattern of TB from which AFB-staining bacteria cannot be found. Melioidosis is diagnosed by identifying organisms with bacteriological staining and culture techniques. Patients are seropositive by indirect fluorescent antibody or ELISA tests. Septicemic forms are treated with TMP/SMX plus ceftazidime, 120 mg/kg per day, with intravenous therapy for 2 weeks and oral treatment for 6 months.
Cat-Scratch Disease Cat-scratch disease, a slowly progressive regional adenitis caused by Bartonella henselae or, less often, Afipia felts is associated with aseptic meningitis in immunocompetent individuals and encephalitis, myelitis, or radiculoneuritis in HIV-infected patients. Several clinical patterns have been recognized. Immunocompetent individuals may have one or several bacteremic episodes with fever, arthralgias, headache, and aseptic meningitis, but the illness is self-limited in the majority of cases. HIV-infected patients with disseminated B. henselae infection may have bacillary angiomatosis (neovascular proliferative skin lesions), which resemble the cutaneous stigmata of verruga peruana or Kaposi's sarcoma, oculoglandular syndrome with preauricular adenitis, palpebral or conjunctival granulomas, anemia, hepatosplcnomcgaly, or encephalomyelitis. Direct plating of homogenized tissue of accessible lesions has yielded bacteria, but cultivation of Bartonella spp. is technically difficult and slow. ELISA tests and PCR amplification from infected tissues are available. Intravenous gentamicin is recommended for encephalitis and oral doxycycline, erythromycin, or ciprofloxacin for bacillary angiomatosis.
Rat-Bite Fever Rat-bite fever is a systemic febrile illness caused by Streptobacillus moniliformis, which is transmitted by the bite of a rat or other small rodents. Patients develop rash or purpuric skin lesions, asymmetrical polyarthralgias, or septic arthritis, with the additional complications of meningitis, brain abscesses, endocarditis, or myocarditis. Diagnosis is by visualization or culture of organisms from
blood, joint fluid, or purulent material. Treatment is with penicillin, streptomycin, or a cephalosporin in penicillinallergic patients.
STAPHYLOCOCCAL SYNDROMES Toxic Shock Syndrome Toxic shock syndrome (TSS), epidcmiologically linked to several toxigenic Staphylococcus aureus strains, is a multisystem disorder characterized by desquamating skin rash, especially on the palms and soles, high fever, hypovolemic shock, vomiting or diarrhea, renal failure, hypcrcmic mucosal surfaces, thrombocytopenia, liver enzyme abnormalities, myalgias, and encephalopathy. Several related exotoxins, chiefly TSS toxin 1 (TSST-1), produced byisolates of 5. aureus from patients, cause the disease. TSS has been reported in children, in menstruating women using hyperabsorbent tampons, and following gynecological and other surgical procedures. CNS complications may be more frequent in nonmenstrual TSS. Confusion, disorientation, agitation, or somnolence independent of anoxic or metabolic changes arc described. Other features include headache, generalized electroencephalographic abnormalities, poor concentration, memory impairment, and other cognitive dysfunction. CSF is usually normal. Serum CK levels, elevated in over one half of patients, reflect the severity of toxic myositis and convalescent-stage weakness. Although blood, vaginal fluid, or wounds may be cultured for S. aureus and isolates tested for production of TSST-1, TSS remains a clinically defined syndrome. Other febrile exanthems with hypotension, such as Rocky Mountain spotted fever, leptospirosis, meningococcemia, gram-negative sepsis, viral exanthems, and drug reaction, should be excluded. Management requires aggressive fluid replacement and treatment with a filactamase-resisrant antistaphylococcal antibiotic or clindamycin, 300 mg intravenously every 8 hours for 10-14 days.
Tropica! Pyomyositis Tropical pyomyositis is a subacute syndrome caused by staphylococcal infection, characterized by the spontaneous appearance of bacterial abscesses within the fascial boundaries of large-bulk skeletal muscles. Tropical pyomyositis accounts for 3 ^ 1 % of surgical admissions to hospitals in sub-Saharan Africa. Although early staphylococcal pyomyositis may respond to an antistaphylococcal penicillin or vancomycin alone, drainage of abscess cavities is usually necessary. In temperate regions, a different, hyperacute pyomyositis, caused by group-A beta-hemolytic streptococcal infection, is recognized. When it occurs, it is usually the earliest sign of critical, potentially fatal, disseminated infection, designated streptococcal TSS.
BACTERIAL INFECTIONS
Therapy includes penicillin or ampieillin, a third-generation cephalosporin, surgical drainage, and supportive treatment with volume expansion.
FILAMENTOUS BACTERIAL INFECTIONS (ACTINOMYCETOSIS) Nocardiosis Nocardiosis is a locally invasive or disseminated infection caused by the aerobic actinomycetes Nocardia asteroides, N. otitidiscaviarum, and N. brasiliensts. The organisms are soil saprophytes, spread to humans by inhalation, through broken skin, from the gut, or after dental procedures. Primary infection, typically manifests as pneumonia with cavitary pulmonary lesions, but sinusitis, keratitis, cutaneous abscesses and fistulae, septic arthritis, or vertebral osteoarthritis are seen also. Disseminated disease commonly involves the CNS. The CNS syndromes, including cerebral abscesses, meningitis, and rarely, hemorrhagic meningitis develop in approximately one third of all pulmonary cases and primary CNS infection in another 5 - 7 % . Cerebral abscesses ofrcn appear as complex multiloculated structures with satellite extensions on neuroimaging studies. Brain abscesses tend to burrow into a ventricle or our to the subarachnoid space, so meningitis is often associated with abscesses.
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trauma or predisposing infection. Abscesses and draining sinuses form and exudates contain sulfur granules, so named because they are yellow. Actinomyces reach the brain by direct extension of oral-cervicofacial disease or hematogenous sptead. Brain abscess is the most common CNS presentation. Abscesses may be single or multiple and may appear multiioculated with ring enhancement (Figure 59A.9) or more homogeneous enhancement on neuroimaging studies. Chronic meningitis may develop as a consequence of spread from a parameningeal extracranial site or paraventricular or parameningeal brain abscess. Spinal epidural abscess, dural sinus rhrombosis, and spinal cord subdural empyema also have been reported. Macroscopic and microscopic examination of pus and granules, followed by culture, establishes the diagnosis. Actinomycosis resembles nocardiosis, but the latter does not form granules in visceral organs. Actinomycosis occurs in immunocompetent patients, whereas nocardiosis is a disease of immunosuppressed patients. Treatment is with penicillin, initially 18-24 million units in divided doses intravenously per day for 2-6 weeks, followed by oral penicillin or amoxicillin for 6-12 months. Surgical drainage and excision may be indicated. Clindamycin penetrates
Nocardia spp. appear as weakly gram-positive, branching filaments in sputum, drainage from fistulas, or histological specimens. Dense bacterial concentrations resemble Chinese calligraphy. Nocardia, when stained with modified acid-fast procedures, are partially acid fast. Because nocardiosis is an infection with a variable, often chronic, course, treatment with sulfonamides (TMP/SMX) may need to extend for months. The recommended intravenous dose is TMP (15 mg/kg per day) and SMX {75 mg/kg per day), rhc equivalent of two double-strength tablets every 8 hours. Second-line drugs include minocycline, imipenem, or an aminoglycoside in combination with a thitd-generation cephalosporin.
Actinomycosis Actinomycosis, characterized by abscesses that cross fascial planes to form sinuses, is a rare cause of brain abscesses. Actinomycosis is caused by a variety of gram-positive anaerobic or microaerophilic rods of the genera Actinomyces (most commonly Actinomyces israelii and A, arachnid, normal mouth and female genital tract flora). Most infections are either cervicofacial, thoracic, abdominal, or pelvic. Cervicofacial actinomycosis or "lumpy jaw" is the most common form and may develop following dental procedures or oral mucosa trauma, as a complication of dental caries or periodontal disease, ot without antecedent
FIGURE 59A.9 Actinomycosis. Gadolinium-enhanced coronal Tl-weighted magnetic resonance image showing multiioculated, ring-enhancing lesion in a patient with intracerebral spread of actinomycosis abscesses from a skull infection. Skull involvement is indicated by resorption of normal fatty marrow signal {arrow).
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NEUROLOGICAL DISEASES
bone well and may be the drug of choice if there is bony involvement.
ENTERIC BACTERIA Salmonellosis A common cause of neonatal meningitis, Salmonella species are associated also with brain abscess, subdural empyema, and recurrent bacteremia in HIV-infected parients, Salmonella typhi and S. paratyphi are recognized agenrs ot enteric fever, vascular (endothelial) infection leading to aortoduodenal fistulas and chronic carrier states. Disseminated intravascular coagulation complicates severe infections. Atypical manifestations include pneumonitis, pericarditis, sacroiliitis, arthritis, and osteomyelitis, the last being particularly common in patients with sickle cell hemoglobinopathies. Until recently, chloramphenicol was used to treat typhoid fever. However, because of outbreaks associated with resistant strains in Latin America, the Middle East, and South and Southeast Asia, ciprofloxacin for adults (500 mg orally twice a day for 10-14 days) or ceftriaxone for children (100 mg/kg per day intravenously or intramuscularly for 10-14 days) or adults (1-2 g daily) are considered better choices for patients in these areas. Antibiotics combined with corticosteroids for the first 48 hours of illness may improve outcome in some critically ill patients with delirium, stupor, coma, or shock.
Shigellosis Shigella species, members of the Enterobacteriaceae family and agents of bacillary dysentery, are postulated to cause a fatal, toxic encephalopathy in children by elaboration of Shiga toxin (Goren et al. 1992). The encephalopathy is a syndrome of sudden headache, cerebral edema, and rapid neurological decompensation, beginning several hours to 6 days after onset of diarrheal illness. Shigellosis is diagnosed by stool culture. Enteric and systemic disease is treated with ciprofloxacin (500 mg orally twice daily for adults for 1-5 days) or TMP/SMX (160 mg of TMP and 800 mg of SMX orally twice daily in adults) and supportive treatment, but antibiotics may not influence the neurological disease.
is usually 2 - 3 weeks after the diarrheal illness and follows an estimated I per 1000-2000 Campylobacter infections. The presence of anti-GMj antibodies in Guillain-Barre patients infected with C. jejuni Penner serogroup 19 and anti-GQlb ganglioside antibodies in Miller-Fisher variant patients infected with C. jejuni Lior serogroup 7 has led to the hypothesis that lipopolysaccharides of these Campylobacter isolates induce neuropathic disease by molecular mimicry (Yuki 1997; Yuki et al. 1997). Campylobacter infection is diagnosed by isolation and identification of the organism from stool or blood. Most strains are treated adequately with erythromycin, 250 mg orally four times daily for 5-7 days.
Whipple's Disease Whipple's disease, caused by Tropherym.a wbippelii, is a multisystem disorder characterized by gastrointestinal disease (abdominal pain, diarrhea, weight loss), arthritis, lymphadenopathy, addisonian symptoms (hypotension, asthenia, cutaneous hyperpigmentation), and protean neurological manifestations including dementia, oculofaciomasticatory myorhythmia, supranuclear ophthalmoplegia, meningitis, neuropathy, and myopathy (Anderson 2000). Classically, the disease occurs as coexisting neurological and gastrointestinal disease, and the diagnosis is made by identifying periodic acid-Schiff-positive bacilli in macrophages in tissue obtained from duodenal or jejunal biopsy. Brain biopsy, demonstrating periodic acid-Schiffpositive material, has been used to establish the diagnosis in the absence of intestinal disease. For its numerous other presentations, sarcoidosis, collagen vascular disease, malabsorption syndromes, Addison's disease, frontotemporal dementia, Creutzfeldt-Jakob disease, progressive supranuclear palsy, or Wernicke's encephalopathy are differential diagnostic considerations. Treatment is with oral double-strength TMP-SMX twice daily for 1 year. Severely ill patients are treated with thrice daily TMP/SMX for the first 2 weeks, together with folinic acid. Oral chloramphenicol, parenteral ceftriaxone, or penicillin arc other treatment options for those who respond poorly.
RESPIRATORY PATHOGENS Chlamydial Diseases Campy 1 obactcrios is Campylobacter, among the most frequent bacterial infections of humans worldwide, causes both acute enteric and systemic illnesses. Sources of infection include raw milk, water, and poultry. Campylobacter jejuni has been identified as the most common antecedent pathogen for the Guillain-Barre syndrome, accounting for an estimated 20^10% of all cases. The onset of Guillain-Barre syndrome
Each of the three chlamydial species, Chlamydia psittaci, C. trachomatis, and C. pneumoniae arc human pathogens, with C. psittaci most consistently associated with neurological complications. Psittacosis (or ornithosis), caused by C. psittaci, is transmitted from bird to humans by the aerosol route. Fever, cough, myalgia, headache, and hepatomegaly are presenting clinical features, occasionally accompanied by
BACTERIAL INFECTIONS
cranial nerve palsy, myelitis, meningoencephalitis, seizures, or cerebellar ataxia. CSF contains few or no lymphocytes and normal protein, although elevated protein has been reported with myelitis. Psittacosis is diagnosed by serology and treated with oral tetracycline or erythromycin, 500 mg four times per day for 10-14 days. In the absence of a firm diagnosis, erythromycin may be preferable, because it also covers other Legionella and Mycoplasma, which also cause atypical pneumonias with neurological symptoms. C. trachomatis causes ocular and venereal Treatment is with erythromycin or tetracycline.
disease.
Mycoplasma Syndromes The human mycoplasmas are Mycoplasma pneumoniae, M. hominis, M. urealyticum, and M, genitalium.. M. pneumoniae, responsible for most clinical disease, causes respiratory infections. Systemic illness with cough and fever are the most consistent clinical presentations, 1 Extrapulmonary involvement includes rash, cardiac abnormalities, arthralgias, vascular diseases (Raynaud's phenomenon, internal carotid artery occlusion, stroke;-, and neurological syndromes (aseptic meningitis, meningoencephalitis, leukoencephalitis, transverse myelitis, brainstem syndromes, Guillain-Barre syndrome, and peripheral neuropathy). Diagnosis depends on recognizing the clinical syndrome and may be confirmed by demonstration of cold agglutinins or complement-fixing antibodies. Erythromycin, 500 mg every 6 hours in adults, 1 g per day in older children, and ."50-50 mg/kg per day in young children for 21 days is the recommended treatment. Tetracycline is an alternative in adults and children older than 8 years.
Legionellosis Legionella pneumophila causes Legionnaires' disease, which can complicate myositis, encephalitis, and meningitis. L. pneumophila is transmitted to humans from its natural aquatic habitat by aerosol or airborne droplets, particularly where humidifiers or air conditioners are used. Legionnaires' disease is characterized by mild to severe pulmonary disease, gastrointestinal disease, hyponatremia, myalgias or myositis, and encephalomyelitis. Encephalopathy, manifesting as altered mental status, is the most common neurological abnormality; ataxia, cranial nerve palsy, mild inflammatory CSF changes, and electroencephalographical abnormalities, have been reported. The diagnosis is suspected in patients with pneumonia and purulent sputum with few or no organisms seen on Gram's stain or in patients who fail to respond to ^-lactam or aminoglycoside antibiotics. Diagnosis is made by culture, serology, or DNA probe. Treatment is with erythromycin, 1 g intravenously every 6 hours until clinical improvement, followed by 2 g orally in divided doses for 3 weeks.
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Alternative agents include clarithromycin, doxycycline, ciprofloxacin, and RIF.
Pertussis Bordetella pertussis causes pertussis (whooping cough), an upper respiratory catarrhal infection followed by paroxysmal coughing in a series of short expiratory bursts and an inspiratory gasp. Pertussis is a severe disease in children younger than 1 year, associated with seizures and encephalopathy. Subconjunctival, scleral, or CNS hemorrhages can follow the increased intrathoracic and intraabdominal pressures during violent coughing at any age. Definitive diagnosis is by isolation of B. pertussis, but because the organism is difficult to culture, a clinical case definition (cough of 2 weeks' duration in the setting of a community outbreak) is used. Treatment is with erythromycin at doses of 4 0 - 5 0 mg/kg per day for 14 days, and erythromycin for prophylaxis of household contacts may be necessary. A vaccine composed of one or more components of the organism combined with diphtheria and tetanus toxoids (DPT) is used for immunization.
CARDIAC INFECTIONS Endocarditis When cerebral emboli from all sources are counted, approximately 3% result from infective endocarditis. Common pathogens include enterococci, Streptococcus viridans, S. aureus, S. epidermidis, or Pseudomonas aeruginosa. Cerebral embolization occurs in at least one third of all infective endocarditis cases, commonly in middle cerebral artery territory. Bland or hemorrhagic cerebral infarcts, arteritis, single or multiple abscesses, mycotic aneurysms (often at bifurcation points of distal branches of the middle cerebral artery), intra parenchymal or subarachnoid hemorrhage, cerebritis, meningitis, and asymptomatic CSF pleocytosis can develop during active endocarditis. Blood culture, a critical diagnostic test for endocarditis, may give negative results in 2 . 5 - 3 1 . 0 % of cases. Reasons for culture-negative endocarditis include fungal endocarditis, slow growth of fastidious organisms such as Haemophilus, variant streptococci or Brucella, failure to culture intracellular pathogens such as chlamydiae or rickettsiae, right-sided endocarditis, and recent antibiotic use. CSF examination, if clinically indicated, most consistently shows increased numbers of polymorphonuclear leukocytes, red cells, elevated protein, and normal glucose levels. Treatment is with parenteral antibiotics for at least 4 weeks. Indications for valve replacement include more than one significant embolic episode or failure of antibiotic therapy; mycotic aneurysms may require neurosurgical intervention.
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NEUROLOGICAL DISEASES
Rheumatic Fever Rheumatic fever, a sequelae of group A streptococcal infection, is diagnosed by one or more clinical criteria (carditis, migratory polyarthritis, subcutaneous nodules, erythema marginatum, chorea), plus culture evidence of recent group A streptococcal infections or elevated antistreptolysin O titers. The childhood chorea, Sydenham's chorea, occurs in less than 10% of patients. Onset may be immediate or several months after the index infection. Even patients with chorea only are treated, according to the American Heart Association guidelines, which advise prophylactic monthly intramuscular injections of 1.2 million units of benzathine penicillin G or daily oral penicillin V to prevent recurrent attacks.
DISORDERS DUE TO BACTERIAL TOXINS Neurotoxigenic Clostridia: Botulism and Tetanus Clostridia, strictly anaerobic gram-positive bacilli, form highly resilient spores that are ubiquitous in the environment. Unlike pathogens that cause neurological disease by inducing inflammation or forming mass lesions, and the consequent tissue injury, several clostridial species elaborate exotoxins that gain access to the nervous system by avid and specific binding to motor nerve terminals. The resulting clinical syndromes are motor disorders that often are accompanied by autonomic dysfunction. Botulism and tetanus require notification of public health authorities, both to obtain therapeutic antisera and to initiate appropriate epidemiological investigation. Knowledge of their characteristic clinical features facilitates early diagnosis of these rare, but rrearable, disorders.
Botulism An unusual cause of acute generalized weakness, botulism develops when the extremely potent neurotoxin secreted by Clostridium botulinum blocks peripheral cholinergic transmission. Clostridia botulinum spores are widespread in soil and aquatic sediment. Seven botulinum toxin serotypes define the various C. botulinum strains (Case Records 1997). Types A, B, E, and rarely, F cause human disease. Types C and D cause botulism in animals, and type G does not appear to cause human or veterinary illness. Foodborne botulism, described in 1895 by van Ermengen, develops when preformed toxin is ingested from contaminated food. Wound botulism, first recognized in 1942, occurs when C. botulinum in an infected wound releases botulinum toxin directly into the tissue. Toxin production by C. botulinum colonizing the gut causes infantile botulism. Less commonly, gut colonization causes botulism in adults with pre-exisring gasrrointestinal disorders,
such as intestinal surgery or inflammatory bowel disease (Midura 1996). Pathogenesis
and
Pathophysiology
Borulinum toxin blocks acetylcholine release at peripheral synapses, leading to the paralytic and autonomic clinical manifestations of botulism (Montecucco and Schiavo 1994). With a median lethal dose as low as 1 ng/kg in mice, it is the most potent toxin known. Unlike C. botulinum spores, the toxin is heat-labile. Botulinum toxin is initially synthesized as a single 150-kD prorein chain and contains a single disulfide bond. Proteolysis forms heavy (100 kD) and light (50 kD) chains. The ("'-terminal region of the heavy chain binds tightly and specifically to presynaptic membranes, whereas the N-terminal domain governs internalization of the toxin into the motor neuron. Once internalized, botulinum toxin cannot be neutralized by therapeutically administered antibodies. After translocation across vesicular membranes into the cytosol, cleavage of the disulfide bond liberates the light chain, which contains the catalytic activity of botulinum toxin. The light chain is a zinc endopeptidase that targets various proteins mediating exocytosis. Hence, botulinum toxin causes irreversible blockade at peripheral cholinergic synapses. Recovery requires sprouring of new nerve Terminals, accounting for rhe protracted clinical course of botulism. Public Health Issues Although the disease is ubiquitous, five western states (California, Washington, Colorado, New Mexico, and Oregon) account for more than half of all reported outbreaks in the United States. First reported in 1976, infant botulism is now the most common form of botulism in the United States. Among adults, food-borne botulism is much more common than wound botulism. Outbreaks of poisoning are more often due to home-preserved than to commercially canned products, and vegetables are incriminated more commonly rhan any other food product. Since the late 1980s, injection drug use, specifically "skin popping" heroin, has been linked to wound botulism. Skin popping refers to subcutaneous injection, typically by chronic addicts whose poor venous access precludes inrravenous administration. Since 1990, a sharp increase in wound botulism in California has been associated with skin popping "black tar" heroin (Centers for Disease Control 1995). Clinical Features Whether toxin is ingested or elaborated in situ from gut colonization or an infected wound, common early symptoms of botulism include diplopia, ptosis, dysarthria, and dysphagia. Extraocular and bulbar muscle weakness
BACTERIAL INFECTIONS
progresses rapidly to the limbs, typically symmetrically, and also to respiratory muscles. Alertness and cognition are normal, unless hypoxemia or hypercarbia supervene because of respiratory failure. Reflexes are depressed or absent, and sensation is normal. These symptoms and signs all indicate neuromuscular blockade. In botulism, impaired cholinergic transmission also involves autonomic synapses, as indicated by dilated poorly reactive pupils, dry mouth, paralytic ileus, and occasionally bradycardia. In food-borne botulism, nausea, vomiting, and diarrhea often accompany early neurological symptoms, typically 12-36 hours after toxin ingestion. Gastrointestinal symptoms may be less prominent in early wound botulism. Clinical features of infantile botulism vary widely (Midura 1996). Constipation, poor suck, weak cry, and listicssness are common, and the baby often appears floppy. The incubation period may be as brief as a few days or as long as a month. A small percentage of cases of sudden infant death syndrome result from infant botulism. Honey has been implicated as the source of C. botulinum spores in infantile botulism. Dust is another important environmental source of spores; however, in most cases of infantile botulism, a source cannot be identified. Diagnosis The differential diagnosis includes other causes of acurc generalized weakness. Preserved alertness and lack of sensory or upper motor neuron signs help exclude acute brainstem disorders such as stroke, demyelinating syndromes, and encephalitis. The descending paralysis of botulism closely resembles the Miller-Fisher variant of Cuillain-Barre syndrome and overlaps with the clinical features of diphtheritic polyneuropathy. However, in botulism, sensation is normal, as is CSF. Electromyography and nerve conduction study results reveal changes indicating presynaptic neuromuscular blockade, in contrast to the often-elevated CSF protein and electrophysiological features that suggest the demyelinating neuropathies of GuillainBarrc syndrome or diphtheria. Pupillary involvement and ileus help distinguish botulism from myasthenia gravis presenting in crisis. In addition, peripheral electrophysiological studies, particularly repetitive nerve stimulation, in myasthenia reveal a postsynaptic defect in neuromuscular transmission (decrement on slow repetitive stimulation; see Chapter 36B), rather than the presynaptic electrophysiological abnormalities that characterize botulism (increment on rapid repetitive stimulation). Normal CSF and prominent ocular signs differentiate botulism from poliomyelitis, in which pleocytosis is the rule and extraocular weakness and ptosis are rare. Tick paralysis also causes acute generalized weakness caused by impaired presynaptic neuromuscular transmission, but weakness typically ascends and spares extraocular muscles. Paralytic shellfish toxicity and organophosphate poisoning are other considerations; the latter causes a syndrome in which cholinergic, rather than
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anticholinergic, features predominate. The differential diagnosis of infantile botulism includes sepsis, pneumonia, failure ro thrive, myasthenia, polio, Guillafn-ftarre syndrome, brainstem encephalitis, meningitis, hypothyroidism, and metabolic disorders. Symptoms and signs suggesting cholinergic blockade at both autonomic and neuromuscular synapses suggest the diagnosis of botulism. History of similar symptoms in family or acquaintances or of eating home-canned foods should be specifically sought, as should evidence of recent trauma or chronic infection. Alrhough many patients with wound botulism have a clinically obvious site of infection, it should be emphasized that the extremely high potency of botulinum toxin means that small, seemingly trivial abscesses can cause botulism. In a patient with a compatible clinical syndrome, the diagnosis of botulism is confirmed by roxin assay or by culturing C. botulinum. Toxin detection requires mouse bioassay, which can be arranged through state health departments or the CDC. Appropriate samples for toxin assay include suspected food sources, blood, and stool in most instances, as well as gastric contents and enema fluid in infant botulism. Rapid determination of the source of toxin helps identify individuals at risk in fooddiorne cases. Because C. botulinum is a srrict anaerobe, culture specimens require special collection, transport, and culture procedures. Appropriate culture materials include suspected contaminated foods, wound specimens, and stool. Treatment Once taken up by neurons, botulinum toxin is invulnerable to antibody inactivation and irreversibly blocks exocytosis. Hence efforts to neutralize circulating antitoxin and eradicate its source often begin before roxin or culture results, which take days, are known (Burningham et al. 1994), In adults, trivalent (types A, B, E) equine antitoxin is given if initial testing reveals no hypersensitivity reaction. Nasogastric suctioning and enemas may help remove toxin in food-borne cases. In wound botulism, infected wounds, even if minor, should be debrided. Because the procedure could liberate more toxin, it may be prudent to debride wounds after antitoxin administration. Whether antibiotics active against C. botulinum should be given is controversial, because of the concern that bacterial lysis could release more toxin. If other intercurrent infections require antibiotic therapy, aminoglycosides are probably best avoided whenever possible, because they also impair presynaptic neuromuscular Transmission. Meticulous supportive care plays a critical role. Close monitoring in an ICU is important, even in patients who do not require intubation at presentation, because respiratory decompensation can develop precipitously. Serial bedside pulmonary function tests are more sensitive than blood gas parameters in determining the need for mechanical ventilation, because vital capacity decreases before hypoxemia
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NEUROLOGICAL DISEASES
and hypercarbia develop. Complications of prolonged immobility, such as stress ulcer, malnutrition, pneumonia, urosepsis, deep venous thromboembolism, and depression should be anticipated and managed appropriately. In infants, supportive care, including mechanical ventilation in many patients, is the mainstay of therapy. Treatment of infant botulism usually does not include antitoxin administration or antibiotics (Midura 1996). Modern critical care has decreased mortality from 6 0 % to 2 0 % (Case Records 1997) in botulism. Because botulinum toxin irreversibly destroys the cellular apparatus responsible for acetylcholine release at neuromuscular junctions, motor recovery depends on motor axon sprouting, which takes weeks to months. Long-term ventilatory support and tracheostomy may be necessaty. Full recovery can take years.
Tetanus Clostridium tetani secretes tetanospasmin, also known as tetanus toxin, and tetanolysin. The function of tetanolysin remains uncertain; tetanospasmin blocks release of inhibitory neurotransmitters by spinal interneurons, causing the dramatic muscle contractions that characterize tetanus. C. tetani spores can survive for years in soil and house dust. When introduced into the anaerobic environment of a suitable wound, conversion to the toxin-producing vegetative form may cause tetanus. Neonatal tetanus complicates umbilical sepsis, which is usually related to improper umbilical stump care. Septic procedures during pregnancy or abortion can cause maternal tetanus. Other circumstances favoring the growth of C. tetani include deep puncture wounds, chronic skin or dental infections, decubitus ulcers, and other contaminated, necrotic wounds. Although trauma precedes most cases, a responsible wound is not identified in 2 0 % of patients. Tetanus, a preventable disease, is an important international public health problem, particularly in the developing world. Pathogenesis
and
Pathophysiology
Tetanospasmin inhibits release of y- amino butyric acid and glycine, which are inhibitoty neurotransmitters in the brainstem and spinal cord (Ernst et al. 1997). A single type of tetanus neurotoxin exists, in contrast to the multiple scrorypes of botulinum toxin. Interestingly, though botulinum and tetanus toxins cause dramatically different clinical syndromes, they share many biochemical featutes (Montecucco and Schiavo 1994). Both are 1.50-kD zinc endopeptidases consisting of light and heavy chains connected by a disulfide bond. The binding specificity and translocation reside in the heavy chain, in the Cand N-termini, respectively. The light chain is the zinc endopeptidase, which blocks exocytosis. Unlike botulinum toxin, which remains in the motor axon terminal, tetanus
toxin travels to the anterior horn cell by retrograde axonal transport, moves into the intersynaptic space, and enters inhibitory neurons. Impaired exocytosis in these spinal inhibitory neurons causes uncontrolled muscle contraction, a prominent clinical feature of tetanus. Similar disinhibition in the intermediolateral column of the spinal cord is thought to produce autonomic dysfunction. Public Health issues Underreporting is the rule for all forms of tetanus in both industrial and developing countries (Galazka and Gassc 1995). Neonatal tetanus remains a significant public health problem in the developing world. In industrialized nations, tetanus is rare, owing to toxoid immunization programs, which usually target children. As a result, tetanus has become particularly rare in children and young adults and is primarily a disease of the elderly in industrialized countries. Interestingly, immunization efforts also decrease mortality from neonatal tetanus. Since the 1980s, tetanus outbreaks have developed among heroin addicts in Hong Kong, reminiscent of similar outbreaks in New York City during the 1960s (Sun et al. 1994), Clinical Features The typical incubation period is 2 weeks but can range from hours to a month or more. Cardinal features include muscle rigidity and spasms, which may be accompanied by autonomic hyperactivity. Local tetanus, in which symptoms remain limited to a limb, is a rare form. Far more common is generalized tetanus, also called lockjaw, as trismus heralds the disorder in over 7 5 % of cases. Tetanus resulting from infected head and neck wounds may present with facial or ocular muscle spasms, so-called cephalic tetanus. Sustained contraction of facial muscles causes a sneering grimace known as risus sardonicus. Other early symptoms include dysphagia and axial muscle involvement, such as neck stiffness, abdominal rigidity, and back pain. Early involvement of face, neck, and trunk muscles has been ascribed to the shorter axons of motor neurons supplying cranial and axial muscles, as compared with the limbs. Laryngospasm compromises ventilation and makes intubation extremely difficult. Sustained contraction of back muscles causes opisthotonos, an arching posture of the back. As tetanus progresses, reflex muscle spasms develop, triggered by sensory stimuli, movement, or emotion. Examination can be difficult, as it may prompt spasms. Diagnosis Differential diagnosis includes hypocalcemia, strychnine poisoning, dystonic reactions to neuroleptics or antiemetics, meningitis, encephalitis (including rabies), status epilepticus, and the acute abdomen. Oral infection or mandibular
BACTERIAL INFECTIONS
fracture or dislocation may cause isolated trismus, without the generalized features of tetanus. Immunization status should be established, if possible, and a history of chronic infection should be sought. The characteristic muscle contractions elevate serum CK, but there are no pathognomonic laboratory abnormalities in tetanus. CSF is normal. Wound cultures must be interpreted cautiously. Positive culture results may indicate wound colonization, rather than true infection with subsequent toxin production. Moreover, in most established cases, wound cultures do not yield C. tetani. Treatment Therapeutic goals include protecting the airway, neutralizing circulating tetanospasmin and preventing its further production, managing spasms and dysautonomia, and general supportive care (Ernst et al. 1997; Reddy 2002). The risk for precipitous respiratory decompensation, even in mild cases, warrants ICU management for all patients with tetanus. Initial management of most patients with generalized tetanus includes endotracheal intubation, because laryngospasm may appear abruptly even in mild cases. Human tetanus immune globulin, given as a single dose of at least 500 IU intramuscularly, neutralizes circulating toxin. Infected wounds should be debrided after human tetanusimmune globulin administration, because the procedure may release further toxin. Metronidazole or penicillin should be given to eradicate C tetani. Because minute amounts of tetanospasmin can produce clinical disease, affected patients frequently do not mount a protective immune response. Hence tetanus toxoid should be administered, either primary immunization series or booster injection as appropriate, to all patients with tetanus, A paucity of randomized clinical trial data means that treatment recommendations for tetanus depend heavily on clinical experience. This is particularly true for managing sympathetic hyperactivity. A quiet, dark environment minimizes sensory stimulation that may precipitate spasms or hypertensive crises. Benzodiazepines, such as parenteral diazepam, lorazepam, or midazolam, reduce rigidity and spasms. Such agents also provide effective sedation, an important consideration because severe tetanus typically requires weeks or months of ICU care. Most patients also require treatment with neuromuscular blockers, such as pancuronium or vecuronium, to control spasms. Intravenous dantrolene and intrathecal baclofen also have been used successfully to manage muscle rigidity and spasms in tetanus. Hypertension and tachycardia often respond to beta blockers such as propranolol or labetalol, although treatment may be complicated by cardiac arrest or hypotension. As with all critically ill patients, optimal supportive care includes attention to nutritional status and measures to prevent stress ulcers, deep venous thrombosis, and decubitus ulcers.
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Tetanus is a reportable illness whose complex management poses considerable challenges for neurointensivists. It is worth noting that tetanus could be largely prevented with simple modifications in peripartum and neonatal care and more widespread use of tetanus toxoid, which is both inexpensive and safe. Complications Without treatment, generalized tetanus is uniformly fatal, The overall case-fatality rate in the United States from 1991 through 1994 was 2 5 % , with substantially higher rates among older patients (Izurieta et al. 1997). Complications include acute respiratory failure from laryngospasm, longbone fractures from severe tetanospasm, and cardiac arrest from dysautonomia. Patients with protracted courses may require tracheostomy or develop seizures or other evidence of withdrawal related to long-term use of benzodiazepines, Most survivors recover fully. Because the disease is caused by the binding of tetanus toxin to receptors, immunodeficiency neither lengthens nor shortens the pure tetanusrelated disease.
Diphtheria Diphtheria is an acute infectious disease of the tonsils, pharynx, larynx, nose, other mucous membranes, or skin caused by Corynebacterium diphtherial.. The potentiallyfatal effects of diphtheria depend on the production of an exotoxin, by a lysogenie t o x + phage. Although toxic to all tissues, the exotoxin's most dramatic activity is against heart and peripheral nerves. Approximately 2 0 % of patients develop myocarditis and neuritis. Faucial diphtheria is the most common form, presenting with fever, sore throat, membranous pharyngitis, cervical lymph adenopathy, and edema. In North America and Europe, skin infections with C. dtphtheriae are now more common than nasopharyngeal disease. Cutaneous diphtheria appears as a pustule or nonhealing ulcer with a gray, dirty membrane. Toxic complications of cutaneous infections are rare, with neuritis more likely than myocarditis. The toxin inhibits protein synthesis, causing segmental demyelination of motor and sensory myelinated axons, producing a toxic cranial and peripheral neuropathy. Early lower cranial nerve signs and symptoms, within 2 weeks of the appearance of faucial disease, suggest IX and X nerve dysfunction with paralysis of the soft palate, nasal speech, and nasal regurgitation of fluids. Blurred vision, caused by ciliary paralysis of accommodation, or diplopia, caused by oculomotor nerve paralysis, appear in the third or fourth week of the disease. Peripheral polyneuritis, more likely in severe cases, typically begins between the sixth and seventh weeks of illness, when the patient may appear otherwise stable. The neuropathy vaties widely in severity. Phrenic and further vagal nerve involvement may produce a rapidly
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NEUROLOGICAL DISEASES
descending paralysis of pharynx, larynx, and diaphragm, A subacute motor neuropathy, involving proximal groups first, sometimes evolves slowly, halting after 1-2 weeks, or rapidly generalizes to quadriplegia and respiratory paralysis. Vibratory, proprioceptive, and other cutaneous sensory loss may be limited to the hands and feet or extend over mueh of the body. Sphincter dysfunction sometimes develops; cardiac vagal denervation can result in arrhythmias or baroreceptor abnormalities. Conduction abnormalities may follow the onset of neurological symptoms by several weeks and peak after clinical recovery has begun. CSF may be normal or reveal elevated protein, which is not a poor prognostic sign, when there is radicular involvement. Primary cutaneous diphtheria is characterized by early, localized anesthesia surrounding the skin ulcer, followed by weakness of surrounding muscles, before progression to generalized disease. Definitive diagnosis requires isolation and identification of the organism from infected sites, but treatment with diphtheria antitoxin (equine hyperimmune serum) should be started as soon as a presumptive diagnosis is made. Diphtheria antitoxin can only neutralize circulating toxin before it enters cells. Antitoxin dose depends on the site of primary infection: 20,000-40,000 units for faucial diphtheria of less than 48 hours, 40,000-80,000 units for faucial diphtheria of longer than 48 hours, and 80,000100,000 units for extensive disease or neck swelling. Patients with sensitivity to horse serum receive a 1 to 10 dilution test dose first and can be desensitized with increasing doses of antiserum, with epinephrine readily available. Antibiotics terminate toxin production and prevent further proliferation of the organism. Hither parenteral or oral penicillin G, 100,000 U/kg twice daily, or erythromycin, 5 mg/kg four times daily for 14 days, are recommended. Additional treatment is largely supportive, with respiratory and eardiac monitoring. Neurological recovery is the rule, although arrhythmias or heart failure may be fatal. Diphtheria is included in the triple vaccine DPT (diphtheria, pertussis, and tetanus), which is administered as three primary doses at 2-month intervals beginning at 6-8 weeks of age. A fourth dose is given 6-12 months after the third, and DT is given at school entry.
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BACTERIAL INFECTIONS Kastenbauer, S., Winkler, F., Pfister, II. W., et al. 2002, "Cranial CT before lumbar puncture in suspected meningitis," N Engl J Med, vol. 346, pp. 1248-1251 Kim, Y, S, & Pons, V. G. 1994, "Infections in the neurosurgical intensive care unit," Neumsurg Clin North Am, vol. 5, pp. 741-754 Koedcl, U., Scheld, W. M., & Pfister, H. W. 2002, "Pathogenesis and pathophysiology of pneumococcal meningitis," Lancet Infect Dis, vol. 2, pp. 721-736 LoBue, P. A. & Catanzaro, A. 1997, "Tuberculosis. Part II. The diagnosis of tuberculosis," Dis Mora, vol. 4 3 , pp. 185-246 Lu, C. H., Chang, W. R, Liu, Y. C, et al. 2002, "Bacterial brain abscess: Microbiological fearures, epidemiological trends and therapeutic outcomes," QjM, vol. 95, pp. 501-509 Maniglia, R. J., Roth, T., & Eiumberg, E. A. 1997, "Polymicrobial brain abscess in a patient infected with human immunodeficiency virus," Clin Infect Dis, vol. 24, pp. 449-451 Mathisen, G. E. & Johnson, J. P. 1997, "Brain abscess," Clin Infect Dis, vol. 25, pp. 763-781 Mdntvre, P. B., Bcrkey, C. S., King, S. M., et al. 1997, "Dexamethasonc as adjunctive therapy in bacterial meningitis: A meta-analysis of randomized clinical trials since 1988," JAMA, ml 278, pp. 925-931 Midura, T. F. 1996, "Update: Infant botulism," Clin Micro Rep, vol, 9, pp. 119-125 Montecucco, C. & Schiavo, G. .1994, "Microreview: Mechanism of action of tetanus and botulinum neurotoxins," Mo/ Microbiol, vol. 13, pp. 1-8 Munoz, P., Miranda, M. 6., Llancaqueo, A., et al. 1997, "Haemophilus species bacteremia in adults. The importance of the human immunodeficiency virus epidemic," Arch Intern Med, vol 157, pp. 1869-1873 Pao, D., Goh, B. T., &' Bingham, J. S. 2002, "Management issues in syphilis," Drugs, vol. 62, pp. 1447-1461 Quagliarello, V. J. & Scheld, W. M. 1997, "Treatment of bacterial meningitis," N Engl ] Med, vol. 336, pp. 708-716 Reddy, V. G. 2002, "Pharmacotherapy of tetanus—a review," Middle East J Anesthcsiol, vol. 16, pp. 419-442 Rompalo, A. N. 2002, "Neurosyphilis," in Current Therapy in Neurologic Disease, 6th ed, eds R. T. Johnson, J. W. Griffin, & J. C. McArther, Mosby, Philadelphia Scheld, W. M., Koedel, U., Nathan, B., &C Pfister, H. W. 2002, "Pathophysiology of bacterial meningitis: Mechanism(s) of neuronal injury," J Infect Dis, vol. 186, Suppl 2, pp. S225-S233
1513
Scheld, W. M., Whitley, R. J., & Durack, D. T. 1997, Infections of the Central Nervous System, Lippincott-Raven, Philadelphia Schucbat, A,, Robinson, K., W e n g c r J . D., et al. 1997, "Bacterial meningitis in the United States in 1995," N Engl J Med, vol. 337, pp. 970-976 Sexton, D. J. £c Kaye, K. S. 2002, "Rocky Mountain spotted fever," Med Clin North Am, vol. 86, pp. 351-360 Small, P. M. & Fujiwara, P. 2001, "Medical Progress: Management of tuberculosis in the United States," N Engl J Med, vol. 345, pp. 189-200 Solbrig, M. V-, Healy, J. F., &C Jay, C. A. 1996, "Bacterial infections," in Neurology in Clinical Practice, 2nd ed, eds W. G. Bradley, R. B. Daroff, G. M. &: Fenichel, C. D. Marsden, Butterworth-Heincmann, Boston Soriano-Gabarro, M., Stuart, J. M., & Rosenstein, N. E. 2002, "Vaccines for the prevention of meningococcal disease in children," Semin Pediatr Infect Dis, vol. 13, pp. 182-189 Steere, A. C. 2 0 0 1 , "Medical progress: Lyme disease," N Engl ) Med, vol. 345, pp. 115-125 Sun K. O., Chan Y. W, Cheung R. T. F., et al. 1994, "Management of tetanus: A review of 18 cases," J R Soc Med, vol. 87, pp. 135-137 Swartz, M. N. 2 0 0 1 , "Recognition and management of anthrax— an update," N Engl J Med, vol. 345, pp. 1621-1626 Tung, Y. R., Lai, M. C, Lui, C. C, et al. 2002, "Tuberculous meningitis in infancy," Pediatr Neurol, vol. 2 7 , pp. 262-266 Tunkel, A. R. & Scheld, W. M. 2002, "Corticosteroids for everyone with meningitis?" N Engl J Med, vol. 347, pp. 1613-1615 Varaine, ¥., Caugant, D. A., Riou, J, Y., et al. 1997, "Meningitis outbreaks and vaccination strategy," Trans R Soc Trap Med Hygiene, vol. 9 1 , pp. 3-7 Woods, M. L„ II, Currie, B. J., Howard, D, M., et al. 1992, "Neurological melioidosis: Seven cases from the Northern Territory of Australia," Clin Infect Dis, vol. 15, pp. 163-169 Yuki, N. 1997, "Molecular mimicry between gangliosides and lipopolysaccharidcs of Campylobacter jejuni isolated from patients with Guillain-Barre syndrome and Miller Fisher s y n d r o m e , " / Infect Dis, vol. 176, Suppl. 2, pp. S150-S153 Yuki, N,,Takahashi, M., Tagawa, Y., et al. 1997, "Association of Campylobacter jejuni serotype with antiganglioside antibody m Guillain-Barre syndrome and Fisher's syndrome," Ann Neurol, vol. 42, pp. 28-33
Chapter 59 Infections of the Nervous System B. VIRAL INFECTIONS Roberta L. DeBiasi, Marylou V. Solbrig, and Kenneth L. Tyler Specific Viral Entities 11 cr pes viruses Poliovirus and Other Nonpolio Enteroviruses Arboviruses Rabies Novel Zoonotic Diseases of Oceana Measles Rubella Mumps Arenaviruses
1515 1515 1527 1529 1534 1535 1535 1537 1537 1537
Other Hemorrhagic bever Viruses Papovaviruses and Progressive Multifocal I .e a k oence p h a lopa th y Retroviruses: HIV and HTLV-I and 11 Influenza Adenovirus Parvovirus Hepatitis Viruses Other Syndromes with Possible, but Unproven, Viral Etiologies
1538 1539 1539 1540 1541 1541 1541 1541
Hundreds of viruses exhibit tropism for the central and/or peripheral nervous system. The clinical spectrum of viral diseases is broad. Signs of primary viral infection may range from asymptomatic infection to systemic febrile illness with or without central (CNS) or peripheral (PNS) nervous system involvement. In the case of many viruses, involvement of the CNS or PNS is the predominant feature of illness, whereas in others, involvement of the nervous system is a rare complication of more generalized illness. The manifestations of viral nervous system involvement are myriad, including meningitis (acute or chronic), encephalitis (acute or chronic forms such as subacute sclerosing panencephalitis [SSPE]), myelitis, ganglionitis, and polyradiculitis. By virtue of their existence as foreign antigenic stimuli, viruses may also incite para- or postinfectious CNS inflammatory or autoimmune syndromes, such as acute disseminated encephalomyelitis (ADEM). The basic clinical featutes of each of these major clinical syndromes are overviewed in Chapter 47 (Neuroendocrinology). In this chapter, the most common etiologies of each of the major clinical syndromes will be discussed, with a review of diagnosis and treatment.
arboviruses, and Herpes simplex virus (HSV). Worldwide, there are over 50,000 encephalitis deaths from rabies each year, and in Asia at least 35,000 cases and 10,000 deaths from Japanese encephalitis (JE). In the United States, nearly 4000 cases of West Nile Virus encephalitis, with 250 deaths, occurred in 2002. Although the basic clinical features of most types of viral meningitis and encephalitis are generally similar, specific skin, mucous membrane, or other physical examination findings may help to narrow the possible viral etiologies of nervous system disease (Tables 59B.3 and 59B.4), It is important to recognize that several nonviral diseases can mimic the clinical features of viral CNS infection (Table 59B.5) (DeBiasi and Tyler 2002). The treatment, prophylaxis, and immunotherapy of specific viral infections are summarized in Tables 59B.7 and 59B.8.
The most common viruses causing nervous system disease in North America are listed in Table 59B.1 in the relative order of frequency with which they occur and with an indication of their relative propensity to cause meningitis, encephalitis, postinfectious encephalomyelitis, or myelitis. Causes of viral nervous system disease that should be considered in patients who have recently traveled abroad arc shown in Table 5.9B.2. In Europe and the United States, the most common causal agents of aseptic encephalitis and meningitis arc enteroviruses (coxsackie and echoviruses),
Herpesviruses
SPECIFIC VIRAL ENTITIES
Herpesviruses are ubiquitous and can infect many mammalian, bird, reptile, and amphibian species. These viruses cause acute infection, but also share the biological capacity of latency, the ability to remain quiescent for periods of time in the host and to be reactivated. Members of the herpesvirus family causing neurological diseases in humans include HSV-type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstcin-Barr virus (EBV), 1515
1516
NEUROLOGICAL DISEASES
Tabic 59B.1:
Primary causes of viral nervous system infection in North America Meningitis
Agent Konpolio enteroviruses Arboviruses (U.S. & Canada) Togavi ruses Flavivirus
Alpha virus
Reoviridae: orbivirus Bunyavirus
Herpes viruses
Ee ho virus Coxsackievirus
s$*
Si. Louis encephalitis virus (SLE) West Nile Virus Powassan Eastern equine (REE) Western equine (WEE) Venezuelan equine (VEE) Colorado tick fever California {La Crosse) Jamestown Canyon Snowshoc hare HSV-1 HSV-2 VZV CMV EBV HHV-6 HHV-7
;:-
Encephalitis
Postinfectious ADFM
Myelitis
K-K-S
:; ^
•>
••:-
•:•
:,
K -
** tf
a-
* * *^ 4
f If
* fr
* = : •
i n rv-8 Herpes B virus Lymphocytic choriomeningitis virus (LCMV) Mumps virus HIV Rabies virus Measles virus Rubella virus Poliovirus (now eradicated from Western hemisphere) Adenovirus Vaccinia Influenza Parainfluenza Rotavirus Parvovirus B-19
human herpes viruses {HHV-6, HHV-7, and HHV-S), and the simian {"monkey") Herpes B-virus. Herpes Simplex Viruses Type 1 and 2 (HSV-1, HSV-2) Herpes Simplex Encephalitis (HSE), HSV-1 encephalitis is the most common cause of sporadic, fatal encephalitis in the United States, accounting for approximately 10% of all eases of encephalitis. Early recognition is important hecause of the efficacy of the antiviral drug acyclovir in reducing morbidity and mortality. Mortality in untreated cases is 7 0 % and is reduced to approximately 2 0 % with rapid institution of antiviral therapy in a timely fashion. However, morbidity due to HSV-1 encephalitis, treated or untreated, remains high, with up to 7 0 % of survivors demonstrating permanent neurological sequelae. HSV-1 strains are etiological agents in over 9 0 % of cases of HSE in adults. Type 2 strains are more commonly isolated in
** ** **
X
*
* * *
monophasic or recurrent meningitis and congenitally acquired neonatal HSV meningoencephalitis. Both types 1 and 2 have been associated with myelitis. HSV-1 and -2 related CNS disease in immunosuppressed hosts is discussed in Chapter 59E. HSV-1 is transmitted by respiratory or salivary secretions. Up to 3 3 % of HSV-1 encephalitis cases may occur in conjunction with primary infection. In these cases, it has been postulated that virus may spread from the olfactory fibers in the nose to orbitofrontal cortex and temporal lobes. In the majority of cases, however, encephalitis is probably a consequence of reactivation and centripetal spread of virus latent in the trigeminal ganglia from a prior infection. Fever and headache are consistent features of HSE. Onset of symptoms may be abrupt with focal or generalized seizures, or more protracted, with behavioral changes, an amnestic syndrome, aphasia, or other focal signs.
VIRAL INFECTIONS Tabic 59B.2:
Additional causes of virai nervous system infection resulting from foreign exposures
Agent
Geographic
Nipah virus Filovirus
Ebola Marburg
Arbovirus Togavirus Mosquito-borne
Eastern equine Venezuelan equine St. Louis Japanese B Kunjin Murray Valley West Nile lilieus Rocio Far Eastern Central European Kyasiinur Forest I.ouping 111 Negislii Russian spring-summer Tahyna Ink oo Rifr Valley Rabies
Tick-borne complex
Bunyavirus
Rhabdovirus
T h e diagnosis of H S E s h o u l d be considered in any febrile patient with an altered level of c o n s c i o u s n e s s , with or w i t h o u t o t h e r focal neutological deficits. T h e presence of hallucinations, particularly olfactory h a l l u c i n a t i o n s , should suggest the possibility of H S E . T h e r e is no p a t h o g n o m o n i c
Table S9B.3:
1517
distribution
[rulonesia Africa
Caribbean and South America (plus U.S.) Central and northern South America (plus U.S.) Caribbean, Central and northern South America (plus U.S.) Japan, China, S.E. Asia, India Australia Australia and New Guinea Africa and Middle East, Parts of Europe South and Central America Brazil Eastern Russia Eastern and Central Europe, Scandinavia India England, Scotland, and Northern Ireland Japan Eastern Europe, Asia Czechoslovakia, Yugoslavia, Italy, Southern France Finland East Africa Many developing countries
set of clinical findings of H S E . Focal signs, h e m i p a r e s i s , h e m i s e n s o r y loss, a t a x i a , or focal seizures a r e seen in a p p r o x i m a t e l y o n e half of patients at p r e s e n t a t i o n . M u l t i p l e c o n d i t i o n s m a y mimic t h e clinical p r e s e n t a t i o n of H S V encephalitis, including o t h e r viral a n d postviral
Skin/mucous membrane findings suggesting specific viral CNS diseases
Exantkem or mucous membrane change
Viral agent
Specific changes
Vesicular eruption
Enterovirus
"Hand, foot and mouth disease"—macules/papules/vcsicles on palms, soles, buttocks Grouped small (3 mm) vesicles on an erythematous base Zoster: Vesicles in dermatomai distribution Primary VZV; multiple vesicles, papules, pustules in various stages of eruption Diffuse maculopapular eruption following ampicillin treatment Diffuse maculopapular erythematous eruption beginning on face/chest and extending downward Roseola: Diffuse maculopapular eruption following 4 days of high fever Maculopapular rash in 5 0 % Occasionally occurs with lymphadenopathy Many rypes of rash Confluent erythema over cheeks ("slapped cheek") followed by lacy, reticular rash over extremities (late) Rare "stocking glove syndrome—purpuric lesions on distal extremities" "Herpangina"—vesicles on soft palate P ha ry ngoc o n j uncti viti s Conjunctivitis Conjunctivitis with pharyngitis (see above)
Herpes simplex Varicella zoster virus
Maculopapular eruption
Epstein-Barr virus Measles HHV-6
Erythema multiforme Confluent macular rash
Colorado tick fever LCMV (Mycoplasma) Parvovirus
Purpura
Parvovirus
Pharyngitis
Enterovirus Adenovirus St. Louis encephalitis Adenovirus
Conjunctivitis
1518
NEUROLOGICAL DISEASES
Table 59B.4: Other specific findings associated with viruses causing CNS disease binding
Viruses
Alopecia Arthritis Biphasic Illness Lymph adenopathy Mastitis Mononucleosis Myelitis
LCMV LCMV, Pitrvovirus LCMV, Colorado tick fever LCMV, Mumps Mumps CMV, EBV St. Louis encephalitis vims, VZV, Herpes B virus, LCMV Enterovirus, (Mumps, LCMV) Mumps (LCMV, EBV) Colorado tick fever, LCMV, Rabies Mumps (LCMV) Influenza, Parainfluenza CMV Arbovirus St. Louis encephalitis virus, VZV, Herpes B virus, LCMV
Myocarditis/pericarditis Orchitis/oophoritis Paresthesias Parotitis Pneumonia Retinitis Tremors Urinary problems
encephalitides (particularly those with focal involvement), cryptococcal abscesses, toxoplasmosis, septic emboli from bacterial endocarditis, amebic meningoencephalitis, sagittal sinus or other cerebral vein thromboses, and mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Examination of cerebrospinal fluid (CSF) is imperative, and the single most important diagnostic test in suspected cases of HSE. CSF is usually under increased pressure, with a lymphocytic pleocytosis of 10-1000 white blood count (WBC) per til.. Cases of documented HSE without CSF pleocytosis are tare, but can occur, particularly in neonatal disease or in immunocompromised patients. Red blood cells (often crenated) or xanthochromia may be present in the CSF, but this finding is neither sensitive nor specific for HSE. CSF protein is usually moderately elevated, and glucose is usuallv normal. Virus may be cultured from the CSF in less than 5% of cases; however, HSV DNA can be detected in the CSF with polymerase chain reaction (PCR) techniques. CSF PCR testing has an estimated sensitivity of greater than 9 5 % and a specificity approaching 100% for the diagnosis of IISV infections of the nervous system, including HSE (Whitley and Lakeman 1995; DeBiasi and Tyler 1999} and has replaced brain biopsy as the diagnostic test of choice for HSE (Table 59R.6). CSF HSV PCR is also useful in diagnosis of cases of HSV-2 brainstem encephalitis and myelitis. CSF PCR remains a sensitive technique for the detection of HSE even in patients who have received up to a week of antecedent antiviral therapy. Newer quantitative, real-time PCR methods, which allow rapid turnaround of CSF sample results within hours, should allow for improved accuracy and rapidity of diagnosis in patients with possible HSE (DeBiasi et ah 2002). Despite the sensitivity of PCR, several recent reports have emerged indicating that CSF PCR may yield false-negative results in
patients in whom CSF is analyzed within the first 24 hours of illness (Weil et ah 2002). For this reason, HSV-specific antiviral therapy should not be discontinued m patients with suspected focal encephalitis on the basis of a single negative CSF PCR test if it is obtained within 72 hours of symptom onset, unless a suitable alternative diagnosis has been established. CT and magnetic resonance imaging (MR1) have both been utilized to assist in the diagnosis of HSE, MRI is a more sensitive modality and is the preferred study. Up to 4 0 % of patients with HSE with normal CT scans will have demonstrable abnormalities on MRI. MRI typically demon si rates focal abnormalities as areas of high signal intensity on T2-weigh ted images in fron to temporal regions (Figure 59B.1). Electroencephalogram (FFG) may be abnormal early in the course of disease, demonstrating diffuse slowing, focal abnormalities in the temporal regions, or periodic latcralizing epileptiform discharges (PLEDS). Brain biopsy is now only rarely performed for diagnosis of HSF. Biopsy is reserved for atypical cases in which the diagnosis remains in question or those who respond poorly to treatment. Biopsy specimens show hemorrhagic necrosis, HSV antigen in infected cells, and accumulations of viral particles forming acidophilic intranuclear inclusion bodies in neurons (Cowdry type A inclusions) (Plate 59B.I). Because of its safety, empitic therapy with acyclovir should be instituted immediately in cases of focal encephalitis (see Table 59B.7). Acyclovir should be administered intravenously at a dose of 10 mg/kg every 8 hours in adults and 20 mg/kg every 8 hours in neonates and children. Treatment should be continued, unless a CSF HSV PCR (obtained 72 hours or later after onset of symptoms) is negative, and/or an alternative diagnosis is made, for a minimum of 14 days. Many experts favor a 21-day course of therapy in adults and neonates with HSV meningoencephalitis. Renal insufficiency is an infrequent, usually reversible, side effect of acyclovir therapy. Acyclovir dosing should be adjusted appropriately in patients with renal insufficiency. Treatment with acyclovir reduces mortality of HSF from 7 0 % to 2 0 % . Over one third of patients with HSE treated with acyclovir recover with mild or no neurological impairment. Relapses following treatment with acyclovir have been reported (more often in neonates and children than adults) and may be due to either immunemediated mechanisms or continued active viral infection. These possibilities can be distinguished by CSF HSV PCR. Patients with immune-mediated relapse are PCR negative, whereas those with residual infection remain PCR positive. Patients with relapse who remain PCR positive should receive an additional course of acyclovir therapy and should be tested for the possibility ol acyclovir-resistant virus. Foscarnet is an alternative therapy for patients with suspected or proven acyclovir-resistant strains or with allergy to acyclovir. Vidarabine is no longer utilized as a treatment for HSF".
VIRAL INFECTIONS Table 5915.5:
Diseases that can masquerade as viral nervous system disease Suggestive
Etiology Infectious
Parameningcal focus (sinusitis, intracranial abscess) Partially treated bacterial meningitis
Bacterial
Lyme disease Tuberculosis Leptospirosis Syphilis Brucella Whipple's disease Bartonella (cat scratch disease) Listeria Typhoid fever Cryptococcus Coccidioides
Fungal
Histoplasma Blastomycosis Candida Nocardia Toxoplasma Cysticercosis Amoebic Malaria (P. falciparum) Rocky Mountain spotted fever
Parasitic
Rickettsial
Ehrlichia Coxsiella brunetti (Q fever) Parainfectious
Noninfectious
Mycoplasma Acute disseminated encephalomyelitis (AD EM) Connective tissue disorders
Uveomeningitic syndromes Intracranial tumors and cysts Drugs
Intracranial hemorrhage Encephalopathy
Neonatal
1M9
Herpes
Simplex
Virus
Systemic lupus erythematosis (SLE) Sarcoidosis Behcet's NSAIDs, antibiotics, immunomodulators, anticonvulsants
features
Very mild pleocyrosis, focal neurological exam Prior antibiotic treatment, right shifted CSE Tick exposure, arthritis, apnmpri.iie geography, erythema migrans Very high protein, hypoglycorrhachia Conjunctival suffusion, jaundice Chronic Farm animal exposure GI complaints Cat exposure, adenopathy Brainstem encephalitis Exposure history, bradycardia Usually immunocompromised pr. Southwestern U.S. exposure, pulmonary symptoms Pulmonary nodules Midwest, pulmonary symptoms Immunocompromised pt. Immunocompromised pt. Retinitis, cat exposure Calcified lesions Fresh water: Naegleria Exposure history Leukopenia, thrombocytopenia, hyponatremia, petechial rash See above F.xposure to sheep, pulmonary disease Precedent pulmonary symptoms Characteristic MRI findings
Malar rash, multisystem organ involvement Hilar adenopathy, erythema nodosum Genital/oral ulcers, uveitis Recurrent episodes, dermal sinus tract Exposure history
Toxic or metabolic
Meningoencephalitis
In c o n t r a d i s t i n c t i o n to a d u l t s , in w h i c h H S F is usually caused by H S V - 1 , H S V - 2 is t h e m o s t c o m m o n causal a g e n t of meningoencephalitis in n e o n a t e s ( a l t h o u g h HSV-1 disease m a y also occur). N e o n a t e s w h o a c q u i r e H S V from the birth canal develop infection of t h e C N S in 5 0 % of cases (Kimberlin et al. 2 0 0 1 ) , C N S disease occurs as either a c o m p o n e n r of an o v e r w h e l m i n g sepsislike disseminated disease w i t h m u l t i - o r g a n i n v o l v e m e n t (in t h e first week of life), or as isolated C N S disease, w h i c h usually presents later (weeks 2 - 1 0 of life), with or w i t h o u t a c c o m panying vesicular skin, m u c o u s m e m b r a n e , o r conjunctival lesions (skin, eye, m o u t h disease). T h e presence of vesicular
skin or m u c o s a l lesions in an infant of this age, even in the a b s e n c e of fever or systemic s y m p t o m s , w a r r a n r s i m m e d i a t e e v a l u a t i o n of CSF for cell c o u n t s , c h e m i s t r y , a n d H S V P C R because u p t o 3 0 % o f infants w i t h p r e s u m e d isolated skin, eye, a n d m o u t h disease m a y s u b s e q u e n t l y be identified as h a v i n g C N S i n v o l v e m e n t . N e o n a t e s w i t h possible H S V disease s h o u l d be treated empirically with i n t r a v e n o u s acyclovir 20 m g / k g every 8 h o u r s w h i l e a w a i t i n g results of CSF H S V P C R . T r e a t m e n t s h o u l d be c o n t i n u e d for 14 d a y s in infants with isolated skin, eye, a n d m o u t h disease a n d 21 d a y s in infants w i t h sepsis or evidence of C N S involvem e n t , Relapses of skin, eye, a n d m o u t h disease (with t h e potential for C N S i n v o l v e m e n t a n d s u b s e q u e n t n e u r o l o g i cal deficits) a r c c o m m o n in t h e first year of life following
1520
NEUROLOGICAL DISEASES
Tabic 59B.6:
PCR diagnosis of viral nervous system disease
Virus denovirus engue itero virus crpesvi ruses CMV
Sensitivity
Specificity
Unknown Unknown >95%
>9S%
Quantitative available
HSV-1 a n d - 2 HHV-6
100% in immunocompromised >6Q% in congenital CMV infection 98.5 as tumor marker in HIV patients with CNS lymphoma >95% >95%
VZV IV
>9S% HIV RNA present at all stages
>9S% Excellent
75% Unknown but > culture Unknown
98.5% Unknown
5 0 - 9 0 % in PML Unknown Unknown Unknown Unknown 100% Poor
98% Unknown Unknown Unknown Unknown Unknown Unknown
EBV
HTLV I and II Influenza Japanese encephalitis virus JC virus LCMV Mumps Measles Parvovirus B-19 Rabies West Nile
CNS or non-CNS presentations of neonatal HSV disease. For this reason, the continuation of oral acyclovir prophylaxis for 3-6 months following intravenous therapy is currently being studied in a randomized multicenter trial (Kimberlin 2001). In the future, quantitative HSV PCR techniques may allow more accurate analysis of response to therapy, required duration of therapy, and determination of prognosis. Meningitis Due to Herpes Simplex
Virus
At the time of their first episode of genital herpes (generally due to HSV-2), approximately 3 6 % of women and 1 1 % of men have symptoms of meningitis, including fever, headache, and nuchal rigidity. Of these patients, 2 0 % will develop recurrent episodes of meningitis (see Mollaret's meningitis following). When aseptic meningitis occurs in this setting, genital lesions are present an average of 1 week before the CNS symptoms. CSF viral cultures are invariably negative during recurrent episodes of meningitis, although the virus may be isolated during the first (primary) episode. Other neurological complications, such as paresthesias, urinary retention, and transverse myelitis, have been described with HSV-2 infections.
Comments
100% >95%
Predictive value in normals unclear Quantitative available Poor positive predictive value in disease (30% normals positive} Quantitative available disease progression? response to therapy? drug-resistance?
Unknown
Recurrent meningitis, or discrete episodes of meningitis, has been linked to other viruses (including human immunodeficiency virus [HIV] and EBV), other infectious agents (such as partially treated or atypical bacterial or fungal pathogens, such as Borrelia burgdorferi), drug exposure (nonsteroidal anti-inflammatory agents, IVIG, monoclonal antibodies), dermoid cysts within CSF pathways that are leaking, and idiopathic inflammatory conditions (sarcoid, uveomeningitis syndromes). Recurrent aseptic meningitis should be distinguished from recurrent bacterial meningitis, in which underlying abnormalities should be sought, such as CSF leak, skull base fracture, dermal sinus, parameningeal infection, or impaired B-cell immunity (DeBiasi and Tyler 2000). CSF PCR has identified HSV-2 in a large subset of patients with the syndrome of benign recurrent lymphocytic meningitis, also known as Mollaret's meningitis. This syndrome may be associated with the presence in the CSF of Mollaret's cells, large cells of monocyte-macrophage lineage. In one of the largest series to date, 8 5 % of patients had detectable HSV DNA, of which 9 1 % were HSV-2 (Tedder et al. 1994). These patients were predominantly females and experienced 3-9 attacks of meningitis over a period of 2 - 2 3 years. Of these, only 2 3 % had a history of
Table 59B.7:
Antviral class Nucleoside analogs
Treatment and prophylaxis of viral infections Antiviral agent Acyclovir
Cytokine
Supplements
Indications
10 mg/kg/dose (IV) q8h x 14-21 days 20 mg/kg/dose (IV) q8h x 21 days 500 mg/m 2 /dose (IV) q8h x 21 days (equivalent to 10-12 mg/kg/dose in adults and up to 20 mg/kg/dose in infants) 15 mg/kg/dose (IV) q8h x 10-14 days 800 mg (PO) JX/day x 7 days
HSV encephalitis in adults Neonatal HSV encephalitis VZV encephalitis in normal or immunocompromised pt
Famciclovir
200 mg (PO) tid x 7 days
Val acyclovir
1 g (PO) qid x 7 days
Ganciclovir Valganciclovir
Cytarabine Trifluridine Pose a met
5 mg/kg (IV) q l 2 h x 14-21 days 900 mg (PO) bid x 21 days (induction), then 900 mg (PO) qd (maintenance) 2 g (IV) x 1, then I g (IV) q6h x 4 days, then 0.5 g (IV) q8h x 6 days 2 0 - 3 5 mg/kg/day x 7 days 2 mg/kg (IV) x 5 days x 4 wks 1 % ophthalmic solution 90 mg/kg (IV) q l 2 x 14-21 days
Amantadine Rimantidine Oscltamivir Zanamivir Interferon-ct
100 mg (PO) bid x 5 days 100 mg (PO) bid x 5 days 75 mg (PO) bid x 5 days 10 mg (PO) bid x 5 days 3 million U/day (SC)
Vitamin A
10- 5 -10 d U/m 2 body surface (intrathecal) 400,000 IU (IM)
Ribavirin
Pyrophosphate analogue Other
Dnse
Herpes B virus Dcrmatomal zoster or primary V in immunocompromised pt Dcrmatomal zoster or primary V in immunocompromised pt Dermatomal zoster or primary V in immunocompromised pt CMV, Herpes B virus CMV Retinitis Lassa fever Measles virus PML Herpetic keratoconjunctivitis Acyc 1 ovir-resistant HSV/VZV Ganciclovir-resistant CMV Influenza A Influenza A Influenza A and R Influenza A and R PML, acyelovir-resistant VZV, Hepatitis C SSPE Acute measles in vitamin A deficiency
CNS = central nervous system; CMV = human cytomegalovirus; HSV = herpes simplex virus; PML ~ progrcssive multifocal panencephalitis; VZV = varicella zoster virus.
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NEUROLOGICAL DISEASES
Tabic 59B.8:
Immunotherapy of viral infections''
Immunotherapy class
Immunotherapy
Dose or route
Indications
Specific hyperimmune globulin (IG)
VZIG (Varicella Zoster)
One vial (125 U) per 10 kg of body weight (IM) Human RIG, 20 IU/ kg (Inject as much as possible in area of wound and remainder IM at site distant from vaccine) IV
Postexposure prophylaxis in hypogammaglobulinemic pt Postexposure prophylaxis
RIG (rabies)
Human cytomegalovirus h yperi mmu n ogl o b u lin Central European encephalitis hy peri mmu noglo b u lin
Polyvalent immune globulin
Cv to toxic T Cells
IM
Mea si es hyp erim m uno gl o b ulin
IV
IV1G
IV
IVIG
IV
Epstein-Barr vims (EBV)-spccific cytotoxic T lymphocytes
Prophylaxis after bone marrow transplantation Postexposure prophylaxis following multiple tick bites in endemic area Treatment of measles inclusion body encephalitis in immunocompromised pt Treatment of chronic enterovirus meningoencephalitis in hypogammaglobulinemic pt Treatment of human T-cell leukemia virus I myelopathy Prophylaxis of KBV 1 ympho p r o life r ative d lsea s e in bone marrow transplant recipients
*Live vaccines include yellow fever, measles, mumps, rubella, smallpox, polio, and varicella zoster virus. Killed vaccines include polio, rabies, influenza, arboviruses (Japanese encephalitis, tick-borne encephalitis, Kyasanur Forest, Rift Valley, eastern equine encephalitis, wcii.cni equine eccepl minis, a:id Vcnc/ueliin equine encephalitis). Soluble protein includes hepatitis V>.
genital herpes, none with lesions concurrent with their most recent episodes of meningitis. Varicella Zoster Virus (VZV) Primary Infection. VZV can involve virtually every part of the CNS and PNS. Primary VZV may produce encephalitis in immunocompromised patients and, rarely, a progressive, fatal encephalitis in healthy children. A self-limited cerebellar ataxia is often seen in otherwise healthy children during or immediately following primary VZV infection (chickenpox). Meningitis, brainstem encephalitis, and myelitis due to VZV can also occur in immunocompetent hosts, VZV can also cause both granulomatous arteritis leading to stroke and/or multifocal infarcts and small vessel vascuiopathy (leukoencephalitis) (Kieinschmidt-DeMasters and
Gilden 2001). Postinfectious encephalomyelitis follows an estimated 1 in 2500 cases of primary VZV infection. Reye's syndrome (2.5 per 10,000 cases) has been associated with primary VZV infection, particularly in children who concomitantly received aspirin. Antiviral treatment of acute VZV encephalitis and myelitis is intravenous acyclovir, at the high dose of a 20 nig/kg (or 500 mg/m 2 per dose) every 8 hours. Treatment of immunocompromised children with primary VZV infection (in the absence of CNS disease) with intravenous acyclovir should begin within the first 24-72 hours after onset of
the rash and be continued for a minimum of 7 days, or until lesions have crusted over. Foscarnet may be used for acyclovir-resistant zoster infections. Corticosteroids are often used for sighr-threatening complications (optic neuritis, orbital apex syndrome) and postviral cerebral (large vessel) vasculitic complications, but when utilized, should be accompanied by antiviral therapy. Corticosteroids may also be used to limit inflammatory response in myelitis. Brief courses of corticosteroid are also used to treat the small and large vessel vasculopathy that accompanies persistent VZV encephalitis in immunocompromised patients, although no clinical trials demonstrating its efficacy are available. VZV immunoglobulin is used for prophylaxis of seronegative immunocompromised patients and pregnant women who have been exposed to VZV. VZV immunoglobulin, one vial (125 units) per 10 kg of body weight intramuscularly, should be given within 96 hours and preferably within 48 hours of exposure (Arvin 1996). Herpes Zoster. Following primary infection, VZV becomes latent in cells of the dorsal root ganglia. Reactivation of endogenous latent virus produces herpes zoster, or shingles. The virus can reactivate after injury or trauma to the spine or nerve roots or in response to waning cell-mediated immunity to VZV caused by age or immunosuppression related to HIV infection, cancer, cytotoxic drugs, or systemic illness. Herpes zoster is
VIRAL INFECTIONS
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FIGURE 59B.1 Herpes simplex encephalitis. T2W-MRI showing increased signal in left media] temporal lobe, inferior frontal lobe, and insular cortex. (Courtesy J. Healy.)
frequently the first clinical presentation of underlying HIV infection, in which case it may he protracted and multidermatomal. In Africa, herpes zoster has a positive predictive value for HIV infection of 95%. Herpes zoster typically begins with pain and paresthesias in one or two adjacent spinal or cranial dermatomes. Pain is followed in 3-4 days by a painful pruritic vesicular eruption in the area supplied by the affected root. The eruption can last 10 days to 2 weeks. Occasionally, a few lesions appear outside the primary dermatome. Herpes /.oster most often involves the thoracic dermatomes, usually T5-T12. Fourteen to 2 0 % of patients have disease in the distribution of a cranial nerve and 16% in lumbosacral dermatomes, usually LI or L2. Involvement of the first division of the trigeminal ganglion produces ophthalmic zoster and may be associated with conjunctivitis, keratitis, anterior uveitis, or iridocyclitis. Occasionally corneal transplantation may be required to correct visual impairment from corneal scarring. Vision loss following herpes zoster ophthalmicus is rare, however, and more commonly is caused by retrobulbar neuritis. Involvement of the geniculate ganglion produces otic zoster, or the Ramsay Hunt syndrome: painful facial paresis accompanied by tympanic membrane and external auditory canal vesicular rash. Older age and cranial nerve involvement are risk
factors for zoster encephalitis, so all cases of ophthalmic zoster in older adults should be treated with antivirals. Herpes zoster involving cervical and thoracic levels may be associated with myelitis, and in the lumbosacral region may be accompanied by bladder dysfunction or ileus. The clinical variant, zoster sine her pete, refers to syndromes of prolonged radicular pain without zoster rash but with detectable VZV DNA in the CSF. Herpes zoster should be considered in the differential diagnosis of new onset acute radicular pain. A CSF lymphocytic pleocytosis, with cell counts to several hundred cells per microliter, may precede the rash. Approximately 4 0 % of healthy individuals with herpes zoster have elevated CSF cell counts and protein concentration, and VZV can frequently be isolated from the CSF of these patients. VZV DNA can be detected in the CSF by PCR techniques, and VZV may be cultured from vesicles or detected by microscopic examination of vesicular scrapings by direct fluorescent antibody testing. Complications of zoster include postherpetic neuralgia, segmental motor atrophy in the affected dermatome, meningitis, myelitis, large vessel vasculitis (usually involving the carotid or its branches on the side of zoster ophthalmicus), and multi-focal leukoencephalitis or encephalitis with generalized cerebral vasculopathy. VZV
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NEUROLOGICAL DISEASES
encephalitis with vasculopathy has been reported in AIDS and cancer patients and in individuals treated with cyclophosphamide or corticosteroids. The syndrome may occur without signs of cutaneous infection or may progress after cutaneous lesions have healed. Mixed ischemic and hemorrhagic infarcts in subcortical gray and white matter, plus ischemic, demyelinative, or both kinds of lesions in deep white matter, are noted radiologically and pathologically.
neuralgia remains uncertain. Intrathecal methylprednisolone and oral gabapentin have been studied as treatments for postherpetic neuralgia and have been efficacious in some studies. A live attenuated varicella vaccine boosts VZV immune responses in adults, raising hope that, in the future, it may be possible to prevent dermatomal zoster eruption (Jumaan 2 0 0 1 ; Johnson 2002).
Risk factors for postherpetic neuralgia in patients with shingles include age over 50 years and prodromal sensory symptoms. Treatments are directed toward lessening pain, reducing virus shedding, and shortening healing time. Acyclovir (800 mg orally five times daily for 7 days), famciclovir (200 mg orally three times daily for 7 days), or valacyclovir (1 g orally four times daily for 7 days) accelerate cutaneous healing and decreases acute zoster pain if begun within 72 hours of onset of rash. Whether these agents significantly decrease the incidence, duration, or severity of postherpetic neuralgia is uncertain. In patients without contraindications, a short course of corticosreroids, such as 40 mg prednisolone per day, tapered over 3 weeks, may be added to antiviral therapy. Compared with acyclovir therapy alone, addition of corticosteroids has been shown to improve comfort levels (pain reduction during the acute phase) following herpes zoster, although its efficacy in reducing subsequent risk of postherpetic
Cytomegalovirus
(CMV)
CMV causes both acute and latent or persistent infections in humans. It is transmitted through saliva, milk, genital secretions, semen, blood transfusions, and organ transplants. In immunocompetent hosts, CMV may cause inapparent infection, a mononucleosis syndrome, aseptic meningitis, or the Guillain-Barrc syndrome. CMV encephalitis is exceedingly uncommon in immunocompetent hosts beyond the neonatal period and usually presents as an encephalopathy, with or without focal features, in the context of a subacute febrile illness. However, immunocompromised adults and developing fetuses are at high risk of developing CNS disease due to CMV. CMV may also infect the peripheral nerves, nerve roots, and spinal cord in patients with advanced HIV, presenting as an ascending myeloradiculitis. Congenital CMV. CMV infection is the most common congenital infection affecting humans and can cause severe injury to the infected fetus. Up to 1 0 % of infants born to mothers with primary CMV infection (the bulk of whom acquire CMV in the first trimester of pregnancy) are symptomatic at birth. 1 0 % of symptomatic infants die, and 8 0 % of survivors suffer severe neurological morbidity (9000 infants each year in the United States) (Ahlfors et al. 1999). Infection by passage through the birth canal or following breastfeeding in the perinatal period accounts for additional infantile cases. Persistent, high levels of viral replication in the eye and brain of the developing fetus produce encephalitis, ependymitis, and retinitis, a pattern similar to that seen in patients with opportunistic CMV infection in the setting of HIV infection. Pathologically, encephalitis occurs in a periventricular pattern and may cause polymicrogyria and hydrocephalus. (Figure 59B.2). CT scans characteristically show periventricular calcifications. Symptomatic infants usually have hepa to splenomegaly and thrombocytopenia in addition to CNS findings. Mild or subclinical congenital infections may also manifest later in childhood as sensorineuronal deafness or developmental delay. Congenital human CMV infection is the most common, nonhcritablc cause of hearing loss in the United States,
FIGURE 59B.2 Human cytomegalovirus ventriculitis. Axial gadolinium-enhanced 'I'lW-MRI showing contrast enhancement of ependyma of lateral ventricles. (Courtesy J. Hcaly.)
Although congenitally infected infants will excrete CMV in their urine throughout the first year of life, diagnosis of congenital CMV infection depends on the detection of virus by culture in urine, saliva, or CSF during the first 3 weeks of life. The clinical utility of CSF PCR for CMV
VIRAL INFECTIONS
in the setting of congenital infection is being investigated, particularly with respect to correlating neurological outcome with CSF viral load. CMV inclusion-bearing cells are found in affected organs (Plate 59B.II) and in stained preparations of urinary sediment and saliva. Diagnosis of acute CMV infection in immunocompetent adults usually relies on serologic methods, specifically the detection of CMV IgM antibody because infected patients may intermittently excrete virus in their urine for years following infection, and CMV lgG persists for life following primary infection. In a study evaluating the efficacy of intravenous ganciclovir therapy (4-6 mg/kg every 12 hours for 6 weeks) in neonates with symptomatic congenital CMV infection, quantitative excretion of CMV in the urine decreased initially, but returned to pretreatment levels after cessation of therapy. Hearing improvement or stabilization occurred in 1 6 % of treated infants at 6 months or later posttreatment. However, a large proportion of treated infants developed cytopenias on prolonged ganciclovir therapy (Whitley et al. 1997). CMV in Immunocompromised Adults. CMV encephalitis in the transplant patient (Tsclis and Lavi 2000) presents as a nonspecific febrile encephalopathy, with or without focal features. AIDS associated CMV encephalitis presents either as microglial nodular encephalitis wirh acute onset of confusion and delirium or as a more slowly progressive ventriculocncephalitis, characterized by confusion and cranial nerve palsies. There is a broad pathological spectrum of CMV infection of the brain in AIDS patients, ranging from scattered microglial nodules, to widespread necrotizing ependymitis and perivascular infiltrates, to necrotizing leukoencephalopathy. The broad spectrum of disease is likely related to variable degrees of immunosuppression resulting in wide ranges of viral load, as well as synergistic interactions between CMV and HIV. Diagnosis of CMV encephalitis can be difficult, particularly by serological resting, because CMV antibody titers can fluctuate spontaneously. Serological and virus detection methods are currently being extended to focus on quantitation of viral burden (particularly in peripheral blood leukocytes) for patients with persistent infection, as well as to help predict which immunosuppressed patients might develop end-organ disease. CMV PCR has a reported sensitivity of 8 2 % and specificity of 99% in AIDS patients with CNS disease due to CMV (Cinque et al. 1997). Findings on brain imaging are poorly characterized in nonimmunocompromised and transplant patients. In AIDS patients, a wide spectrum of imaging results has been reported, ranging from normal to generalized atrophy, periventricular abnormalities, and focal, discrete lesions, often involving white matter. MRI is more sensitive than CT and most characteristically demonstrates periventricular increased signal on T2-weighted images and ependymal enhancement on TI-weighted images.
1525
Ganciclovir, foscarnct, and cidofovir are all antiviral agents with efficacy against CMV, However, the clinical response of AIDS-associated CMV encephalitis to antiviral drugs appears to be poor. The response to peripheral nerve and nerve root infection with CMV appears to be better. Systemic and retinal CMV infections arc known to respond very well to ganciclovir and foscarnct, either alone or in combination. In immunocompromised patients with CMV retinitis, encephalitis, or myeloradiculitis, antiviral therapy should be instituted with intravenous ganciclovir, 5 mg/kg every 12 hours for 2 weeks of induction, followed by maintenance dosing of 5 mg/kg per day, 5 days per week. The addition of foscarnct should be considered. There is less clinical experience with cidofovir, which is currently licensed only for treatment of retinitis. Recently, valganciclovir, an orally administered prodrug that is rapidly hydrolyzed to ganciclovir, has been shown to be efficacious for the treatment of CMV retinitis (Martin et al. 2002). An extended discussion of CMV treatment in HIV-infected patients is presented in Chapter 59E. Because of the frequency of subclinical infection in the adult population, bone marrow transplant recipients should receive human CMV hyperimmune globulin as prophylaxis (see Table 59B.8). Epstein-Barr
Virus
(EBV)
Primary EBV infection may be asympromatic, present as a nonspecific febrile illness, or classically, as the infectious mononucleosis syndrome with cervical lymphadenopathy, exudative pharyngitis, and splenomegaly. Nervous system disease occurs in less than 1% of EBV infectious mononucleosis cases and can manifest as meningitis, encephalitis, cerebellitis, transverse myelitis, optic neuritis, cranial neuropathy, Guillain-Barre syndrome, or as small fiber sensory or autonomic neuropathy syndromes. As a B-cell transforming virus, EBV is also associated with the development of CNS lymphomas. Detection of latent EBV nucleic acid has been demonstrated in the jaw, orbit, and CNS of patients with endemic and sporadic Burkitt's lymphoma, as well as in the CNS of patients with AIDSassociated CNS lymphoma. The diagnosis of EBV is suggested by the presence of serum heterophile antibodies (monospot), although this is a nonspecific test that may be positive in other disease states such as hepatitis and lymphoma or in the presence of certain drugs. Specific diagnosis of CNS EBV disease requires the detection of serum and CSF EBV-specific antibodies. In serum, the presence of EBV Viral Capsid Antigen (VCA) IgM antibody is indicative of recently acquired, active infection. The presence of EBV VCA IgG antibody in the absence of VCA IgM and Epstein-Barr Nuclear Antigen (EBNA) antibodies is indicative of recent infection within the previous 2 months. The presence of EBNA antibodies indicates distant infection, and these antibodies remain positive for the lifetime of the infected individual.
1526
NEUROLOGICAL DISEASES
CSF PCR for EBV is positive during the acute phase of illness in children with infectious mononucleosis and neurological complications such as transverse myelitis, meningoencephalitis, and aseptic meningitis. CSF PCR is negative in EBV-seropositive individuals in the absence of CNS infection. However, positive EBV PCR may be seen in patients with evidence of other viral or nonviral CNS infection, raising the possibility that these infections may trigger viral reactivation. EBV has been one of the most frequent agents associated with dual-positive CSF PCR testing and may not always correlate clinically with the presence of CNS infection known to be caused by this virus (Studahl et al. 2000). CSF PCR testing for EBV has been found to be nearly 100% sensitive as a tumor marker for EBV-related CNS lymphoma and has changed the way in which clinicians diagnose CMS lymphoma in immunocompromised individuals. EBV DNA may even be detectable in CSF before CNS lymphoma is clinically apparenr. Immunomodulation with intravenous immunoglobulin may Improve EBV-associated small fiber sensory or autonomic neuropathies if treatment begins during acute disease. None of the currently available antiviral agents, including acyclovir, ganciclovir, and foscarnct, have significant activity against EBV. However, there are case reports describing successful treatment with ganciclovir of EBV meningoencephalitis following bone marrow transplantation. Vaccine and immune therapies are in development for treatment of these conditions, including the use of virus-specific cytotoxic T lymphocytes as prophylaxis for EBV lymphoproliferative disease in bone marrow transplant patients {Heslop and Rooney 1997).
Human
Herpesvirus-Type
6
(HHV-6)
HHV-6 is a prevalent, E lymphotropic virus, causing a spectrum of diseases ranging from inapparent infection to disseminated, fatal disease. Exanthem subitum (or roseola) of infants or lymphadenopathy syndromes are the most common presentations of primary infection. HHV-6 genome has been demonstrated in CSF from children younger than 1 year of age who have febrile seizures and has also been seen in children with recurrent febrile convulsions with CNS involvement. However, primary infection may also rarely result in meningoencephalitis in immunocompetent children. Retrospective studies from Whitley's group indicated that approximately 6% of a series of children and adults with focal encephalitis had HHV-6 genome demonstrable in the CSF by PCR analysis. HHV-6 has increasingly been recognized as an opportunistic infection resulting in encephalitis in immunocompromised patients (Figure 59B.3), and can mimic HSV encephalitis. A possible role for HHV-6 in the etiology of multiple sclerosis (MS) has been suggested but remains unproven. (Caserta et al. 2001). In a large study of immunocompromised (HIV-infected) patients, conducted to assess the diagnostic reliability of CSF PCR by comparison with biopsy or autopsy diagnoses, the most frequent false-positive herpesvirus detected was HHV-6. In another large study of mostly immunocompetent patients, detection of HHV-6 by CSF PCR did not always correlare clinically with the presence of a CNS infection known to be cause by that virus (Studahl et al. 2000). Additional large studies are necessary to determine
FIGURE 59B3 Concurrent human herpesvirus 6 and human immunodeficiency virus disease. Contrast CT scans showing multiple, ring-enhancing frontal, parietal, and occipital lesions. The second image shows parietal recurrence 3 months later. Pathology demonstrated perivascular lymphocytic infiltrates, demyehnation, and axonal sparing. (Courtesy S. Busono.)
PLATE 59B.I Hippocampal granule cell neurons in herpes simplex 1 encephalitis. Many of the nuclei contain acidophilic Cowdry type A intranuclear inclusions, which are surrounded by haloes and which marginate the nuclear chromatin. (Hematoxylin-eosin stain, x .350) (Courtesy R. Kim.)
••
PLATE 59B.II Ballooned cell with eccentric nucleus in human cytomegalovirus encephalitis. An acidophilic Cowdry type A intranuclear inclusion body, with its surrounding halo, marginates the nuclear chromatin. The cytoplasm also contains granular inclusion material. (Hematoxylin-eosin stain, x 350) (Courtesy R.Kim.)
PLATE 59B.IV Cerebral cortex in subacute sclerosing panencephalitis. A pyramidal neuron contains both a Cowdry type A intranuclear inclusion and a cigar-shaped cytoplasmic inclusion, Cowdry A inclusions are present also in the nuclei of several nearby glia cells. (Hematoxylin-eosin stain, x 3.50) (Courtesy R. Kim.)
PLATE 59B.HI Hippocampal neurons in human rabies encephalitis. The cytoplasm of these neurons bears one or more rounded or oval Negri inclusion bodies. (Hematoxylin-eosin stain, x 350) (Courtesy R. Kim.)
PLATE 59B.V Cerebral white matter in progressive multifocal leukoencephalopathy. Oligodendroglial cell nuclei are greatly enlarged and their nuclear chromatin replaced by glassy acidophilic material. (Hematoxylin-eosin stain, x 350) (Courtesy R. Kim.)
VIRAL INFECTIONS
the reliability of positive CSF PCR results for HHV-6 in immunocompromised and immunocompetent hosts. The B variant of HHV-6, the variant most commonly isolated from immunocompromised patients, has a susceptibility to ganciclovir that is similar to the susceptibility of CMV in vitro. Human Herpesviruses-7 and -8
(HHV-7 and HHV-S)
The role of HHV-7 in neurological disease is unclear, although detection of HHV-7 DNA in CSF and serum of children with roseola and encephalopathy has been reported. HHV-7 genome has also been detected by PCR in neoplastic brain tissue from patients with primary and metastatic brain tumors (Chan et al. 1999), but whether this represents reactivation from latency in an immunocompromised state, or contributes to the pathogenesis of tumor development is unknown. Encephalitis in immunocompromised individuals associated with HHV-8 has been described, but awaits additional confirmation (Said ct al. 1997). HHV-8 DNA has been detected in primary CNS lymphomas in some studies but not others.
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or water for 15 minutes. Postexposure prophylaxis within 5 days of exposure can be considered using acyclovir, valacyclovir, or famciclovir. Based on animal studies, many experts prefer valacyclovir 1 g three times a day for 2 weeks. Symptomatic patients without CNS symptoms should be treated with either intravenous acyclovir, 15 mg/kg every 8 hours or intravenous ganciclovir 5 mg/kg every 12 hours, although some experts recommend ganciclovir for all symptomatic B virus infections due to the unpredictability of rapid and life-threatening brainstem involvement. When CNS symptoms are present, treatment should be initiated using intravenous ganciclovir 5 mg/kg every 12 hours. Treatment should be continued until symptoms resolve and the results of two sets of cultures are negative for B virus after being held for 10-14 days. Following IV therapy, most experts suggest that therapy should be switched to oral valacyclovir, famciclovir, or acyclovir in the dosages used for postexposure prophylaxis. Although no good data exist to aid in determination of when therapy should he discontinued, many experts recommend continuing trearmem for months to years, with regular cultures of the conjunctiva and oropharynx to assess for viral shedding.
Herpes B Virus (Cercopithecrine Herpes Virus 1) Herpes B virus of Old World monkeys is highly pathogenic to humans, and infection is fatal in 7 0 % of cases. Ocular, oral, and genital secretions of monkeys, as well as CNS tissues and CSE of monkeys, are potentially infectious. Disease is transmitted by direct contact with the virus, usually by animal bite or by virus-containing fomites. However, the first fatal case of B virus infection due to mucosal splash exposure was reported in 1998, leading to updated recommendations for prevention and treatment by the Centers for Disease Control (CDC) in 1999 (Cohen e t a l . 2002). Fever, myalgia, herpctiform rash, meningismus, and early stage nystagmus or diplopia are followed by an ascending encephalomyelitis causing flaccid paralysis, urinary retention, and signs of CNS involvement, including seizures, progressive lethargy, and coma. Diagnosis is by wound or contact site culture and demonstration of increasing antibodies in paired acute and convalescent sera. Median nerve somatosensory evoked potential may identify early brainstem and cervical cord involvement and aid in differentiating R virus from HSV encephalitis. Suggested preventative measures for primate workers include use of protective eyeware including side shields and a mask to protect from mucous membrane exposure. Should exposure occur, the most critical period for prevention of infection is within the first few minutes after exposure. Immediate cleansing of the affected skin surface should be undertaken by soaking or scrubbing the contact area with povidone-iodine, ehlorhexidine, or detergent soap for 15 minutes. Eyes or mucous membranes should be immediately irrigated with sterile saline solution
Poliovirus and Other Nonpolio Enteroviruses The enterovirus (EV) family comprises over 70 different serotypes, within the Picornaviridae family. They can be subgrouped into the polioviruscs, coxsackieviruses A and B, echoviruses, and the newer sequentially numbered enteroviruses. The most common forms of infecrion by any of the enteroviruses are subclinical or mild febrile illness. Collectively, the enteroviruses are the leading causes of viral meningitis for which a pathogen can be identified. However, severe neurological syndromes, including encephalitis and acute anterior poliomyelitis, are associated with several of these agents. Poliovirus Poliovirus, one of the most virulent members of the enterovirus group, is the agent of acute anterior poliomyelitis (infantile paralysis). The virus is worldwide in distribution (although wild-type poliovirus circulates only in six countries in Southeast Asia and Africa as of 2002), is more prevalent in temperate regions, and causes disease most commonly in late summer and early fall. Poliovirus is transmitted by fecal-oral contact and, during epidemics, also by pharyngeal spread. Three antigenically distinct types of poliovirus have been defined. All can cause paralytic disease through destruction of motor neurons in the spinal cord and brainstem. Clinically apparent infection with poliovirus results in aseptic meningitis ( 8 % of cases) or paralytic illness {1% of all cases). A 7- to 14-day incubation period is followed by
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NEUROLOGICAL DISEASES
headache, fever, signs of meningeal irritation, drowsiness, and seizures in infants. Asymmetric flaccid weakness of limbs, diaphragm, or cranial nerve-innervated muscles develops within days and progresses, on average, for 3-5 days. Cercbellitis, transverse myelitis, and facial paresis also have been reported. Diagnosis is suspected based on the clinical picture and presence of CSF pleocytosis and confirmed by serology, virus isolation, or PCR amplification of poliovirus RNA from CSF. In the CSF, polymorphonuclear cells predominate early, with a shift to lymphocytes after several days. CSF protein concentration is slightly elevated; levels of 100-300 mg/dL may accompany cases of severe paralysis. The differential diagnosis of nonparalytic polio includes viral meningitis caused by other pathogens. The differential diagnosis of an acute, pure motor neuronopathy with CSF pleocytosis is broad and includes West Nile virus, Japanese encephalitis virus infection, and carcinomatous meningitis. Bulbospinal disease with inflammatory spinal fluid is seen in the Russian spring and summer encephalitis variant of arbovirus infection and in rabies. The Guiilain-Barre syndrome is distinguished by antecedent rather than concurrent febrile illness, CSF albuminocytological dissociation, absent reflexes, more common facial nerve involvement, and nerve electrophysiological abnormalities consistent with proximal demyelination. Approximately one quarter of polio patients develop progressive lower motor neuron weakness 30-40 years after acute polio ("the postpolio syndrome"). Atrophy, fasciculations, and electromyographic evidence of active denervation are found in previously involved muscle groups. Treatment of poliomyelitis is supportive, with particular attention to ventilatory assistance. Mortality from paralytic poliomyelitis is less than 10%, but bulbar forms have a poorer prognosis, and mortality may approach 5 0 % . Clinical and virologic improvement has been reported with pleconaril in several cases of wild-type and vaccineassociated paralytic polio (Rotbart et al. 2001). The W H O has set 2005 as a goal for eradication of poliovirus from the globe. Great progress has been made toward this goal using aggressive vaccination campaigns. In 1988 there were 350,000 cases of wild-type polio occurring in 125 countries; as of 2002 there were approximarely 1400 cases of wild-type polio, with circulation restricted to only six countries in Southeast Asia and Africa. There have been no cases of circulating wild-type polio in the United States since 1979 and in the Western Hemisphere since 1991. Fot this reason, as of the year 2000, the Advisory Committee on Immunization Practices has recommended the use of inactivated (Salk, intramuscular) polio vaccine in the United States for the entire primary immunization series in the first year of life, as well as the booster dose prior to school entry. In areas of the world in which poliovirus is still endemic, primary immunization should be carried out with trivalcnt live attenuated (Sabin, oral) vaccine. The advantages of oral polio vaccine are ease of administration
and induction of intestinal immunity. The disadvantage is the risk of reversion to neurovirulence and production of paralytic disease in vaccinees and contacts. Therefore, inactivated polio vaccine should always be used for vaccination of persons with immunodeficiency diseases, in which the risk of vaccine-associated paralytic polio from live attenuated vaccine strain is high. Vaccine-related cases of paralytic polio have included infants with unrecognized immunodeficiency who have received their first oral polio vaccine dose and immunocompromised patients who have been in contact with recipients of live attenuated oral polio vaccine. Nonpolio
Enteroviruses
The nonpolio enteroviruses may cause a wide spectrum of CNS and PNS disease, including aseptic meningitis, encephalitis, acute anterior poliomyelitis, acute cerebellar ataxia, peripheral and optic neuropathy, cranial polyneuritis, and epidemic myalgia. In neonates, encephalitis is generally part of an overwhelming sepsis-like illness, with up to 1 0 % mortality. Congenital CNS defects are associated with infection acquired in utero. Infection of hypogammaglobulinemic patients commonly leads to progressive meningoencephalitis. Certain strains have also been associated with an acute motor neuron disease in association with epidemic hemotrhagic conjunctivitis. Meningitis Nonpolio enteroviruses are the most common cause of viral meningitis (Pallansch and Roos 2001). Over 75,000 cases of EV meningitis occut in the United States each year, and these also occur in a worldwide distribution. The strains most commonly isolated in aseptic meningitis are Coxsackie A9, B3-5, and echovirus 4, 6, 7, 8, 11, 18, and 30. Spread of infection is by fecal-oral and, rarely, respiratory routes. Outbreaks tend to cluster in the late summer and early fall and may be associated with pharyngitis and gastrointestinal symptoms, such as anorexia, vomiring, or diarrhea. Other findings suggestive of enteroviral infection include the cxanthem of herpangina or the rash of hand-foot-and-mouth diseases. Although EV is the most common cause of viral meningitis in the adult as well the pediatric population, children are epidemiologically over-represented as victims of enteroviral infection. Fortunately, EV meningitis occurring beyond the neonatal period in immunocompetent hosts is only rarely associated with severe disease or subsequent neurological deficits (Sawyer 2002). Meningitis caused by coxsackievirus produces CSF cell counts typically up to 250 WBC per uL with 1 0 - 5 0 % polymorphonuclear cells. Echovirus infections are associated with CSF pleocytosis from several hundred to greater than 1000 WBC per uL, 9 0 % of which may be polymorphonuclcocytes in the first 24 hours of infection. Until
VIRAL INFECTIONS recently, recovery of enteroviruses was the primary means of establishing the diagnosis of CNS cntcroviral disease. Recovery of nonpolio EV from throat or rectal swabs is also suggestive, but not diagnostic, m .1 patient with viral meningitis because shedding from a previous, unrelated, F,V infection may be detectable for 1-3 weeks following infection in respiratory specimens and up to 6 weeks in stool specimens. The clinical utility of obtaining viral CSF culture is further limited by the amount of time required for EVs to grow (days to weeks), the relatively low sensitivity (65-75%), as well as the poor cultivability of some EV serotypes. The development of a reliable PCR for the detection of EV has been extremely useful in circumventing these problems (Ramcrs et al. 2000). PCR primers and probes are directed against the 5' nontranslatcd region of the viral genome, which is highly conserved among almost all cntcroviral strains. The newest generation of cntcroviral reverse transcriptase-polymerase chain reaction (RT-PCR) on CSF has > 9 5 % sensitivity and 100% specificity for known strains of EV. Conventional RT-PCR methods produce results within 24 hours, but more recently developed colorimetric assays, and real-time quantitative techniques can yield results in 4 hours. The availability of rapid turnaround EV RT-PCR should allow for more rapid diagnosis of this common illness and limit unnecessary hospitalizations, imaging procedures, and empiric antibacterial therapy. Although treatment has been supportive to date, resolution of the atomic structure of EVs by x-ray crystallographic studies has led to the design of new antiviral therapy. These studies demonstrate a deep cleft or canyon in the center of each protomeric unit of the EV viral capsid, which engages specific cellular receptors on targer cells. The drug pleconanl was specifically designed to fit into this cleft and can block the cell/receptor interaction required for viral entry into the host. This drug may allow treatment of meningitis and encephalitis caused by EV and may be particularly useful in the case of more severe or overwhelming disease as in neonates and agammaglobulincmic patients. Clinical trials in childhood and adult meningitis demonstrated minimal improvement in symptoms, but the drug is available for compassionate release in more severe cases of EV disease, including vaccine-associated paralytic polio (Rotbart et al. 2001). Meningoencephalitis Although more commonly the etiologic agent in aseptic meningitis, EVs may also cause encephalitis, particularly in immunodeficient patients with hypogammaglobulinemia, and in neonates. Focal and generalized presentations of encephalitis have been reported. EV strain 70 has been implicated most frequently in instances of encephalitis. In neonates, meningoencephalitis is generally a component of an overwhelming sepsis-like illness, with up to 10% mortality. Infection of hypogammaglobulinemic patients
1529
leads to a chronic and progressive meningoencephalitis; these patients should be treated with IV inimnrniejolnilui therapy. Pleconaril, an antiviral therapy with activity against EVs (described earlier), has become available and can be used in neonates and immunodeficient patients on a compassionate use basis. Epidemic Disease
Conjunctivitis and Acute
Motor Neuron
Enterovirus type 70 is the etiological agent of a syndrome of conjunctivitis and an acute motor neuron disease. Epidemic acute hemorrhagic conjunctivitis first appeared in Ghana, West Africa, in 1969 and spread across Africa, Asia, and Europe in 1970 and 1971 to involve tens of millions of people. The eye disease was characterized by severe eye pain, photophobia, blurred vision, and varying degrees of subconjunctival hemorrhage. In a minority of patients, usually young men, a neurological (polio-like) phase developed 2 weeks after the conjunctivitis as acute asymmetric hypotonic or flaccid weakness of the lower extremities. Isolated facial nerve palsy, upper limb weakness, radicular, myelopathic, dysautonomic syndromes, or multiple cranial neuropathies were also reported. Acute hemorrhagic conjunctivitis surfaced again in 1981 in many of the same countries, in French Polynesia, and in other Pacific Islands; was imported to the United States; and spread among household contacts. A similar disease caused by enterovirus type 71 has occurred in Bulgaria and moved around the world. The other agent of epidemic hemorrhagic conjunctivitis, coxsackie A24, has not been associated with an acute motor neuron disease. These are highly contagious viruses for which there is no specific antiviral treatment, underscoring the importance of surveillance, public health measures, and sanitation in limiting disease, Enteroviruses and Amyotrophic
Lateral Sclerosis
Viruses have been proposed to play a potential role in the pathogenesis of amyotrophic lateral sclerosis (AI.S) because of the predilection of viruses such as polioviruses for motor neurons and some climcopathological similarities between ALS and poliomyelitis. A report describing detection of echovirus 7 sequences by RT-PCR in formaldehyde-fixed spinal cord samples suggested a possible association between persistent enterovirus infection and ALS (Berger et al. 2000). However, subsequent studies have not confirmed this finding (Walker et al. 2001).
Arboviruses The term arbovirus (ffrthropod-frorne virus) is a general term for viruses transmitted to humans by mosquito and
1530
NEUROLOGICAL DISEASES
tick (arthropod) vectors. Arboviruses exist in nature in complex cycles involving birds and mammals, which serve as reservoirs of disease. When transmitted to humans, arboviruses can cause fever, headache, meningitis, and encephalitis. Arboviruses comprise a group of over 500 RNA viruses, of which > 100 are known ro infect humans. The three taxonomic families into which arboviruses are divided are togaviruses (subdivided into flaviviruses and alphaviruscs), reoviruses, and bunyaviruses. Considered l()j;e[her,
.; r b o v i m s r s
represent
lhe
li'.uliii;;
, ausc
of
encephalitis worldwide (Lowry 1997). The salient features of arboviral infections occurring in North America are summarized in Table 59B.9. St. Louis Encephalitis Virus (Flavivirus) St. Louis encephalitis (SLE) virus is a cause of late summer encephalitis outbreaks in North America. In epidemic years, SLE accounts for a significant number of viral encephalitis cases reported in the United States. SLE virus cycles between Cutex mosquitoes and birds each summer. In the United States, there are an average of 135 endemic cases per year, although during epidemics there can be thousands of cases. The illness is characterized by febrile headache only, aseptic meningitis, or encephalitis. Signs and symptoms of CNS infection progress over several days to a week. The incidence of encephalitis is higher in the elderly; in this population, case-fatality rates reach 3 0 % . Season, place of residence, exposure, and presence of similar cases in the community are important considerations in the diagnosis. CSF cell counts are generally less than 200 WBC per uL, with lymphocytic predominance. CSF protein concentration is mildly elevated. Although the virus may be isolated from scrum or CSF, specific diagnosis usually relies on serological testing. IgM antibodies may be present in the CSF as early as day 3 of illness and are diagnostic. The slower evolution of neurological symptoms, the presence of generalised weakness and tremor, and the absence of focal findings and seizures favor a diagnosis of SLE over HSV encephalitis. No specific antiviral treatment exists. Treatment, as for all the arboviral encephalitides, is supportive, with control of cerebral edema, hyperthermia, and seizures. West Nile Virus {Flavivirus) West Nile virus (WNV) was already one of the world's most widely distributed arboviruses, present in many parts of Africa, West Asia, the Middle East, Eastern Europe, and Australia, when it emerged in North America in 1999. l-'ili1. mm- people IVITI hospitalised with encephalitis or meningitis in late summer in the New York City metropolitan area, with seven resultant fatalities (Nash et al. 2001). Transmission occurs primarily by insect bite; however, person-to-person transmission through organ transplantation, blood and blood product transfusion,
and intrauterine infection have been reported as of 2002. Mosquitoes of the genus Culex arc the principal maintenance vectors; wild birds served as the principal amplifying hosts for the New York epidemic. Concurrent epizootics with high mortality occurred in wild and exotic birds and horses. The rapid spread of the epidemic across the United States between 1999 and 2002 is causing concern that this virus has not only emerged, but also established itself as a major cause of viral meningitis and encephalitis in I he I iiiteJ States, with human cases reported in all but five states by the end of 2002. During the 2002 season, 4008 cases were reported, of which approximately 2500 cases presented as West Nile virus encephalitis (WNVF), resulting in 263 deaths. The 2002 W N V epidemic in the United States was the largest arboviral meningoencephalitis epidemic documented in the western hemisphere and the largest reported WNVE epidemic ever. West Nile should be included in the differential diagnosis of encephalitic illness in the summer and fall, particularly in patients with associated lower motot neuron weakness, Most human infections are completely asymptomatic. Following an incubation period of 3-14 days, illness presents as a nonspecific febrile illness in approximately 2 0 % of infected persons. One in 150 infected persons will develop encephalitis and/or meningitis, and the elderly (>50 years) are at most significant risk for severe neurological disease and death. The high frequency of associated motor weakness in patients with WNVE is a characteristic feature of nervous system involvement and has been reported in nearly 6 0 % of cases. As illustrated by the New York epidemic, in which a large proportion of patients had some degree of associated weakness, patients may be flaccid, a reflex ic, or have milder weakness with diminished reflexes and cranial neuropathies (Tyler 2001). Nerve conduction studies show axonal or demyelinating neuropathy. More recently, it has been recognized that the bulk of cases preventing with weakness have a clinical and pathological picture more consistent with a poliomyelitis-like involvement of anterior horn cells, rather than Guillain-Barre type illness. The case fatality among hospitalized patients is approximately 12-14%. Diagnosis is best achieved by detection of IgM antibodies in CSF and/or IgM and IgG antibodies in serum. CSF PCR is less sensitive than serological studies, although when positive, it is diagnostic, WNV may be isolated from serum, blood, and CSF early in the febrile stage and from brain tissue. Currently, commercial testing for WNV-spccific antibody is limited. Because of potential cross-reactions with antibodies to other flaviviruses (yellow fever, dengue, Japanese encephalitis antigen-complex members), experience in test interpretation is important, and positive tests should be confirmed by experienced laboratories such as the CDC and/or local public health departments (Marfan and Gulber 2001). Neuroimaging is often unremarkable, although meningeal and periventricular enhancement has been reported using MRI. CT scan is usually normal,
Table 59B.9:
Details of North American arboviruses
Agent
Geographic
Eastern equine
Atlantic and Gulf coasts, Great Lakes region Western U.S. and Canada Texas and Florida
\\ estern equi"t' Venezuelan equine St. Louis
California (La Crosse) West Nile virus Powassan Colorado tick fever
distribution
Throughout U.S.. but greatest prevalence in Texas, Florida, and Ohio-Mississippi River Valley Midwest and Northeast U.S., Southern Canada Throughout U.S. North Central U.S., Eastern Canada U.S. and Canadian Rocky Mountains
Reservoir
Vector
Season
Group affected
Birds
Mosquito
June-Aug
Children
Birds and small m a in in a Is Horses, small animals Birds
Mosquito
June-Sept
Infants, adults >50 ye
Mosquito
Adults
Mosquito
Rainy season May-Sept June-Aug
Chipmunk, squirrel, small mammals Birds
Mosquito
June-Sept
Children
Mosquito
June-October
All ages, adults >50 with severe disease
Squirrel, porcupine, groundhog Chipmunk, squirrel, rodent
Tick
Spring /SuiniTU'r
Tick
March-Sept
Adults >50 years
Children and adulrs
1532
NEUROLOGICAL DISEASES
Treatment of WNV encephalitis is supportive, but clinical response to intravenous immunoglobulin (1VIG) was reported after administration of an immunoglobulin preparation contained high titers (1:1600) of anti-WNV antibodies (Shimoni ct al. 2001), Unfortunately, the batches of IVIG currently available in the United States do not contain significant titers of WNV antibody and would therefore presumably be of limited benefit. Clinical trials are needed to determine optimal therapy for this disease. laj'.uir-;f Encephalitis Virus
Ehwirtrus)
JEV)
JEV is widely distributed in Asia, through Japan, China, T:rv, .in, Korea, [he far Eastern former Soviet Union, Southeast Asia, and India. Worldwide, JEV infection is the most important cause of arboviral encephalitis and produces the greatest number of deaths worldwide each year. The virus cycles between Culex, Aedes, or Anopheles species of mosquitoes; pigs; and birds. Recently detected in Northern Australia, JE virus may soon become endemic on that continent as well (Mackenzie et al. 2001). Following an incubation period of 6-16 days, patients may present with a febrile headache syndrome, aseptic meningitis, or encephalitis. The encephalitic form is characterized by a 2- to 4-day viremic prodrome of headache, fever, nausea, vomiting, dizziness, drowsiness, and abdominal symptoms in children, progressing to meningoencephalitis with signs of cortical, subcortical, extrapyramidal, bulbar, cerebellar, and spinal cord involvement. Excitability or delirium, seizures, hyperthermia, expressionless facies, axial rigidity, limb tremors and other involuntary movements, erratic eye movements, cranial nerve palsies, ataxia, limb paresis, including lower motor neuron type weakness in the arms, and segmental sensory disturbance are reported. Prolonged fever, seizures, coma, respiratory complications, and high CNS virus load arc all associated with a poorer prognosis. The case-fatality rate is 30-40%. Sequelae include parkinsonism, seizure disorders, paresis, mental retardation, and psychiatric diseirdci s,
In JEV encephalitis, there is a CSF pleocytosls with 10-500 (rarely up to 1000) WBC per LII„ with an early polymorphonuclear predominance later replaced by lymphocytes. CSF protein is elevated (50-100 mg/dE). Specific diagnosis is made by demonstrating a fourfold increase in IgG antibodies between acute and convalescent sera, or IgM antibodies in serum and CSF. Virus isolation from the blood is infrequent, but may be isolated from the CSF in one third of patients. MRI studies may show areas of abnormal signal in thalamus and basal ganglia. No specific therapy is available for JEV encephalitis. A formalin-inactivated vaccine with excellent efficacy in prevention of disease is available for travelers to and residents of endemic areas. The risk of disease among travelers has been estimated to be between 1 in 5000 and 1 in 20,000 per
week of travel. Primary immunization is with two doses, separated by 7-14 days and a single booster dose at 1 year. Revaccination is recommended at 3-year intervals. California Serogroitp of Viruses (Family Bunyaviridae) The California serogroup contains several viruses with mosquito vectors, small mammal or deer hosts, and limited geographic range. Among this group, La Crosse virus is an endemic cause of summer encephalitis in the mid western United States. Most cases are in children, who have seizures and polymorphonuclear or mononuclear pleocytosis on CSF examination. Children who recover may have sequelae including seizures (10%), cognitive dysfunction (2%), or weakness (49
There are over 20,000 fungal species identified in the world. They form an integral part of our ecosystem and have been harnessed to make bread, beer, and antibiotics. Among them, over 250 fungal species have been reported to be pathogenic. From the common Candida infections to the deadly mucormycosis, fungal infections influence all levels of clinical practice (Luna 2000). Fungi differ from bacteria in that they have a nucleus that is bounded by an organized membrane, they divide by mitosis, and they usually have a chitinous cell wall. The cell wall and a lack of mobility differentiate fungi from protozoa (Davis 1999). The absence of chlorophyll distinguishes them from most plants. Most pathological fungi are dimorphic and can exist in yeast and filamentous states, depending on growth conditions and temperature. In the yeast state, they are unicellular, are round to elongated, and reproduce by budding or fission. In the filamentous or mold state, they grow by extension of their tips forming tubular structures called hyphae, which often have septae that divide them into many segments. Spores arc the reproductive elements of these hyphae. Spores develop into yeast when infecting humans or animals but remain in the filamentous form when grown in vitro. Fungi have varying predilection for involvement of the central nervous system (CNS). In general, fungi found in the meninges and the cerebrospinal fluid (CSF) are in the yeast phase (e.g., Cry/)(ococci«), whereas those causing brain parenchymal infection are in filamentous stage (e.g., Aspergillus). CNS fungal diseases are often difficult to diagnose and, as a consequence, are misdiagnosed or undiagnosed during life. Although many therapeutic
Therapy of Fungal Infections Antifungal Agents Newer Agents Surgery Treatment of Specific Infections Crypcococcal Central Nervous System Infection Coccidioidal Central Nervous System Infection Histoplasmal Central Nervous System Infection Central Nervous System Mucormycosis
1552 1552 I 552 1553 1553 1553 1553 1554 1554
options have been developed to treat superficial fungal infections, invasive and deep CNS fungal infections often prove tenacious to therapy.
EPIDEMIOLOGY AND CURRENT TRENDS The incidence of CNS fungal infections varies greatly with the geographic location. For example, histoplasmosis is common in areas infested with bats, and cryptococcosis and histoplasmosis are common in patients exposed to birds. Histoplasmosis is commonly seen in the central United States (Ohio River Valley) and in restricted areas of the tropics. H. dubaisii is frequently found in West Africa. Coccidioidomycosis is mainly found in the southwestern United States (San Joaquin Valley) and in Central America, where it resides in the soil. Blastomycosis is endemic in Ohio ,uul Mississippi IVIMIIS in IIIL- United Si.; us. Oihci"
fungi such as Cryptococcus, Aspergillus, zygomycetes (Mucor), and Candida species are more universally distributed. With respect to clinically recognized fungal CNS illnesses, Cryptococcus and Candida infections arc the most common, followed by Coccidioides, Aspergillus, and the zygomycetes. Fortunately, other fungi involve the CNS rarely. Candida and the zygomycetes rarely invade the deep viscera or CNS in the normal host and are therefore considered to be opportunistic in nature in immunocompromised hosts. Recently fungal disease of the CNS has become increasingly common as a consequence of the acquired immunodeficiency syndrome (AIDS) epidemic and the use of 1545
1546
NEUROLOGICAL DISEASES
aggressive immunosuppressive regimens for cancer, and for solid organ and bone marrow transplantations. A study from the San Francisco Bay area found that more than 7 5 % of patients who had invasive mycoses had serious underlying medical conditions that affected their immune systems (Rees et al. 1998). Only 9% were thought to be healthy at the time of the systemic fungal infection. The authors reported an overall incidence of invasive mycotic infections at 178 per million per year in 1992 to 1993, but the rate climbed to 5000 per million per year in individuals who were infected with the human immunodeficiency virus (HIV). The study found that the rates of invasive fungal infections per million per year for individual fungi were highest for Candida followed by Cryptococcus {73% and 6 6 % , respectively). In another study from Australia, the two most common strains of Cryptococcus had different epidemiological features. C. neoformans, var. neoformans primarily caused meningitis in immunosuppressed patients, whereas C. neoformans, var. gatti infected healthy hosts. The reason for this difference is unclear. There is no specific epidemiological data available from the developing countries (Bharucha et al. 1999).
CENTRAL NERVOUS SYSTEM FUNGAL SYNDROMES Myriad clinical presentations of the CNS fungal infections occur. Meningitis, meningoencephalitis, cerebral abscess, CNS granuloma, rhinocerebral necrotic mass, and base of skull lesions are the common modes of presentation. Cerebrovascular accidents or epidural fungal abscess are rare. The manner in which fungal CNS disease manifests is largely determined by the growth characteristics of the particular fungal species during systemic invasion. Fungi that are true yeast when invasive (e.g., Cryptococcus) most often present as chronic meningitis. Fungi that are pseudohyphae (e.g., Candida] often present with encephalitis as a consequence of multiple intraparenchymal microabscesses. Those that are true hyphae {e.g., Aspergillus) can present as strokelike illness because of their propensity to invade blood vessels. Clinicians must remain aware that these presentations are not mutually exclusive and that it is not uncommon for the various forms of clinical illness to coexist (Miszkiel et al. 1996).
INDIVIDUAL FUNGAL PATHOGENS PATHOGENESIS
The True Yeasts Cryptococcus
fungi produce disease by direct invasion, allergic phenomenon, or liberating toxins (e.g., ergotism resulting from rye ergot, which thrives on cereals, especially groundnuts, and trichothecene mycotoxins, which are misused in aerosol form as "yellow rain" in biological warfare to produce an illness characterized by weakness, ataxia, hypothermia, and shock). Fungi are generally not invasive unless there are predisposing factors. They gain entry into the body mainly byinhalation of spores. This causes a localized lung infection, which may be asymptomatic or produce mild respiratory symptoms and is usually successfully terminated by a functional immune system. Failing this, the infection reaches the bloodstream and produces fungemia. If the fungemia overcomes the liosi's reticuloi'iicnilidi.i!, cellular, and humoral defense systems and penetrates the bloodbrain or blood-CSF harrier, it reaches the brain parenchyma or the meninges. Fortunately, in the healthy individual, this seldom happens. Indwelling arterial or venous catheters can also he infected (Candida), forming a direct source for fungemia. Less common routes of infection are from the skin (sporotrichosis), the mouth, the gastrointestinal tract (Candida), and the nasal sinuses (Aspergillus and zygomycetes). Finally, direct inoculation of fungi into skull fractures or during neurosurgical procedures that place indwelling devices such as intraventricular shunts also predisposes to CNS infection. Certain conditions predispose a patient to infection with a particular fungus (Table 59C.1).
Cryptococcus is by far the most common cause of fungal meningitis and meningocerebral syndromes. Cryptococcosis is a systemic infection caused by the encapsulated yeast fungus, C. neoformans, which has a ubiquitous distribution in soil and pigeon excreta. Infection occurs by inhalation. Occasionally a mild pulmonary clinical infection occurs at the time of invasion. Meningitis is the most common neurological presentation, though multiple small cryptococcomas or a single large granulomatous lesion and abscess may also occur, presenting with symptoms of a mass lesion, seizures, or focal neurological deficits. Cystic lesions or hydroecpb.ilus may develop in patients who survive. Rarely, chronic infection presents with a dementialike syndrome. The progression of the disease depends on the degree of immunosuppression. A papular or ulcerative skin lesion, lytic bone lesions, prostatitis, pulmonary, and renal involvement occur in disseminated systemic cryptococcosis. Histoplasma Inhalation of infectious spores found in soil containing bird excreta causes histoplasmosis. The primary infection may be subclinical, and many cases are diagnosed by chest radiography done for another reason. Acute pulmonary histoplasmosis may result in an influenza-like illness that may be accompanied by erythematous skin eruptions. The disease, often mistaken for miliary tuberculosis, presents
Table S9C.1:
Therapy for CNS fungal infections Ciinicopathological features Predisposing cause
Meningitis
C. netifomulns
Inherited immunodeficiency (CGD, SCID, etc-l, HIV/AIDS, cytotoxic agents, corticosteroids
++++
AMP B, 0.5-1 mg/kg/d, p 100 mg/kg/d (in four d doses) for 6-10 wks or nation for 2 wks follow FLUCO 400 mg/d for Consolidation with FL 6 mo-1 year.
C. hnrrtitis
Inherited immunodeficiency [CGD, SCID, etc.), HIV/AIDS, cytotoxic agents, corticosteroids
+++
H. capsulatum
Inherited immunodeficiency (CGD, SCID, etc.), HIV/AIDS, cytotoxic agents, corticosteroids Inherited immunodeficiency (CGD,
++++
FLUCO 400-800 mg/d fo yrs or IV 0.25 to 1.5 m with or without IT AM rimes/wk for many w dual tapering to biwee then monthly, a cumul of 35-100 mg in conju with IV AMI1 B 0.5 m to a total cumulative d 0.5-2.0 g for 1 year. AMP B 0.7-1.0 mg/kg/d. Maintenance FTRA, 40 for 4-12 weeks for 6 AMP B, 0.5-1 mg/kg/d, w FLU, 100 mg/kg/d (in divided doses) for 4-6
C. albicans
SCID, etc.), HIV/AIDS, cytotoxic
Z. rhizopus
A. fumigattts
B. dermatitidis
++
agents, corticosteroids, cancer, trauma, indwelling catheters, prematurity, alcoholism, intt a venous drug abuse, ma lnutririon, pregnancy Diabetic ketoacidosis, intravenous drug abuse, iron chelation therapy Inherited immunodeficiency (CGD, SCID, etc.), HIV/AIDS, cytotoxic agents, corticosteroids •+++
Abscess
Infarct
Therapy in immunocompetent host
Organism
++
(Microabscesses)
+++
++++
+—
++++
AMP B, 1-1.5 mg/kg/d u total dose of 3 g. Surg debridement. AMP B, 0.7-1.5 mg/kg/d up to a total dose of 3 followed by ITRA, 40 mg/d for extended per AMI' b, 2-3 g total until followed by ITRA, 40 for 6 mo.
AMP B, Amphotericin B; CGD, chronic granulomatous disease; d, day; FLU, Flucytosine; FLUCO, Fluconazole; IT, intrathecal; ITRA severe combined immunodeficiency; wks, weeks.
1S4S
NEUROLOGICAL DISEASES
as an acute or chronic febrile illness with diffuse pulmonary infiltrate, abnormal liver function, mucosal ulceration, and less often with neurological involvement (10-20%) in the form of a basilar meningitis, focal cerebritis, or CNS granuloma. Headache, fever, and neck stiffness are seen in about half of the cases. Manifest disease may occur even after leaving an endemic /one indicating the importance of taking a travel history. Diffusedisease is seen in immunocompromised hosts and at the extremes of age. Approximately 5 0 % of patients who have a CNS infection develop subacute meningitis, whereas 4 0 % have cerebral abscess. The meningitis usually occurs in the setting of disseminated infection but may occur by itself. Blastomyces Blastomycosis is a systemic disease caused by B. dermatitidis, which proliferates as a saprophyte in soil, and it typically infects healthy individuals. Inhalation of the mycelial form results in the disease. Both systemic and cutaneous forms of blastomycosis may follow pulmonary infection. Neurological involvement occurs in 6 - 3 5 % of individuals with disseminated blastomycosis and is characterized by intracranial or spinal abscesses or meningitis. Meningitis is often accompanied by rapid deterioration. Infection of vertebrae may lead to osteolytic lesions, which are often painless and may spread to the contiguous soft tissue. For some reason, blastomycosis is not significantly more frequent in HIV/AIDS, and it is not identified as an AIDS-defining infection. Coccidioides Inhalation of airborne spores of C. immttis found in soil results in coccidioidomycosis. Although the majority of the cases are self-limiting, chronic pulmonary, skin or disseminated disease occurs in approximately 1% of patients. The male gender, extremes of age, nonCauc.]-.i.iu MCC, pregnancy, and immunosuppressed state are known to predispose to disseminated coccidioidomycosis. Lytic skull and vertebral lesions are seen in approximately one third of patients with disseminated disease. The vertebral arch is most frequently involved initially. Involvement of the vertebral body and disc space classically seen in tuberculosis is uncommon. Meningitis may be the presenting feature and usually occurs within 6 months of symptomatic or asymptomatic primary infection. Nonspecific signs and symptoms of headache, fever, malaise, and weakness are common, but seizures, cranial nerve palsies, and focal neurological deficits may also occur. The meningitis, if present, is more intense than cryptococcal meningitis. Prominent basilar meningitis frequently leads to the development of obstructive hydrocephalus, and meningeal vasculitis may cause occlusions of arteries, leading to cerebral infarcts. If untreated,
nunv ilian iO'.'•ee around midbrain \arrow] and in suprasellar cistern) and ventricular dilatation from obstructive hydrocephalus Courtesy Dr. S. K. Gaekwad.)
1550
NEUROLOGICAL DISEASES
Hydrocephalus resulting from blockage of CSF flow at the level of the basal cisterns ot at the outflow pathways from the fourth ventricle by arachnoiditis may also be observed. If the fungus directly invades the brain, neuroimaging often demonstrates an enhancing localized cerebral mass with variable surrounding edema (Figure 59C.2 and Figure 59C.3). Large space-occupying abscesses or granulomas are associated generally with Aspergillus, Mucor, Blastomyces, and Vseudallescherla. Bland or occasionally
hemorrhagic cerebral infarcts may be seen if meningitis causes vasculitis with thrombosis of arteries or veins. In suspected rhinocerebral syndromes, sinus and orbit imaging must be reviewed. Mucosal thickening, air-fluid levels or erosion of bone in the walls of the sinus or orbit suggests rhinocerebral infection. Lumbar puncture and analysis of the CSF is the most crucial test in establishing the diagnosis of fungal meningitis. The cerebrospinal pressure is often elevated. The fluid is
FIGURE 59C.2 Rhinocerebral aspergillosis. Coronal Tl MR1 showing sphenoid sinus mass extending to left frontal lobe and through corpus eallosum to the right frontal lobe (A), coronal FLAIR image showing left frontal mass (also extension to the right) of heterogeneous intense signals (B), and sagittal Tl postgadolinium image showing enhancing contiguous sphenoidal, frontal lobe and corpus eallosum mass (C). (Courtesy Dr. S. K. Gaekwad.)
FUNGAL INFECTIONS
1551
and range from 10-39 mg/dL. Very low glucose levels (1 deu-ain-i In 10- VS"„.
THERAPY OF FUNGAL INFECTIONS Antifungal Agents Amphotericin B is the treatment of choice for most fungal infections of the CNS (see Table 59C. 1). This agent is a polyene compound that binds to the ergosterol component of fungal cell membranes. It acts by increasing the permeability of the cell membrane resulting in the leakage of intracellular contents and lysis of the cells (Patel 1998). The serum half-life of amphotericin B is approximately 12 to 24 hours with peak serum levels lasting 6 to 8 hours. Excretion is chiefly in the urine. Depending on achievable concentrations, it is either fungistatic or fungicidal. It has no effect on other classes of pathogens. Limitations of amphotericin B include its poor penetration of the blood-brain barrier, making it difficult to achieve effective fungicidal levels in brain. The drug also has renal toxicity (up to 80%), and it causes electrolyte wasting (K + and M g + + ) , normochromic—normocytic anemia and a flulikc allergic reaction after intravenous (IV) use. CNS toxicity limits its intrathecal use. Occasionally lifethreatening reactions such as anaphylaxis, acute hepatic failure, seizures, ventricular fibrillation, and cardiac arrest may occur. Premedication with diphenhydramine, hydrocortisone, and ihuprofen for the fever and chills, antiemetics for nausea, and oral potassium supplement to guard againsr hypokalemia reduce adverse effects. Renal toxicity of amphotericin B is related to its peak serum concentrations and the cumulative dose. Patients should be monitored by frequent urinalyses for detection of red blood cell (RBC) or WBC casts, serum creatinine levels, and creatinine clearance. Inability to use this dtug orally limits its use in therapy. Idiosyncratic reactions may fotce stoppage of medication. Amphotericin B should be avoided in patients who are hypersensitive to the drug unless it is the only possible therapy in the face of a lifethreatening fungal disorder. In spite of all these limitations, it is the initial choice in induction therapy for most CNS infections, particularly those that are life threatening. New lipid formulations of amphotericin B (vide infra) have been developed to overcome the toxic it}', and though they are expensive, they are as effective as the original drug, Flucytosine, which was initially developed as an antineoplastic agent, is commonly given as an adjunct to amphotericin B to patients with invasive infections by Ci-yptnctiLLiis, Ciimi'uh, and Aspergillus. The drug interferes with the metabolism of fungal nucleic acid and disrupts its genetic code. It is rapidly absorbed from the
alimentary tract, has minimal protein binding, and is excreted unchanged in urine. CSF concentrations reach 7 5 % of serum. The serum half-life is 3-5 hours. When given alone, flucytosine has few side effects, which include rash, cosinophilia, diarrhea, and hepatic dysfunction; however, in com hi nation with amphotericin B, bone marrow suppression is the major side effect. Blood levels exceeding 100 ug/ml, are associated with increased incidence of these complications. Existing renal failure calls for adjustment of dosage. A twice weekly leukocyte count and platelet count is mandatory in these cases. Flucytosine blood level estimations are done in reference mycology laboratories and are important in patients with azotemia. Blood levels for flucytosine should be drawn 2 hours after the last flucytosine dose and just before the next dose once or twice a week and should be between 50 and 100 (.tg/mL. Fluconazole and itraconazole are synthetic broad-spectrum antifungal agents that belong to the triazole (azoles) class. They act by inhibition of the synthesis of ergosterol and cause accumulation of substituted sterols, which interfere with the permeability of the fungal cell membrane. Fungal cell membranes are far more sensitive to these agents than mammalian ones. Azole antifungals are generally considered to be fungistatic rarher than fungicidal. The advantage of these drugs is that they are less toxic, can be administered orally, and have good blood-brain barrier penetration. The disadvantage is a lower cure rate, The cure rate is low for cryptococcosis and still lower for aspergillosis with azoles alone. In vitro and animal studies have suggested that concomitant administration of amphotericin B and azole drugs may show antagonistic effects, The use of azoles is hence limited for maintenance therapy to prevent recurrences of coccidioidal, cryptococcal, and bistoplasmal meningitis. Itraconazole has properties similar to fluconazole except for its poor penetration of the bloodbrain barrier. Adverse effects of azoles are uncommon but include nausea, abdominal pain, headache, dizziness, rash, reversible alopecia, pedal edema, and transiently increased liver enzymes. Physicians must watch for drug interactions of antifungal azoles with other drugs to prevent side effects or lack of effectiveness of the primary medication.
Newer Agents Lipid amphotericin preparations (liposomal amphotericin B, amphotericin B cholesteryl, and amphotericin B lipid complex) have the advantage of lower toxicity and infusion-related side effects. The half-life of these preparations varies, and the larger particles are mostly cleared by the reticuloendothelial system faster. The disadvantages of lipid formulation are higher cost and lower CNS permeability compared to the original drug. The CSF/plasma concentration at steady state for amphotericin B is typically
FUNGAL INFECTIONS
less than 2 5 % and lower for lipid formulations. Doses of lipid formulations range from 3-5 mg/kg per day. There seems to be no major difference in the overall efficacy between the two preparations. A favorable initial response of amphotericin B may permit a switch to a less toxic antifungal preparation after a period of time. Voriconazole, a new triazole derivative, has broad-spectrum antifungal activity and is especially useful for aspergillosis and candidiasis. Doses vary from 50-200 mg per day. SCH59562 is another triazole with apparently greater potency than voriconazole and is currently under investigation. Agents that boost the immune system, which is often deranged in patients with fungal infections, may help in treating invasive fungal infection. Cytokines and gamma interferon are being tried in CNS fungal infections and continue to remain experimental at this stage (Stevens 1998).
Surgery Surgical procedure may be critical for CNS fungal treatment, especially in cases of invasive rhinocerebral fungal disease. Surgical biopsy may also be essential for establishing the diagnosis. Among the procedures of therapeutic relevance are exenteration of infected facial, nasal, and intracranial tissues in cases of mucormycosis and aspergillosis, extirpation or drainage of fungal cerebral abscess, repair of rare mycotic aneurysm, and surgical drainage of hydrocephalus complicating fungal meningitis. Hydrocephalus can occur in any fungal meningitis and is seen in as many as 1 5 % of cases of cryptococcal meningitis. Acute hydrocephalus may require emergent ventricular drainage, and chronic hydrocephalus may require a ventriculopcritoneal shunt. Ventricular shunt in the face of active fungal meningitis may produce venrriculitis. In cryptococcal meningitis with communicating hydrocephalus, daily lumbar puncture may also alleviate symptoms. However, lumbar puncture is contraindicated in patients with intracranial mass lesions, such as fungal abscess and intracranial shifts on imaging studies. With elevated intracranial pressure, lumbar puncture should be performed cautiously, especially in patients with low-lying cerebellar tonsils, to avoid tonsillar herniation. The later has even been observed following lumbar puncture in the absence of focal mass brain lesion.
TREATMENT OF SPECIFIC INFECTIONS Cryptococcal Central Nervous System Infection Practice guidelines by the Infectious Diseases Society of the United States of America (Saag et al. 2000) have suggested therapy beginning with amphotericin B in the dose of 0.5-1 mg/kg per day plus flucytosine 100 mg/kg per day for
1S53
6-10 weeks in immunocompetent hosts with CNS cryptococcal disease. An alternative regimen is to use this combination for 2 weeks followed by fluconazole 400 mg per day for 10 weeks or more, especially if the patient develops amphotericin B toxicity. The consolidation therap\ with fluconazole mai be continued for d months to a year, depending on the clinical and CSF response. In patients with HIV infection, induction with amphotericin B (0.7-1 mg/kg per day) plus flucytosine (100 mg/kg per day) for 2 weeks followed by fluconazole 400 mg per day is recommended. The fluconazole dose can later be reduced to 200 mg per day but generally has to be continued for life in HIV/AIDS patients. An alternative regimen consists of amphotericin B in dosage of 0.5-1 mg/kg per day plus flucytosine 100 mg/kg per day for 6-10 weeks followed by fluconazole maintenance therapy. If the patient does not tolerate amphotericin B, fluconazole 400-800 mg per day with flucytosine 100-150 mg/kg per day for 6 weeks can be used. Renal function must be monitored, and serum flucytosine blood levels must be kept between 50 and 100 ug/mL. Neutropenia requires that the treatment be halted. Repeat lumbar puncture evaluation at 2 weeks of therapy to obtain CSF for antigen titers and fungal culture is needed to ensure the response to treatment. Relapse rates may be as high as 5 0 % . An important predictor of final outcome in patients with HIV is the CSF culture sterility 14 days after the initiation of treatment. Patients likely to have poor response are those with a high cryptococcal antigen level, low CD4 count, and low serum albumin level. Mass lesions greater than 3 centimeters may require surgery. Prophylaxis with fluconazole in AIDS is important as about 5-10% of patients develop cryptococcal meningitis, especially when their CD4 count falls below 100 cells/mm (Van der Horst et al. 1997).
Coccidioidal Central Nervous System Infection Prolonged treatment is usually required for coccidioidal CNS infections. Recent reports suggest that long-term oral fluconazole is as effective as amphotericin B and is now the treatment of choice. Its use in the dose of 400 mg per day orally for 4 years has been shown to result in improvement in 7 5 % cases. Occasionally higher doses of 600-800 mg per day may be required. Signs of improvement may come only 4 to 8 months after beginning the treatment, Intrathecal administration of amphotericin B in the dose of 0.25-1.5 mg/dose 3 times per week for several weeks with a gradual tapering to biweekly and then monthly to a total cumulative dose of 35-100 mg may be given in difficult to control infections. Intrathecal drug is given in conjunction with IV amphotericin B 0.5 mg/kg per day, up to a total cumulative dose of 3 g. The duration of treatment may need to be extended to up to 1 year (Stevens 1995). As many as 7 8 % cases may relapse when the therapy is discontinued. This is especially so in immunocompromised
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NEUROl OCiCAI. DISEASES
patients. Hence, lifelong m a i n t e n a n c e (200 mg per day) m a y be required.
with fluconazole
Histoplasmal Central N e r v o u s System Infection IV Amphotericin B ( 0 . 7 - 1 . 0 mg/kg per day) for a total cumulative dose of at least 30 mg/kg or 1.5-2 g) is used in most cases. Intrathecal amphotericin B in a d o s e of 0.25—1.0 mg/dose on alternate days can be given if there is no contraindication. Four to 12 weeks of induction therapy is required. M a i n t e n a n c e therapy is required because m a n y patients s h o w relapse following induction t h e r a p y alone (Wheat et al. 1990).
Central N e r v o u s System M u c o r m y c o s i s M u c o r m y c o s i s generally occurs in rhino-orbito-cerebral form in patients with diabetic ketoacidosis or o t h e r associated illnesses (see T a b l e 5 9 C . 1). Surgical d e b r i d e m e n t is required, diabetes should be controlled, and in patients with h e m o c h r o m a t o s i s , d e s f e r o x a m i n e should be discontinued. Amphotericin B should be administered in rapidly increasing doses of 1—1.5 mg/kg per d a y , with an anticipated dose of 2 . 5 - 3 g. H y p e r b a r i c o x y g e n a t i o n has been suggested by some investigators. T h e prognosis is generally poor. T h e r a p y of other major C N S fungal diseases is s u m m a rized in T a b l e 5 9 C . 1 . C u r e rate for cryptococcal meningitis is a b o u t 7 5 % , coccidioidal meningitis 5 0 % , bistoplasyna meningitis 4 0 % , and for aspergillosis a n d zygomycetes approximately 2 5 % . O u t c o m e i n i m m u n o s u p p r c s s c d patients is less favorable, a n d m a n y of these patients die due to c o n c o m i t a n t infections. Shott- a n d long-term complications in C N S fungal infections are as high as 4 0 - 7 5 % , and these include h y d r o c e p h a l u s , infarction, cranial nerve palsies, seizures, and dementia (del Brutto 2 0 0 0 ) .
REFERENCES Bharucha, N. E., Raven, & R. H. 1999, "Ncuro epidemic logy in rlii1 tropics," In Neurology in 'I'rttfiics, eels. J, S. Chopra, 1. M. Sawhney, B.I. Churchill Livingstone, New Delhi Davis, L. E. 1999, "Fungal infections of the central nervous system. Central nervous system infections," Neurologic Clinics, vol. 17, no. 4, pp. 761-781 del Brutto, O. H. 2000, "Central nervous system mycotic infections," Rev Neurol, vol. 30, no. 5, pp. 447-459 Luna, B„ Drew, R. H., & Perfect, J. R. 2000, "Agents for treatment of invasive fungal infections. Fungal rhinosinusitis: A spectrum of disease," Otolaryngologic Clinics of North America, vol. 2, pp. 277-299 Miszkici, K. A., Hall-Craggs, M. A., Miller, R. G., et al. 1996, "The spectrum of MR] findings in CNS cryptococcosis in AIDS," Clin Radiol, vol. 5 1 , no. 12, pp. 842-850 Porel, R. 1998, "Antifungal agents. Part I. Amphotericin R preparations and flucytosine," Mayo Clin Proc, vol, 73, pp. 1205-1225 Rees, J. R., Pinner, R. W., Hajjeh, R. A., et al. 1998, "The epidemiological features of invasive mycotic infections in the San Francisco Bay area, 1992-1993: Results of a population based laboratory active surveillance," Clin Infect Dis, vol. 27, no. 5, pp. 1138-1147 Saag, M. S., (Waybill, R. J., Larsen, R. A., et al. 2000, "Practice guidelines for the management of cryptococcal disease. Guidelines from the Infectious Diseases Society of America," Clin Infect Dis, vol. 30, no. 4, pp. 710-718 Stevens, D. A. 199,5, "Coccidioidomycosis," N Eng j Med, vol. 332, no. 16, pp. 1077-1082 Stevens, D. A. 1998, "Combination immunotherapy and antifungal chemotherapy," Clin Infect Dis, vol. 26, no. 6, pp. 1266-1269 Van der Horst, C. M., Saag, M. S„ Cloud, G. A., et al. 1997, "Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Croup and AIDS Clinical Trials Group," N Eng) Med, vol. 337, pp. 15-21 Wheat. I.. J., Rarreiger, R. i-'., LV Sathapatayavongs, B. 1990, "Hisioplasma capiuiatttm infections of the central nervous system: A clinical review," Medicine, vol. 69, no. 4, pp. 244-260
Chapter 59 Infections of the Nervous System D. PARASITIC INFECTIONS Madhuri Behari, Sumit Singh, and Ashok Verma 25% of adult population aged between 15 and 49 is HIV infected. The epidemic in Asian countries, particularly India and Thailand, has lagged temporarily behind that in Africa; however, the number of new cases in these countries is accelerating rapidly (Anonymous 2002). In the United States, the cumulative number of AIDS cases reported to the Centers for Disease Control and Prevention (CDC) as of December 2001 was 816,149. Adult and adolescent AIDS cases were at 807,075, with 666,026 males and 141,048 females, and 9074 were children under age 15. The total number of AIDS deaths reported during this period is 467,910, including 462,653 adults and adolescents, 5257 children under age 15, and 388 persons whose age at death is unknown. It is estimated that between 650,000 and 900,000 adults and adolescents in the United States are living with HIV infection, including 120,000 to 160,000 women. This estimate results in an overall nationwide prevalence of HIV infection of approximately 0.3%. The number of new infections per year is estimated to be approximately 40,000, and this number has remained stable for several years (Fauci 1999). Following the use of the highly active anti retroviral therapy (HAART), the death rate from AIDS declined 4 0 % from 1996 to 1998, and it has further declined over the subsequent years. It is currently the fifth leading cause of 1581
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NEUROLOGICAL DISEASES
death among Americans aged 25 and 44, having dropped from first within the past six years. The high prevalence and striking diversity of neurological disorders complicating AIDS were recognized early in the epidemic (Snider et al. 1983). Neurological opportunistic infections (OIs} and malignancies predominated in early reports, but it became also clear that AIDS was associated with distinct neurological syndromes, such as dementia, myelopathy, and painful neuropathy, that appeared to result from the HIV itself. It also became recognized that the risk of neurological complications increased with the progression of the HIV infection and decline of the C D 4 " T cell counts. Clinically apparent neurological disease develops in approximately one half of HIV-infected patients. Neuropathological abnormalities arc nearly universal in patients dying with AIDS, suggesting subclinical disease, underdiagnosis, or both. Neurological disorders cause significant morbidity and mortality, and they may be the AIDS-defining illnesses in previously asymptomatic HIV disease or, occasionally, hetald unrecognized HIV infection. Nervous system complications may directly lineal en life, as well as impair ability to comply with complex HA ART regimens necessary to manage HIV disease optimally. These disorders affect every level of the neuraxis, and a given patient may suffer more than one HIV-associated neurological disease. Familiarity with the common HlV-telated neurological syndromes (Tables 59E.1 and Tables 59E.2) facilitates their recognition, even in the medically complex patient with several medical and neurological diagnoses. The stage of systemic HIV infection influences both the risk of neurological disease, .is well as likely ecologies, and hence C D 4 + T cell count provides critical information that helps guide the evaluation (Figure 59E.1). In early infection, corresponding to C D 4 + T cells greater than 500/jiL, autoimmune disorders, such as demyelinating neuropathies, may develop. During midstagc infection, or C D 4 + T cell levels of 200-5 00/uL, ptimary HIV-reiated disorders, such as dementia, may become symptomatic, as may some infections such as varicella-zoster virus (VZV) radiculitis (shingles). In advanced HIV infection, defined as C D 4 ' T cell count less than 200/uL, the risk of dementia, myelopathy, and painful neuropathy increases further, and patients become vulnerable to major OIs such as cerebral toxoplasmosis, progressive multifocal leukoencephalopathy (PML), and cryptococcal meningitis, as well as to neoplasms such as primary central nervous system lymphoma (PCNSL).
Table S9E.1: Major HIV-associated CNS disorders classified by neuroanatomical localization Meninges Aseptic HIV meningitis C) ry p toeocca l meningitis Tuberculous meningitis Syphilitic meningitis Listeria monocytogenes meningitis Lymphomatous meningitis (metastatic! 15 rain Predominantly nonfocal HIV-associated dementia (HAD) HIV-associated minor cognitive motor dysfunction (MCMD) Toxoplasmic encephalitis Cytomegalovirus (CMV) encephalitis Aspergillus encephalitis Herpes encephalitis Metabolic encephalopathy (alone or concomitantly) Predominantly focal Ore bra I toxoplasmosis Primary CNS lymphoma (PCNSL) ['in;,;:;-.\i>. •.• multifocal leukoenceplia lopa tlii I'M I i Cryptococcoma Tuberculoma Varied la-zoster virus (VZV) encephalitis Stroke Spinal cord Vacuolar myelopathy (VM) Cytomegalovirus (CMV) myeloradiculopathy VZV myelitis Spinal epidural or intradural lymphoma (metastatic) HTI.V-1-associated myelopathy
advanced disease. It is best to regard HIV disease as beginning at the time of primary infection and progressing through various stages. In most patients active viral replication and progressive immunological impairment occur throughout the course of HIV infection. With some exceptions, HIV disease in untreated patients inexorably progresses, even during the clinically latent stage. Accumulating clinical and laboratory observations clarify that the brain is infected early at the time of primary HrV infections, the infection and low-grade inflammation of brain continue through the latent phase of HIV infection, and significant central nervous system (CNS) morbidity and mortality are due to the continued CNS infection in the late stages of the HIV disease. In this context, the CNS serves as a parallel compartment to the systemic HIV disease. The CNS manifestations relate principally to the continued infection in the CNS compartment, the interaction of the virus with the systemic immune system, and the consequent failure of the immune defense system,
NATURAL HISTORY OF HIV INFECTION AND NEURO-HW DISEASE The Acute HIV Syndrome The clinical consequences of HIV infection encompasses a spectrum ranging from an acute syndrome associated with primary infection to a prolonged asymptomatic state to
It is estimated that 50-70 % of individuals with HIV infection experience an acute clinical syndtome
NEUROLOGICAL MANIFESTATIONS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION IN ADULTS Tabic 59E.2: disorders
Classification of HIV-associated neuromuscular
Peripheral neuropathies Early stages (immune dysregulation) Acute inflammatory demyclinating polyradiculoneuropathy (AIDP) Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Vasculitic neuropathy Brachial plexopathy Lumbosacral plexopathy Cranial mononeuropathy Multiple mononeuropathies Mid- and late stages (HlV-rcplieation driven) Distal sensory polyneuropathy Autonomic neuropathy Late stages (opportunistic infection, malignancy) CMV poiyradiculomyelitis Syphilitic poiyradiculomyelitis Tuberculous poiyradiculomyelitis Lymphomatouspoly radiculopathy Zoster ganglionitis CMV mononeuritis multiplex Nutritional neuropathy (vitamin Bij, BJ ?AlDS-cachexia neuropathy ?AI.S-like motor neuronopathy AH stages (toxic neuropathy) Nucleoside reverse transcriptase inhibitors (ddl, ddC, d 4 T) Other drugs (vincristine, I N H , ethambutol, thalidomide) Myopathics
Polymyositis Pyomyositis PInclusion body myositis Toxic (Zidovudine) myopathy
AlDS-cachexia myopathy
approximately 1-6 weeks after the p r i m a r y infection. T h e s y n d r o m e is typical of an acute viral s y n d r o m e a n d has been likened to acute infectious m o n o n u c l e o s i s . Fever, e r y t h e m a t o u s or m a c u l o p a p u l a r rash, h e a d a c h e , nausea, anorexia, lethargy, arthralgia, sore t h r o a t , a n d l y m p h a d e QOpathy occur in different c o m b i n a t i o n s in this s y n d r o m e . Neurological manifestations occur in a p p r o x i m a t e l y 10 % of cases at the time of initial H I V infection. Several general principles of this early interaction a r e a p p a r e n t . First, the neurological complication, as also the seroconversion s y n d r o m e , usually occurs 1-6 weeks after t h e e x p o s u r e and primary infection. Second, the neurological presentation frequently involves multiple parts of t h e n e r v o u s system, a l t h o u g h one p a r t is usually d o m i n a n t . T h i r d , the illness is m o n o p h a s i c , with t h e majority of patients recovering within weeks. Meningitis, meningoencephalitis of varying severity, seizures, m y e l o p a t h y , a n d cranial and peripheral n e u r o p a t h i e s have all been linked to the p r i m a r y H I V infection or seroconversion. Occasionally, o p p o r t u nistic C N S infections have been reported d u r i n g this stage of infection, reflecting the t e m p o r a r y immunodeficiency that results from the reduced n u m b e r a n d the likelydysfunction of CD4""" T cells. In a review of 1 3 9 published
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cases of p r i m a r y HIV infection, e n c e p h a l o p a t h y a n d n e u r o p a t h y were each reported in 8% of the cases (Clark ct al. 1 9 9 1 ) . Meningitis and less severe s y m p t o m s , such as h e a d a c h e , h a v e been reported in up to 3 0 - 4 5 % of patients. L a b o r a t o r y analysis at this stage (with or w i t h o u t neurological disease) reveals cerebrospinal fluid (CSF) a b n o r m a l i t y with mild m o n o n u c l e a r pleocytosis a n d m o d e r a t e rise in protein. Imaging of the brain is usually n o r m a l , w h e r e a s the e l e c t r o e n c e p h a l o g r a m (EEC) m a y be diffusely or focally slow in b r a i n - s y m p t o m a t i c cases. T h e diagnosis of these neurological s y n d r o m e s can be difficult because they are indistinguishable from o t h e r acute vital or postinfectious s y n d r o m e s , m o s t of w h i c h are self-limiting a n d never achieve specific diagnoses. M o s t patients recover s p o n t a n e o u s l y from these acute systemic a n d neurological H I V s y n d r o m e s in one to several w e e k s and a r e left with only a mildly depressed C D 4 h T cell c o u n t t h a t r e m a i n s stable for a variable period of time. In m o s t cases, p r i m a r y infection with or w i t h o u t the acute H I V s y n d r o m e is followed by a p r o l o n g e d period of clinical latency.
T h e A s y m p t o m a t i c or Latent Stage A l t h o u g h t h e length of time from initial infection to the d e v e l o p m e n t of clinical AIDS varies greatly, t h e median time for u n t r e a t e d patients is a p p r o x i m a t e l y 10 years. D u r i n g this a s y m p t o m a t i c p h a s e the virus is actively replicating, a n d t h e disease is gradually progressing. T h e rate of disease progression is directly correlated with H I V R N A levels (viral load). Patients with high vital load in the plasma progress to s y m p t o m a t i c disease faster t h a n do patients with a l o w viral load. During a s y m p t o m a t i c H I V infection, t h e average rate of C D 4 + T cell decline is a p p r o x i m a t e l y 5 0 / u L per year. W h e n the C D 4 ~ T cell c o u n t falls to < 2 0 0 / u L , the resulting state of immunodeficiency is severe e n o u g h to place the patient at high risk of OIs a n d n e o p l a s m s . Evidence indicates t h a t the C N S c o n t i n u e s t o h a r b o r a n d m o u n t a host reaction to the H I V t h r o u g h the a s y m p t o m atic or latent stage, yet w i t h o u t a p p a r e n t immediate clinical sequelae. T h e CSF in patients with latent H I V infection generally s h o w s a b n o r m a l i t i e s , including a b n o r m a l cell c o u n t , protein and i m m u n o g l o b u l i n , and local synthesis of a n t i - H I V antibodies within the C N S c o m p a r t m e n t ; the intact virus can be recovered from the CSF (Price 1 996). Pathological studies h a v e s h o w n evidence of inflammatory reactions in the C N S , with perivascular m o n o n u c l e a r cell infiltrations, a l t h o u g h t h e H I V R N A b u r d e n , as evident by polymerase chain reaction (PCR) from CSF and brain s a m p l e s , a p p e a r s to be negligible at this stage. Neither overt n o r subclinical cognitive or m o t o r dysfunction a p p e a r s to be c o m m o n in t h e early latent stage. F r o m a practical s t a n d p o i n t , t h e risk of isolated cognitive decline in a s y m p tomatic individuals is sufficiently small as to p r o v i d e no
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NT.UROr.OGICAI. FITSFASFS
FIGURE 59E.1 Systemic and neurological events in human immunodeficiency virus (HIV) infection. Temporal sequence is ^ppni^iin.iv: ;md indicates the increasing risk oi systemic and neurological complications as HIV infection advances. [CMYT — Cytomegalovirus encephalitis; CMV-PR = CMV polyradiculitis; CNS = central nervous system; CSF = cerebrospinal fluid; ITP = idiopathic thrombocytopenic purpura; Ols = opportunistic infections; PML = progressive multifocal leukoencepbalopathy; PNS — peripheral nervous system.) 'Includes, in addition to HIV-related meningitis and asymptomatic cerebrospinal fluid abnormalities, meningoencephalitis, acute demyelinating syndromes, myelopathy. Includes, in addition to acute inflammatory demyelinating polyneuropathies, sensory ganglioneuritis, brachial plexitis, and rhabdomyo lysis. Common neurological syndromes are in bold italics.
basis for disability or disqualification from work based simply on HIV-positive status. Some patients who are termed "long-term nonprogressors" show little if an\ decline in ( 1)-1 ! I cell comic-, over a prolonged period of time (Samson et al. 1996). These patients generally have extremely low levels of HIV RNA, Certain other patients remain entirely asymptomatic despite the fact that their CD4 h T cell counts show a progressive decline to extremely low levels. In these patients, the appearance of a systemic or CNS opportunistic infection may be the first manifestation of HIV disease. The length of asymptomatic stage is determined by the viral and host factors.
Symptomatic Stage Following the initial burst of viremia during primary infection, HIV-infected individuals generally mount a
robust immune response that usually curtails the level of viremia and likely contributes to delaying the ultimate clinically apparent disease. The host immune response is directed against multiple antigenic determinants of the HIV virion as well as against viral proteins expressed on the surface of infected cells. Ironically, those C D 4 + T cells with T cell receptors specific for HIV are the cells most likely to bind to the virus, be infected, and themselves be destroyed. Thus, the early consequence of HIV infection may be dysimmune in the face of persistent high antigenemia, and the late consequence is an immunocompromised state, through the elimination of HIV-spccific C D 4 + T lymphocytes. HIV-associated neurological complications in late-stage HIV infection include primary manifestations, secondary complications related to the Ols and neoplasia, and complications arising from antiretroviral or prophylactic therapy. The primary neurological complications include HIV-associated dementia (HAD) or its less severe form,
NEUROLOGICAL MANIFESTATIONS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION IN ADULTS
minor cognitive motor dysfunction (MCMD), vacuolar myelopathy (VM), and distal sensory polyneuropathy (DSP). Generally, the nature and severity of illnesses (systemic and neurological) that one observes change as the C D 4 + T cell count progressively declines. The frequent and life-threatening complications of HIV infection occur in patients with C D 4 + T cell count 100/uL may not require continued prophylaxis after 3-6 months prophylactic therapy. Rarely, toxoplasmosis manifests as acute meningoencephalitis, variably accompanied by muscle involvement (Gherardi et al. 1992), In the even more unusual circumstance in which the diagnosis is made premortem, antiroxoplasma therapy may be lifesaving. Patients with CD4 1 T cell counts 100/uL at baseline and the ability to maintain an HIV viral load of less than .500 copies per milliliter. Baseline viral load docs not seem to have independent predictive value of survival. Unfortunately, immune reconstitution takes considerable time, in some cases longer than the survival expectation from PML and, hence, the necessity to develop therapy directed against the JC virus. Cidofovir, a drug used for cytomelovirus in AIDS patients, topotecan, a topoisomerase inhibitor, and IFN-a have been tried in AIDS-related PML with varying, generally unsatisfactory, results (Gasnault et al. 2001; Dworkin 2002). HIV-associated
Vacuolar
Myelopathy
VM is the most common cause of spinal cord dysfunction in patients with AIDS, apparent pathologically in 2 5 - 5 5 % of AIDS autopsy series (Dal Pan et al. 1994; Dt Rocco and Simpson 1998). VM complicates late HIV infection and frequently coexists with HAD and DSP. Affected patients develop gait difficulty, caused by spasticity, leg weakness, and impaired proprioception, often accompanied by sphincter dysfunction, evolving over several months. Back pain is not a prominent feature. Examination reveals spastic paraparesis with Babinski's signs and hyper-reflexia, unless concomitant neuropathy is severe. Sensation in the legs,
NEUROLOGICAL MANIFESTATIONS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION IN ADULTS
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FIGURE 59E.7 Pyogenic brain abscess in AIDS. Postgadolinium axial T'l-W-MRI showing ring-enhancing lesion (A) with surrounding edema best seen in T2-W sequence (B) and with associated intralesional diffusion restriction (DW-MRI, C). (Courtesy Dr. S. Ouanounou.) particularly proprioception and vibratory sense, is usually impaired, but a clear sensory level on the trunk is unusual. The arms are typically spared until VM is advanced. MRI may occasionally reveal cord atrophy, but usually is unremarkable. Pathological findings are most striking in the dorsolateral thoracic cord and include vacuolar changes in myelin sheaths with relative preservation of axons. Despite the clinical and pathological resemblance to combined systems degeneration, vitamin Bi 2 levels are typically
normal in affected patients. HIV-induced release of neurotoxic cytokines or abnormalities in vitamin B12 utilization may contribute to the development of VM. Evidence that viral control can result in unproved neurological function is not well documented in VM, but there are such reports, making the effort to control the infection important. Additionally, VM is often associated with HAD, in which improvement following HA ART and virus control is better documented. One should construct a
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NEUROLOGICAL DISEASES
potent and toletahle regimen individualized to the patient's virus and medical history (discussed previously, principles of antiretroviral therapy). Patients with myelopathy and paraplegia require considerable assistance, comparable with that fot multiple sclerosis patients with severe spinal cord demyelination. Care of the neurogenic bladder, bladder infection, management of limb spasticity, prevention of skin breakdown and dccubiti, and assist devices to improve mobility are the issues that tequire individualized attention, Numerous other infectious, neoplastic, and metabolic disorders occasionally cause myelopathy in patients with HIV infection, and they need to be differentiated from VM. Compared with VM, these disorders may progress more rapidly, often with associated back or radicular pain. CMV, VZV, and herpes simplex virus may cause myelitis. Helpful diagnostic tests include spinal MRI, which may teveal cord swelling with intramedullary enhancement and T2 signal changes, and CSF PCR testing for viral DNA. Because HIV shares risk factors with human T-cell lymphotropic virus I and II, cotnfection with these retroviruses ;iko may cause myelopathy ill the HIV-infected patient. Othet causes of myeloneuropathy complicating HIV infection include neurosyphilis and vitamin B l 2 deficiency. HIV-infected parenteral drug users may develop spinal epidural abscess, a neurosurgical emergency whose clinical manifestations do not appear to be significantly modified by HIV infection (Heary et al. 1994). Rarer infectious causes of myelopathy include M. tuberculosis and T. sioiulii. Patients with AIDS arc susceptible to systemic lymphoma, which can cause myelopathy ftom epidural metastases. Stroke Cerebrovascular disease also causes focal brain dysfunction in HIV infection. Ischemic and hemorrhagic stroke have been reported in up to 4% of clinical series and up to 34% of autopsy series (Pinto 1996). Whether HIV infection itself elevates stroke risk remains uncertain. Thrombocytopenia, coagulopathy related to liver disease or disseminated intravascular coagulation, PCNSL, metastatic Kaposi's sarcoma, and rarely, toxoplasmosis, may be associated with cerebral hemorrhage. Causes of ischemic stroke include bacterial endocarditis, particularly in IDUs, as well as nonbacterial thrombotic endocarditis, vasculitis, and procoagulant states. Granulomatous angiitis of the nervous system has been reported in AIDS. VZV, tuberculous meningitis, and meningovascular syphilis can cause infectious vasculitis, as can the angioinvasivc fungi Aspergillus and Mucar. Other Focal CNS Disorders Numerous other infections have been reported to cause focal cerebral dysfunction in HIV-infected patients.
Bacteremia from indwelling catheters needed to manage other aspects of HIV infection or from parenreral drug use predisposes to bacterial brain abscess (Figure 59E.7). Other bacterial causes of focal cerebral dysfunction include Mycobacterium tuberculosis abscess, syphilitic gumma, Bartotiella henselae (Marra 1995), and Nocardia asteroides. Fungal causes of focal brain disease, in addition to the angioinvasive fungi discussed previously, include cryptococcoma, Blastomyces dermatitidis, and Histoplasma capsulatum (Minamoto and Rosenberg 1997}. Among parasites, relevant diagnostic considerations in patients who have lived in or traveled through endemic areas arc cysticercosis and intracerebral Chagas' disease {Trypanosoma cruzii) (Gluckstein et al. 1992). VZV can cause a demyclinating syndrome with lateralmng fearures (Gray et al. 1994), and CMV has been reported to cause mass lesions (Moulignier et al. 1996). Interestingly, HIV infection docs not appear to increase significantly the risk for herpes simplex virus encephalitis.
H1V-ASSOCIATED NEUROMUSCULAR DISORDERS Neuropathies Peripheral neuropathies are common in HIV infection (Sadler and Nelson 1997; Wulff et al. 2000; Verma 2001; Sacktor 2002). Peripheral neuropathies complicate all stages of the HIV disease and cause considerable morbidity and disability in HIV-infected individuals and AIDS patients. Although symptomatic neuropathy occurs in approximately 10 to 1 5 % of HIV-infected patients overall, pathological evidence of peripheral nerve involvement is present in virtually all end-stage AIDS patients. There are five major clinical types of HIV-associatcd neuropathies that are regularly seen in large HIV clinics: DSP, acute and chronic inflammatory demyelination polyradiculoneuropathies (AIDP and CIDP), CMV-associated polyradiculomyelopathy, and nucleoside-associated toxic neuropathies. A vasculitic neuropathy is less common but often responds well to corticosteroid treatment. Distal
Sensory
Polyneuropathy
Of the various peripheral nerve syndromes that complicate HIV infection, the most common is DSP, also called HIVassociated neuropathy or AIDS neuropathy. This axonal, predominantly sensory, length-dependent polyneuropathy develops in approximately one third of patients with AIDS, becoming more prevalent as the CD4~ T cell count decreases (Sadler and Nelson 1997; Childs et al. 1999). Depressed or absent ankle jerks and mild pain, Temperature, and vibratory sensory loss in the feet, with or without associated foot parcsthesiae and numbness, may be the only evidence of the disorder, and probably make up the more common clinical syndrome. Less frequently, severe burning
NEUROLOGICAL MANIFESTATIONS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION IN ADUITS
1599
pain and parcsthesiae develop in the feet, often disrupting sleep in a manner reminiscent of diabetic or nutritional sensory polyneuropathies. Symmetrical involvement is a characteristic clinical feature, and the hands are usually spared until the disorder is advanced. F.ven though DSP typically spares motor function and proprioception, walking may be impaired because of severe pain. The pathogenesis of DSP is not well understood. Cytokine upregulation in advanced infection has been proposed, as have dorsal root ganglion toxicity of HIV antigens and the effects of chronic, multisystemic illnesses.
neuropathy over several months, although coasting, in which symptoms worsen for several weeks before improvement, may complicate the evaluation of this strategy for diagnosis. Although pre-existing DSP increases the risk for nucleoside neuropathy, many patients with DSP tolerate neurotoxic anciretrovirals, particularly if the dose is kept low. Similarly, many patients who develop nucleoside neuropathy can resume therapy at a lower dose or may tolerate a different neurotoxic drug. Other aspects of the evaluation and treatment are similar to DSP.
The rather typical clinical features usually obviate the need for electromyography and nerve conduction studies. Exposures to neurotoxins, including ethanol, should be reviewed. Neurotoxic drugs commonly used to manage HIV infection include the nucleoside analogs didanosine, zalcitabine, and stavudine (see Table 59H.3), in addition to isoniazid, pyridoxine, dapsone, metronidazole, and vincristine. Screening for vitamin B 1 2 deficiency and diabetes mellitus is important. Goals of treatment include minimizing neurotoxic exposures, virus suppression by HAART, and management of pain. Tricyclic antidepressants and anticonvulsants ameliorate neuropathic pain in DSP. When there is coexisting dementia or other cerebral disease, the anticholinergic effects of amitriptylinc may be poorly tolerated. Using very low doses or switching to a less anticholinergic tricyclic antidepressant such as nortriptyline, plus addition of a selective serotonin reuptake inhibitor, may facilitate tolerance. With regard to anticonvulsants, the high rate of adverse reactions and drug interactions with carbamazepine in patients with AIDS limits its utility for the management of neuropathic pain, The favorable side effect and drug interaction profile of gabapentin makes it the treatment of choice for managing neuropathic pain in AIDS. Mexiletine, selective serotonin reuptake inhibitors and topiramate have been tried with variable success, A recent trial with nerve growth factors failed to show clinically significant improvement. Topical capsaicin is an appealing choice for select patients with DSP. but is rarely dramatically beneficial. Other occasionally useful adjuncts include nonsteroidal anti-inflammatory drugs, transcutaneous electrical nerve stimulator units, and acupuncture, but some patients may require chronic narcotic therapy.
inflammatory Demyel'mating
Nucleoside
Analogue-Associated
Toxic
Neuropathy
A painful polyneuropathy that closely resembles DSP is the major dose-limiting toxicity of the nucleoside analogue antiretroviral agents didanosine, zalcitabine, and stavudine (Verma 2001; Sacktor 2002). Two clinical features can help distinguish nucleoside neuropathy from DSP. First, nucleoside neuropathy typically evolves over weeks following initiation of therapy, in contrast to DSP, which progresses over months or even years. Second, stopping the offending agent eventually leads to regression of nucleoside
Polyradiath>!u-itrojhHk'w). The current gold standard test for HIV infection in infancy is HIV-DNA PCR on peripheral blood lymphocytes. Because most infants are infected intrapartum and circulating HIV levels may still be very low, HIV DNA cannot be amplified from the plasma in all infected infants at birth. Indeed a positive HIV-DNA PCR result within 48 hours of birth has been taken as evidence of intrauterine transmission. Finally, 1 iPE, clinical equivalent of HIVassociated dementia (HAD) in adults, is more frequent in children and is generally more amenable to treatment with HAART. The current classification system of infection used for children was revised in 1994 prior to the availability of measurements of HIV plasma viremia. This classification is based on clinical signs and symptoms, giving a clinical score (Table 59F.1), as well as age-related CD4+ T cell count, giving an immunological score (Table 59F.2). Clinical signs and symptoms are allocated to four categories: N (none), A (mild), B (moderate), and C (severe). OIs and other conditions associated with an AIDS diagnosis are all category C. Originally, LIP was an AlDS-defining diagnosis, despite its good prognosis, but it is now listed as a category B condition (see Table 59F.1).
NEUROLOGICAL MANIFESTATIONS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION IN CHILDREN Table 59F.1:
1607
Symptom categories of HIV disease in children
Category N: Not symptomatic No signs or symptoms considered to be the result of HIV-1 infection or only one of the conditions listed in category A. Category A: Mild symptomatic Two or more conditions listed following, but none of the conditions listed in categories B and C: Lymphadenopathy (0.5 cm or greater at more than two sites; bilateral = one site) Hepatomegaly Splenomegaly Dermatitis Parotitis Recurrent or persistent upper respiratory infection, sinusitis, or otitis media Category B: Moderately symptomatic Symptomatic conditions other than those listed for categories A or C that are attributed to HIV infection. Including: Anemia (2 months
Cardiomyopathy Cytomegalovirus infection with onset before age I month Diarrhea, recurrent or chronic Hepatitis Herpes simplex virus stomatitis, recurrent (i.e., >2 episodes within I yr) Herpes simplex vims bronchitis, pneumonitis, or esophagitis with onset before age 1 mo Herpes zoster (i.e., shingles) involving at least two distinct episodes or more than one dermatome I i-iomj nsarcoma Lymphocytic interstitial pneumonia or pulmonary lymphoid hyperplasia coinpleN Nephropathy Nocardiosis Fever lasting > 1 month Toxoplasmosis with onset before age 1 month Varicella, disseminated (i.e., complicated chickenpox) Category C: Severely symptomatic Any condition listed in the 1987 surveillance case definition of AIDS, with the exception of lymphocytic interstitial pneumonia (which is a category B condition).
Adapted from Centers for Disease Control and Prevention. 1994, "Revised classification system for human immunodeficiency virus infection in children less than 13 years of age," MMWR, vol. 43, no. 12, pp. 1-10.
AIDS-RELATED NEUROLOGICAL DISORDERS Neurological disorders associated with HIV may be divided into two major categories: (1) HIV-associated primary neurological diseases (e.g., HPE, a syndrome complex with cognitive, motor, and hehavioral features related to primary HIV CNS infection), and (2) HIV-associated secondary neurological complications (e.g., disorders related to immunosuppression). The secondary complications include CNS neoplasms, CNS infections caused hy pathogens other than HIV, and strokes. The child's nervous system may also be adversely affected by complications related to systemic HIV disease and its therapy and metabolic and toxic complications associated with and retro viral therapy. These conditions are not mutually exclusive, and coexisting pathological conditions are common at the same or different anatomical levels of the nervous system in HIV-
Table 59F.2:
infected children. Ncurodevelopmental status may also be affected by non-HIV-related comorbid conditions. Some of these conditions relate to maternal high risk factors during pregnancy (malnutrition, drug abuse), complications in the perinatal period (premature birth), as well as postnatal psychosocial stressors. OIs, neoplasia, neuromuscular i:i.im\-.uiiiiM.v and antircu-m iral i:ui\ip\ i v h u o compli cations associated with HIV infection arc described in Chapter 59E.
HIV-ASSOCIATED PROGRESSIVE ENCEPHALOPATHY (HPE) Neurological involvement associated with pediatric AIDS was reported early in the AIDS epidemic. Longitudinal follow-up of HIV-infected children showed several patterns
Immune categories of 1 IIV disease in children CD4+- T ceil: No./fiL(%)
Immune
category
Category L(no suppression, N l ) Category 2:(modcrate suppression, N2) Category 3:(severc suppression, N3)
< 12 months
J - 5 years
6-12 years
> 1,500 ( > 2 5 ) 750-1499 (15-24) 25) 500-999 (15-24) 25) 200-499 (15-24) ^, p. 117 Eraser, H., & DiDario, A. (.',., 1978, "Studies of the lymphoreticulat system in the pathogenesis of scrapie: The role of spleen and t h y m u s , " / Comp Pathol, vol. 88, pp. 563-573 Gabizon, R., Meiner, Z,, Cass, C, et al. 1991, "Prion protein gene mutation in Libyan Jews with Creutzfeldt-Jakob disease," Neurol, vol. 4 1 , p. 160 Gabizon, R., Telling, G., Meiner, Z., cf al. 1 996, "Insoluble wildtype and ptotease-tesistant mutant prion protein in brains of patients with inhetited prion disease," Nature Med, vol. 2, pp. 59-64 Gajdusek, D. C, Gibbs, C. J., Jr., & Alpers, M. 1966, "Experimental transmission of a kuru-like syndrome to chimpanzees," Nature, vol. 209, pp. 794-796 Gambetti, P., Medori, R., Tritschler, H., et a!. 1992, "Fatal familial insomnia (Ffi)—a prion disease with a mutation at Codon-178 of the prion protein gene," / Neuropath Exp Neurol, vol. 5 1 , p. .^S^ Gambetti, P., Parchi, P., Petersen, R, B., et al. 1995, "Fatal familial insomnia and familial Creutzfeldt-Jakob disease—clinical, pathological and molecular-features," Brain Pathol, vol. 5, pp. 43-51 Gcrstmann, J., Straussier, E., 6c Scheinker, I. 1936, "Uber eine eigenartige here ditar-f am ilia re erkrankung des zentralnervensystems sugleich cm beitrag zur fragc des vorzeitigen lokalen alterns," Z Neurol, vol, 154, pp. 736-762 Ghetti, B., Dlouhy, S. R., Giacconc, G., et al. 1995, "GcrstmannStraussler-Schcinkcr disease and the Indiana kindred |Reviewj," Brain Pathol, vol. 5, pp. 61-75 Ghetti, B., Piccardo, P., Fariow, M. R., et al. 1996, "Distribution of abnormally phosphorylated tau in Gerstmann-StrausslerScheinker disease with mutation at codon 198 of the prion protein gene," Neurol, vol. 46, p. 2065 Ghetti, B., Piccatdo, P., Frangione, B., et al. 1996, "Prion protein hereditary amyloidosis: Parenchymal and vascular," Semin Virol, vol. 7, pp. 189-200 Ghetti, B., Piccatdo, P., Spillantini, M. G., et al, 1996, "Vascular variant of prion protein cerebral amyloidosis with T-positive neurofibrillary tangles: The phenotype of the stop codon
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Klatzo, I., Gajdusek, D. C, & Zigas, V. 1959, "Pathology of kuru," Lab Invest, vol. 8, pp. 799-847 Klatzo, I., Wisniewski, H. M., & Streicher, E. 1965, "Experimental production of neurofibrillary degeneration," / Neuropath Exp Neurol, vol. 24, pp. 187-199 Klein, M. A., Frigg, R., Rechsig, E. et al, 1997, "A crucial role for 15 cells in ncuroinvasive scrapie," Nature, vol. 390, pp. 687-690 kiiopnuiii, D. S., DeKosky, S. T., Cummings, J. L. et al. 2001, "Practice parameter: Diagnosis of dementia (an evidence-based review)—Report of the Quality Standards Subcommittee of the American Academy of Neurology," Neurol, vol. 56, pp. 1143-1153 Korth, C, May, B. C, Cohen, F. E., & Prusiner, S. B. 2001, "Acndine and phenothiaziuc derivatives as pharmacothcrapcutics for prion disease," Proc Natl Acad Sci USA, vol. '>K, pp. 9836-9841 Kretzschmar, H. A., Gicsc, A., Brown, I"). K.. el al. 11>97, 'Cell death in prion disease," J Neur Tra?is, vol. 104, pp. 191-210 Kretzschmar, H., Prusiner, S. B., Stowring, L. F.., & DcArmond, S, J., 1986, "Scrapie prion protein are synthesized in neurons," Am J Pathol, vol. 122, pp. 1-5 Laplanche, J. L., Chatclain, J., Westaway, I)., et al. 1993, "PrP polymorphisms associated with natural scrapie discovered by denaturing gradient gel-electrophoresis," Genomics, vol. 15, pp. 30-37 Libcrski, P, P., Guiroy, D. C, Williams, E. S., et al. 2001, "Deposition patterns of disease-associated prion protein in captive mule deer brains with chronic wasting disease," Acta Neuropathol, vol. 102, pp. 496-.500 Manetto, V., Medori, R., Gortelli, P., et al. 1992, "Fatal familial insomnia—clinical and pathological-study of .5 new cases," Neurol, vol. 42, pp. 312-319 Masters, C. L., Gajdusek, D. C, & Gibbs, C. J. 1981, "The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease," Brain, vol. 104, pp. 535-558 Masters, C. L., & Richardson, E. P. 1978, "Sub-acute spongiform encephalopathy (Creutzfeldt-Jakob Disease)—nature and progression of spongiform change," Bram, vol. 101, pp. 333-344 Mastrianni, J. A., Nixon, R., Layzet, R., et al. 1999, "Prion protein uintormatioii .:: .1 p.iticnl with spm-adit ratal niM>m nia," N Eng ] Med, vol. 340, pp. 1630-1638 Mcdori, R., Montagna, P., Tritschlcr, H. J., et al. 1992, "Fatal familial insomnia—A 2Nd kindred with mutation of prion protein gene at Codon-178," Neurol, vol. 42, pp. 669-670 Medori, R., Trischlcr, H. J., LeBlanc, A., et al. 1992, "Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene," N Eng J Med, vol. 326, pp. 444-449 Mittal, S., Farmer, P., Kalina, P., et al. 2002, "Correlation of diffusion-weigh ted magnetic resonance imaging with neuropathology in Creutzfeldt-Jakob disease," Arch Neurol, vol. 59, pp. 128-134 Murata, T., Shiga, Y., Higano, S., et al. 2002, "Conspicuity and evolution of lesions in Creutzfeldt-Jakob disease at diffusionweighted imaging," Am J Neuroradiol, vol. 23, pp. 1164-1172 Oesch, B., Westaway, D„ Wakhli, M., et al. 1985, "A cellular gene encodes scrapie PrP 27-30 protein," Cell, vol. 40, pp. 735-746 Otto, M., Wiltfang, )., Cepek, [.., et al. 2002, "Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease," Neurol, vol. 58, pp. 192-197
PRION DISEASES Owen, F., Poulter, M., Lofthouse, R., et al. 1989, "Insertion in prion pro re in gene in familial Creutzfeldt-Jacob disease," Lancet, vol. 1, pp. 51-52 Palmer, M. S., Dryden, A. J., Hughes, J. T., & Collinge, J. 1991, "Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease," Nature, vol. 352, pp. 340-342 Parchi, P., Capellari, S., Chin, S., et al. 1999, "A subtype of sporadic prion disease mimicking fatal familial insomnia," Neurol, vol. 52, pp. 1757-1763 Parchi, P., Castellani, R., Capellari, S., et al. 1996, "Molecular 1I.L-.I-- DI phenorypic variabilit; in sporadic O v u r / k l d i |acoh disease," Ann Neurol, vol. 39, pp. 767-778 Parchi, P., Giese, A., Capellari, S., et al. 1999, "Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects," Ann Neurol, vol. 46, pp. 224-233 Pearlman, R. L., Towfighi, J., Pezeshkpour, G. H., et al. 1988, "Clinical-significance of types of cerebellar amyloid plaques in human spongiform encephalopathies," Neurol, vol. 38, pp. 1249-1254 Piccardo, P., Ghctti, B., Dickson, D. W., e t a l . 1995, "GerstmannStraussler-Scheinker disease (PRNP P102L): Amyloid deposits are best recognized by antibodies directed to epitopes in PrP region 90-165," / Neuropath Exp Neurol, vol. 54, pp. 790-801 Piccardo, P., Seller, C, Dlouhy, S., et al. 1996, "Proteinase K (PK) resistant prion protein (PrP) isoforms in Gerstmann-SttausslerScheinker disease (CSS) FT98S," / Neuropath Exp Neurol, vol. 55, p. 125 Prusiner, S. B. 1982, "Novel proteinaceous infectious particles cause scrapie," Science, vol. 216, pp. 136-144 Prusiner, S. B. 2001, "Neurodegenerative diseases and prions," N Eng} Med, vol. 344, pp. 1516-1526 Prusiner, S. B., Scott, M. R., DcArmond, S. J., & Cohen, F. E. 1998, "Prion protein biology," Cell, vol. 93, pp. 337-348 Qin, K., Yang, Y., Mastrangelo, P., & Westaway, D. 2002, "Mapping Cu(Il) binding sites in prion proteins by diethyl pyrocarbonate modification and matrix-assisted laser desorption ionization-time of flight (MAI,Dl-TOF) mass spectrometrie footprinting," j Biol Chemt vol. 277, pp. 1981-1990 Qin, K., Yang, D. S., Yang, Y„ et al. 2000, "Copper(II)-induced conformational changes and protease resistance in recombinant and cellular PrP. Effect of protein age and deamidation," / Biol Cbem, vol. 275, pp. 19121-19131 Raymond, G. J., Bossers, A., Raymond, L. D., et al. 2000, "Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease," EMBO j, vol. 19, pp. 4425-4430 Scott, M. R., Will, R., Ironside, J., et al. 1999, "Compelling transgeneric evidence for transmission of bovine spongiform encephalopathy prions to humans," Proc Natl Acad Sci USA, vol. 96, pp. 15137-15142 Scipclt, M., Zcrr, I., Nau, R., ct al. 1999, "Hashimoto's encephalitis as a differential diagnosis of Creutzfeldt-Jakob disease," / Neurol Neurosurg Psychiatry, vol. 66, pp. 172-176 Sigurdsson, E. M., Brown, D. R., Daniels, M., et al. 2002, "Vaccination delays the onset of prion disease in mice," Am J Pathol, vol. 161, pp. 13-17 Sigurdsson, F^. M., Permannc, B., Soto, C, ct al. 2000, "In vivo reversal of amyloid f) lesions in rat brain," J Neuropath Exp Neurol, vol. 59, pp. 11-17 Siijuril-ison, !•'.. M., Scholr/ova, II., Mchr.i, P., er ,il. 2001, "Immunization with a noutoxic/nonfibrillar amyloid-/?
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homologous peptide reduces Alzheimer's disease associated pathology in transgenic mice," Am J Pathol, vol. 159, pp. 439-447 Snow, A. D., Kisilevsky, R., Willmcr, J., et al. 1989, "Sulfated Glycosaminoglyeans in Amyloid Plaques of Prion Diseases," Acta Neuropathol, vol. 77, pp. 337-342 Snow, A. D., Wight, T. N., Nochlin, D., ct al. 1990, "Immunolocaiization of heparin sulfate proteoglycans to the prion amyloid plaques of Gerstmann-Strausslcr-Schcinker syndrome, Creutzfeldt-Jacob disease and scrapie," Lab Invest, vol. 63, pp. 601-611 Soto, C, Kascsak, R. J., Saborio, G. P., et al. 2000, "Reversion of prion protein conformational changes by synthetic /3-shect breaker peptides," Lancet, vol. iSS, pp. 192-197 Sparkes, R. S., Simon, M., Cohn, V. H,, et al. 1986, "Assignment of the Human and Mouse Prion Protein Genes to Homologous Chromosomes," Proc Natl Acad Sci USA, vol. 83, pp. 7358-7362 Tagliavim, F., McArthur, R. A., Canciani, B., et al. 1997, "Effectiveness of anthracycline against experimental prion disease in Syrian hamsters," Science, vol. 276, pp. 1119-1122 Tagliavini, F., Prelli, F., Ghiso, J,, et al. 1991, "Amyloid protein of Gersrmann-Straussier-Scheinker disease (Indiana kindred) is an 1 1 kd fragment of prion protein with an N- terminal glycine at codon 5 8 , " EMBO j, vol. 10, pp. 513-519 Tateishi, J., Brown, P., Kitamoto, T., et al. 1995, "First experimental transmission of fatal familial insomnia," Nature, vol. 376, pp. 434-435 Telling, G. C, Parchi, P., DeArmond, S. J., et al. 1996, "Evidence for the conformation of the pathologic isoform of the prion protein enciphering and ptopagating prion diversity," Science, vol. 274, pp. 2079-2082 Telling, G, C, Scott, M., Hsiao, K. K., er al. 1 994, "Transmission to Creutzfeldt-Jacob disease from human to transgenic mice expressing chimeric human-mouse prion protein," Proc Natl Acad Sci USA, vol. 9 1 , pp. 9936-9940 Telling, G. C, Scott, M., Mastnanni, [., ct al. 1995, "Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein," Cell, vol. 83, pp. 79-90 Toblcr, 1., Gaus, S. E., Deboer, T., et al. 1996, "Altered eircadian activity rhythms and sleep in mice devoid of prion protein," Nature, vol. 380, pp. 639-642 Tyler, K. L. 2003, "Creutzfeldt-Jakob disease," N Engl J Med, vol. 348, 681-682 Van Everbroeck, B., Green, A. J. E., Vanmechelen, E., et al. 2002, "Phosphorylated tau in cerebrospinal fluid as a marker for Creutzfeldt-Jakob disease," / Neurol Neurosurg Psychiatry, vol. 73, pp. 79-81 Westaway, D,, Cooper, C, Turner, S,, et al. 1994, "Structure and Polymorphism of the Mouse Prion Protein Gene," Proc Natl Acad Sci USA, vol. 9 1 , pp. 6418-6422 Westaway, D., DeArmond, S. )., Cayetanocanlas, J., et al. 1994, "Degeneration of Skeletal-Muscle, Petipheral-Nerves, and the Central-Nervous-System in Transgenic Mice Ove rex pressing Wild-Type Prion Proteins," Cell, vol. 76, pp. 1 17-129 Westaway, D., Zuliani, V., Cooper, C. M., et al. 1994, "Homozygosity for Prion Protein Alleles Encoding Glutamine171 Renders Sheep Susceptible to Natural Scrapie," Genes & Development, vol. 8, pp. 959-969 Will, R. G., Ironside, J., Zeidler, M., et al. 1997, "A new variant of Creutzfeldr-Jacob disease in the UK," Lancet, vol. 347, pp. 921-925
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Wisniewski, T,, Aucouturicr, P., Soto, C, & Frangione, B. 1998, "The prionoses and other conformational disorders," Amyloid, vol. 5, pp. 212-224 Wisniewski, T. & Sigurdsson, E, M. 2002, "Immunization treatment approaches in Alzheimer and prion diseases," Curr Neurol Neumsci Rep, vol. 2, pp. 400-404 Wisniewski, T., Sigurdsson, E. M., Aucouturier, P., & Frangione, B. 2001, "Conformation as a therapeutic target in the prionoses and other neurodegenerative conditions," in Molecular and Cellular Pathology in Prion Disease, ed H. F. Baker, Humana Press, Totowa, New Jersey
Zannsso, G., Ferrari, S., Cardone, F., et al. 2003, "Detection of pathogenic prion protein in the olfactory epithelium in sporadic Creutzfeldt-Jakob disease," N Engl } Med, vol. 348, pp. 711-719 Zerr, I. & Poser, S. 2002, "Clinical diagnosis and differential diagnosis of CJD and vCJD—With special emphasis on laboratory tests," APMIS, vol. 110, pp. 88-98 Zhang, H., Kaneko, K., Nguyen, J. T., cr al. 1995, "Conformational transitions in peptides containing two putative alpha-helices of the prion protein," / Mol Biol, vol. 250, pp. 5 1 4-526
Chapter 60 Multiple Sclerosis and Other Inflammatory Demyelinating Diseases of the Central Nervous System Michael J. Olek and David M. Dawson Pathophysiology Pathology Etiology Autoimmunity Infection Epidemiology Age of Onset Sex Distribution Mortality Geographic and Racial Distribution Genetic and Raeial Distribution Clinical Symptoms and Physical Findings Cognitive Impairment Cranial Nerve Dysfunction Impairment of the Sensoty Pathways Impairment of Motot Pathways Impairment of Cerebellar Pathways Impairment of Bladder, Bowel, and Sexual Functions Clinical Features Distinctive of Multiple Sclerosis Diagnostic Criteria Differential Diagnosis Course Prognosis Optic Neuritis Myelopathic Syndromes Neutoimaging l. i:,i:r Oi I Ll-.K I M I . W U I A I (IKY N I - M Y 1 ! [NIA I 1 \ C DIST.AM S
Table 60.4.1: MRI demonstration of space dissemination for McDonald et al. (2001) diagnostic criteria for multiple sclerosis Three or four of the following: 1. One gadolinium-enhancing lesion OR nine T2-hyperintense lesions if there is no gadolinium enhancing lesion 2. At least one infratentorial lesion 3. At least one juxtacortical lesion 4. At least three periventricular lesions (Adapted from Barkhof et al. [1997] and Tintore et al. (20001.) study of Brex ct al. (2002), which followed patients with initial demyelinating episodes for up to 14 years, in p r a c tical terms no diagnoses were encountered o t h e r t h a n MS or suspected M S . Rarely, cases of postinfectious encephalomyelitis, A D F M . or vasculitis may present in a similar fashion. In addition, follow-up studies have s h o w n t h a t a significant percentage of patients w i t h M R I lesions detected at onset do not progress to clinically s y m p t o m a t i c M S , even after m a n y years of follow-up. T h e issue of the m o n o p h a s i c demyelinating disease is discussed in the next section. Such patients may be classed as suspected M S ; they m a y , in fact, represent particularly benign forms of the disease.
Differential Diagnosis T h e differential diagnosis of MS (Table 60.5) is quite limited in the setting of a y o u n g a d u l t with t w o or m o r e clinically distinct episodes of C N S dysfunction with at least partial resolution. 1' rob I ems arise with atypical presentations, m o n o p h a s i c episodes, or progressive illness. T h e unusual nature of some sensory s y m p t o m s and the difficulty patients experience in describing such s y m p t o m s m a y result in a misdiagnosis of hysteria. T h e retrospective n a t u r e of inquiries also blurs details of prior events, m a k i n g clear ascertainment of prior attacks difficult in s o m e cases, A m o n o p h a s i c illness with s y m p t o m s a t t r i b u t a b l e to one site of the C N S creates a large differential diagnosis t h a t includes n e o p l a s m s , vascular events, or infections. Table 60.4.2:
Table 60.5:
] 1.-41
Differential diagnosis in multiple sclerosis
Inflammatory diseases Granulomatous angiitis Systemic lupus erythematosus Sjogren's disease Behcet's disease Polyarteritis nodosa Paraneoplastic encephalomyelopathies Acute disseminated encephalomyelitis, postinfectious encephalomyelitis Infectious diseases Lyme neuroborreliosis Human T-cell lymphotropic virus type 1 infection' Human immunodeficiency virus infection Progressive multifocal leukoencephalopathy* Neurosyphilis* Granulomatous diseases Sarcoidosis Wegener's granulomatosis Lymphomatoid granulomatosis Diseases of myelin Metachromatic leukodystrophy (juvenile and adult)* Adrenomyeloleukodystrophy* Miscellaneous Spinocerebellar disorders"1 Arnold-Chiari malformation Vitamin B|2 deficiency* "Indicates disorders that are predominantly important to differentiate in the setting of progressive disease.
A p p r o p r i a t e imaging studies m a y help clarify t h e situation, d e p e n d i n g on t h e site of involvement a n d clinical p r o gression. T h e m o s t t r o u b l e arises with progressive C N S dysfunction, in which great care must be t a k e n to exclude treatable etiologies (e.g., vitamin B ( 2 deficiency, compressive spinal c o r d lesions, a r t e r i o v e n o u s m a l f o r m a t i o n s , c a v e r n o u s a n g i o m a s , A r n o l d - C h i a r i m a l f o r m a t i o n ) , infectious causes (syphilis, H T L V - 1 , h u m a n immunodeficiency virus), or hereditary disorders (adult m e t a c h r o m a t i c leukod y s t r o p h y , a d r e n o m y e l o l e u k o d y s t r o p h y , spinocerebellar disorders).
MRI demonstration of time dissemination for McDonald et al. (2001) diagnostic criteria for multiple sclerosis
If a first scan occurs 3 months or more after the onset of the clinical event, the presence of a gadolinium-enhancing lesion is sufficient to demonstrate dissemination in time, provided that it is not at the site implicated in the original clinical event. If there is no enhancing lesion at this time, a follow-up scan is required. The timing of this scan is not crucial, but 3 months is recommended. A new T2 or gadolinium-enhancing lesion at this rime then fulfills the criteria for dissemination in time. If the first scan is performed less than 3 months after the onset of the clinical event, a second scan done 3 months or more after the clinical event showing a new gadolinium-enhancing lesion provides sufficient evidence for dissemination in time. However, if no enhancing lesion is seen ar this second scan, a further scan not less than 3 months after the first scan that shows a new T2 lesion or an enhancing lesion will suffice, The new criteria have advantages. The former categories of possible, probable, and definite MS have become obsolete. The MRI criteria are based on extensive data of Barkof et al. (1997) and Tintore ct al. (2000) and are designed ro retain sensitivity while enhancing specificity. They will have liulc usefulness in patients with clear-cut demyelinating syndromes such as optic neuritis or a brainstem syndrome: in such cases many clinicians will be satisfied with less stringent MRI criteria. In patients with obscure symptoms the criteria will help avoid premature or erroneous diagnosis and treatment. In addition, criteria for primary progressive MS are proposed. Revisions to the McDonald criteria have been proposed. For example, the role of spinal cord lesions needs to be evaluated and expanded, It may take some time before the final crircrm are decided on and accepted as the standard for diagnosis.
1644
NEUROLOGICAL DISEASES
A common error is to overinterpret multiple hypei intense lesions on MR1 as equivalent to MS. Clinical symptoms must be consistent with MS. A few white matter lesions in T2-weighted MRI scans are not infrequent, particularly in the elderly, and do not indicate a diagnosis of MS. CNS vasculitidcs such as systemic lupus erythematosus (SLE), Sjogren's disease, polyarteritis nodosa, syphilis, retroviral diseases, and Behcet's disease may all produce multifocal lesions with or without a relapsing-remitting course. SLE can present as a recurrent neurological syndrome before the systemic manifestations of this disease declare themselves. Behcet's syndrome is characterized by bucco-genital ulcerations in addition to the multifocal neurological findings, CNS sarcoidosis can be mistaken for MS with multifocal neurological and MRI lesions. Although rare, ADEM must be considered in the. differential diagnosis (sec Acute Disseminated Fivephalomyelitis, later in this chapter). An MS-like phenotype associated with mitochondrial gene defects has been described; it is of note that when there arc multiple MS cases in a family, maternal transmission is more frequent than paternal transmission. More important than features characteristic for MS are features that should prompt the clinician to reconsider the diagnosis oi MS-red flags indicating that another diagnosis is more likely. Many physicians fail to pursue further diagnostic steps when a patient is labeled as having .MS. Features that should alert the clinician to the possibility of other diseases include (1) family history of neurological disease, (2) a well-demarcated spinal level in the absence of disease above the foramen magnum, (3) prominent back pain that persists, (4) symptoms and signs that can be attributed to one anatomical site, (5) patients who are over 60 years of age or less than 15 years at onset, and (6) progressive disease (see Table 60,3). None of these features excludes the diagnosis of MS, but in these situations one should seek other etiologies before accepting the diagnosis of MS.
Course The most characteristic clinical course of MS is the occurrence of relapses (Figure 60.8), which can be defined as the acute or subacute onset of clinical dysfunction that usually reaches its peak from days to several weeks followed by a remission during which the symptoms and signs resolve partially or completely. The minimum duration for a relapse has been arbitrarily established at 24 hours. Clinical symptoms of shorter duration arc less likely to represent what is considered as a true relapse (i.e., new lesion formation or extension of previous lesion size). Worsening of previous clinical dysfunction can occur concurrently with fever, infection, physical activity, or metabolic upset and last for hours to a day or more. Such worsening is thought to reflect conduction block in previously demyelinated axons. Relapses of MS vary
FIGURE 60.8 The course of multiple sclerosis. (A) Severe relapses, increasing disability, and early death. (B) Many short attacks, tending to increase in duration and severity. (C) Slow progression from onset, superimposed relapses, and increasing disability. (D) Slow progression from onset without relapses. (E) Abrupt onset with good remission followed by long latent phase. (F) Relapses ot diminishing frequency and severity, slight residual disability only. (G) Abrupt onset, few if any relapses after first year, no residual disability. (Reprinted with permission from McAlpine, D., Compston, A., Fbers, G., et at. 1VVK, AIIVW/JW'S Multiple Sclerosis, 3rd ed, Churchill Livingstone, London, p. 32.)
markedly with regard to the CNS site involved; the frequency of attacks (the free interval between relapses ranges from weeks to years); the mode of onset (from quite sudden to subacute); and the duration, severity, and quality of remission. The frequency of relapses is highly variable and depends on the population studied and the closeness of observation and recording by patients and physicians. Summaries of many studies provide an average figure of 0.4-0.6 relapses per year. Patients followed closely in clinical trials have higher relapse rates, probably reflecting self-selection and closer reporting and examinations in such studies. The attack rate in the placebo group in clinical studies ranges from 0.8-1.2 attacks per year. In general, relapses arc more frequent during the first years of the disease and tend to wane in later years. A course marked by relapses, interspersed by periods during which the disease seems relatively dormant, is termed relapsing-remitting. Approximately 15% of patients never experience a second relapse. The exact frequency of such benign MS is unknown, however, because many such individuals never come to medical attention. Autopsy studies found a significant numbers of cases with CNS pathology consistent with MS and yet no documented clinical evidence of
MULTIPLE SCLEROSIS AND OTHER INFLAMMATORY [^MYELINATING DISEASES
such disease. Similarly, MRI studies have shown MS-like plaques in T2- weigh ted scans in patients who have neverhad a neurological episode. Asymptomatic relatives of patients with MS have MRI lesions consistent with dcmyelination in up to 1 5 % of these relatives (Sadovnick et al. 1993). The use of MRI may expand the specttum of MS by detecting milder cases that previously were not included in prognosis studies. A standardization of terms has been agreed on to determine the pattern and course of the illness (Lublin and Reingold 1996). Four categories of disease are described: 1. Relapsing-remitting MS: Clearly defined relapses with full recovery or with sequelae and residual deficit on recovery. The periods between disease relapses are characterized by a lack of disease progression. 2. Primary-progressive MS: Disease progression from onset with occasional plateaus and temporary minor improvements allowed. 3. Secondary-progressive MS: Initial relapsing-remitting diseast course followed hy progression with or without occasional relapses, minor remissions, and plateaus. 4. Progressive-relapsing MS: Progressive disease from onset, with clear acute relapses, with or without full recovery. The periods between relapses are characterized by continuing progression. Two severity outcomes are also described: (1) Benign MS is disease in which the patient remains fully functional in all neurological systems 15 years after the disease onset; and (2) malignant MS is disease with a rapid progressive course, leading to significant disability in multiple neurological systems or death in a relatively short time after disease onset. Data from a clinic-based study of 1100 patients who represented the population of the region found that 6 6 % of patients at onset had relapsing and remitting disease, 1 5 % had relapsing-progressive, and 19% had progressive disease from the onset. Patients evolved from a relapsingremitting course to a progressive course; 8 5 % of patients began with a relapsing course, but the proportion continuing as relapsing disease decreased steadily, so that by 9 years from onset, only one half were still relapsing. Likewise, the probability of reaching 6 on the Kurtzke disability score was 50% 16-17 years after onset. The course of MS with onset after the age of 40 was progressive in over 60% of patients. The rate of clinical progression of MS is variable. The commonly used index of clinical disability, the Kurtzke disability status score (DSS), or the expanded version called the expanded disability status score (EDSS), uses numbers ranging from 0 for normal examination and function, to 10 for death caused by MS. This scale is nonlinear, with great emphasis on ambulation capabilities with scores above 4. Most MS populations have bimodal distributions of EDSS
1645
scores, with peaks at values of 1 and 6 (ambulation with unilateral assistance). The time spent by a patient at a given level of disability varies with the score. Thus, for patients with DSS scores of 4 or 5, median time spent at these levels was 1.2 years, whereas for those at DSS 1, median time to stay at that level was 4 years, and at DSS 6, it was 3 years. These results have powerful implications for the conduct of clinical studies with respect to patient selection, stratification, and duration of follow-up: If many patients of DSS 1 or 6 are included, little movement is seen in a group followed for a year or two. The rate of progression with chronic progressive disease in the placebo groups of three clinical trials ranged from 0.5-0.7 points per year on the DSS scale. In a cohort of patients followed for 25 years, the following data emerged (Runmakcr and Andersen 1993): 8 0 % of the patients had reached the progressive phase by 25 years, 1 5 % of the patients had died, 65% of the patients had reached EDSS 6 (requiring aids for walking), and 5 0 % of the patients reached EDSS 6 within 16 years of onset. The HDSS, although universally used m clinical trials, has a number of serious limitations. Even with special training and examiner blinding, interrater and intrarater variations in scoring are common. EDSS scores of 4 and higher depend almost entirely on the ability to walk, and developing dementia, vision loss, or weakness of hands may pass undetected by the scoring. An obvious implication of these facts is that other outcome measures should be used as well and that minor changes in EDSS alone should not be ovcrinterpreted. The Multiple Sclerosis Functional Composite Scale (MSEC) is a clinical tool designed to avoid the problems encountered with the EDSS. The MSFC consists of three parts: (1) Paced Auditory Serial Addition Test (PASAT) (2) 9-Hole Peg Test (9HPT) and (3) Timed 25-Foot Walk (T25FW), These three measures take into account cognition, upper extremity, and lower extremity functions, A z-score is obtained for each measure and a combined z-score is then derived. The MSFC has been validated in several clinical trials. The tests can be performed by a nonphysician and are highly reproducible and predictable. Effect of Exogenous Factors on the Course The role of a variety of exogenous factors cither influencing the development of MS or inducing disease exacerbations has been examined using epidemiological techniques. A disproportionately high number of relapses occur in patients with MS who have suffered recently from viral infections, and a high number of infections are followed by acute attacks. Increased interferon-)' and TNF-a produced by cells of the immune system during viral infections may play a role in this increased relapse rate by increasing expression of ma]or histocompatibility complex class II antigens and adhesion molecules on cells of the immune
1646
NEUROLOGICAL DISEASES
system and CNS, with a resultant increase in the number of activated T cells being attracted to the CNS. Controversy exists about a link between occurrence of stressful events and exacerbation of MS. Trauma appears not to be implicated in disease induction or relapse, although in the experimental animal model EAE, lesions are most prominent at sites of pre-existent traumatic lesions. Performance of neurological diagnostic procedures such as myelography and lumbar puncture has not been linked with aggravation of the MS disease coutse, nor has administration of local or general anesthetics. Recent data do not establish a link between vaccination and disease exacerbations, and few clinicians withhold immunization programs, for example, for influenza or hepatitis. Effect of Pregnancy on the Course MS is a disease that predominantly affects women and has a maximum incidence during child bearing years. The influence of pregnancy on MS has been repeatedly examined, with evidence that relapses are reduced late in pregnancy and are more frequent than expected in the 3-monrh postpartum period. However, this is not the finding in all studies. There is general agreement that the overall prognosis is no different in women who have been pregnant, compared with those who have not. Studies of women with MS reveal no increase in stillbirths, ectopic pregnancies, or spontaneous abortions. These data would suggest that pregnancy has no ill effect on MS and that MS has no negative effect on the fetus or the course of pregnancy. In a study of postmenopausal women, there was no difference in disease severity in multiparous or nulliparous women. An important issue in the pregnant woman with MS is to avoid exposing the fetus to toxic drugs (Table 60.6).
PROGNOSIS Although great individual variability exists with regard to disease prognosis, a variety of factors have been identified as possible prognostic indicators. Sex: MS appears to follow a more benign course in wumui il'i.ii: in men. Age at onset: The average age at onset of MS is 29 years. Onset at an eatly age is seemingly a favorable factor, whereas onset at a later age carries a less favorable prognosis. As previously stated, the pattern of disease varies in different age groups, with the re lapsing-remitting form being more common in younger patients and the progressive form being more common in the older age group. Data arc lacking as to whether prognosis differs as a function of age in patients with similar patterns of disease.
Tabic 60.6: Safety in pregnancy of drugs used in the treatment of multiple sclerosis Category B: Animal data showing no harm to the fetus; no human data available Glatiramer acetate [Copaxone) Pemoline Oxybutymn Fluoxetine (and other selective serotonin reuptake inhibitors) Desmopressin Category C; Animal data shows harm to the fetus; no human data available Corticosteroids Interferon-^, Interferon-^] b Baclofen
Amantadine Tizanidinc Carbamazepine Category D: Known to cause fetal harm when administered to pregnant women Azathioprine Cladribine Cyclophosphamide Category X: Contraindicated for use during pregnancy Methottexate Source: Modified from Damek, D. M. & Sinister, E. A. 1997, "Pregnancy and multiple sclerosis," Mayo Clin Proc, vol. 72, pp. 977-989. Initial disease course: The relapsing form of the disease is associated with a better prognosis than progressive disease. A high rate of relapses early in the course of illness may correlate with shorter time to reach EDSS 6, as docs a short first interval between attacks. Initial complaints: Among initial symptoms, impairment of sensory pathways or cranial nerve dysfunction, particularly ON, is found in several studies to be ;• favorable prognostic feature, whereas pyramidal and particularly brainstem and cerebellar symptoms carry a poor prognosis. Both benign and fulminant forms of MS arc recognized. There is no agreement among workers in the field as to the meaning of these terms, ft is the general experience that a patient whose disease has had a benign course for 15 years only rarely develops a more severe course. Patients with mild disease (KDSS score O-.i) 5 years after diagnosis only uncommonly progress to severe disease (EDSS score 6) by 10 years (7.5% of patients) and 15 years (11.5% of patients). The term malignant MS is variably used by different workers; some use it to imply a rapid course, others a clinical course in which there are frequent severe relapses with little tecovery. Clues to etiology, susceptibility, and resistance factors must be present in such extremes of the clinical spectrum but they remain elusive at present. Entities such as Devic's disease, Balo's concentric sclerosis, and particularly Marburg disease are more fulminant variants of MS with early disability and even death (Tabic 60.7).
MULTIPLE SCLEROSIS AND OTHER INFLAMMATORY DEMYtLINATTXG DISEASES Table 60.7:
1647
Risk of multiple sclerosis after monosymptomark episodes
Investigator
Follouf-uf)
Patients
MR! lesions
Conversion rate to CDMS
EDSS >3
F.DSS >S.S
Morrissey 1993
5 years
O'Riordan 1998
10 years
Brex 2002
14.1 years
32 6 18 13 1ft 27 3 16 15 20 21 18 15 17
0 1 2-3 4-10 >10 0 1 2-3 4-10 >10 0 1-3 4-10 >10
6% 17% 67% 92% 80% 1 1% 33% 87% 87% 85% 19% 89% 87% 88%
0 0 17% 30% 56% 0 0 31% 27% 75% 0 11". 53% 80%
4% 0 13% 20% 35% 0 12.5% 38% 73%
Conversion rate to clinically definire MS (CDMS) indicates that the patient had second clinical episode,
Optic Neuritis
Chronic
The incidence of MRI abnormalities in children with ON is less than that in adults, and this factor, coupled with clinical experience, siii'.i'.i^f. tiui ihe r.iu- ;>' |ir(«-;vssuin i MS in children with isolated ON may well be less than that in adults. Five-year data from the original Optic Neuritis Treatment Trial revealed that the 5-year cumulative probability of developing clinically definite MS was 3 0 % and did not differ by treatment group (oral prednisone, intravenous methylprednisolonc, placebo). However, MRI was a strong predictor; the 5-ycar risk of developing clinically definite MS was 16% in patients with no brain MRI lesions and 5 1 % in patients with three or more lesions.
In patients with chronic progressive myelopathy, 60-70% have cranial MRI abnormalities consistent with MS in the absence of clinical evidence of disease above the level of the spinal cord. What remains unclear is whether the remaining 3 0 % have a disease other than MS or whether MS can manifest as a purely spinal disorder. Probably both situations apply; improved spinal neuroimaging should help resolve this issue. Diagnostic
Myelopathy
Studies
Although the diagnosis of MS remains clinical, a number of ancillary laboratory tests can aid in the diagnosis of MS. The tests used most often are neuroimaging, particularly MRI, analysis of CSF, and to a lesser extent, EP studies.
Myelopathic Syndromes Acute
Myelopathy
Patients presenting with acute complete transverse myelitis have a cited risk of MS of only 5-10%. However, partial or incomplete myelitis is a much more common clinical entity and bears more relevance to MS. Studies examining the issue of acute partial myelitis as an initial presentation of MS found that 5 7 - 7 2 % of such patients had cranial MRI abnormalities consistent with MS. Follow-up from i-5 years found that 6 0 - 9 0 % of these patients developed MS, whereas 10-30% of those with normal MRI developed MS (Morrissey et al. 1993). CSF studies suggest that patients with monosymptom a tic disease with positive oligoclonal bands (OCBs) have a higher risk of evolution ro MS than those without OCBs, although CSF results do not help further in prognosis when compared with MRI alone. CSF analysis would be most useful in a situation in which MRI is not available.
Neuroimaging Magnetic
Resonance
imaging
MRI has changed significantly the approach to MS and is now the modality of choice as an aid to the diagnosis. MS pi a (.pies are typically found in the periventricular region, corpus callosum, centrum semiovale, and to a lesser extent, deep white matter structures and basal ganglia. Features typical of MS plaques have an ovoid appearance; lesions are arranged at right angles to the corpus callosum as if radiating from it ("Dawson's fingers"). The plaques appear hyperintense on proton density and T2-weightcd studies (Figure 60.9), whereas the plaques appear (if visible at all) hypointense on T l wcighted images. Such hypointense lesions on T l weighted scans ("black holes") are associated with evidence of axonal loss in addition to demyelination.
if,4s
NKISROI.OCICAI nisi \sis take into account the typical sites of MS plaques and also consider the relatively frequent finding of scattered hyperintense signals on T2-weightcd images seen in the more elderly population and thought to he caused by vascular disease. Patients with at least three lesions, lesions abutting the ventricles, lesions in the posterior fossa, and lesions of greater than 5 mm are likely to have MS. If at least two of these thtee criteria were met in an initial group of patients with MS and elderly controls, these ctiteria had a sensitivity of 8 8 % and specificity of 100%. Testing of a target, more diverse patient population indicated that these criteria had a sensitivity of 8 1 % and a specificity of 9 6 % (Offenbacher et al. 1993).
FIGURE 60.9 Magnetic resonance imaging studies in a 29-yearold man. (A) Multifocal lesions in the centrum semiovale (proton density image). (B) Multiple, at times confluent, white matter lesiims abutting the lateral ventricles (proton density image). (C) Lesions distributed in a radiating fashion from the corpus callosum ("Dawson's fingers"). Significant cerebral atrophy with vcntriculomcgaly and cortical atrophy is also noted (T2-wcightcd image). The earliest studies of cranial MRI in MS rapidly established that MRI detected many more lesions than did computed tomographic (CT) scanning. Furthermore, plaques were readily detected in regions that were rarely abnormal on CT, such as the brainstem, cerebellum, and spinal cord. Most lesions seen on MRI correlate with lesions seen on pathology. However, some lesions that arc quite extensive on MRI show only small plaques on pathological examination, suggesting that much of the abnormal MRI signal may be a result of increased water content of the brain around such plaques caused by presumed BBB disruption. This would be consistent with the finding of reduction of size of plaques in serial studies of MS using MRI. The major effect of MRI technology has been on diagnosis. Patients with clinically definite MS have white matter lesions typical of MS in over 90% of cases. One mnsl keep ::i mind lh.it other t. !NS diseases (e.g., ischemia, SLE, Behcet's disease, other vasculitides, HTLV-1, sarcoidosis) may have lesions on MRI that appear similar to MS. This is particularly true for ischemic lesions, which make MRI criteria much less reliable for the diagnosis of MS in patients over the age of 50 (Offenbacher et al. 1993). Several sets of criteria have been proposed for determining whether lesions seen on MRI arc caused by MS. The criteria
MRI scanning is both mote sensitive and more specific for predicting evolution to clinically definite MS than other paraelmieal investigations such as CT scans, CSF, or EP. Two-year follow-up of 200 patients tefetred for suspected MS showed that 3 0 % {50% of those under age 50) bad developed clinically definite MS, of whom 84% had initial MRI scans thai were strongly suggestive : MS. Subsequent studies have shown even higher rates of progression to MS (Morrisscy et al. 1993) and that total MRI lesion number and load correlated with subsequent development of MS, degree of disability, and lesion load at follow-up (FUippi et al. 1994). Efforts continue to delineate differences in the MRI appearance of acute or active lesions and chronic lesions. Acute lesions tend to be larger, with somewhat ill-defined margins when acute and become smaller with sharper margins as resolution occurs. This presumably reflects resolution of edema and inflammation present at the time of acute plaque formation, leaving only residual areas of demyelination, gliosis, and enlarged extracellular space with lesion evolution. The MRI appearance of primary progressive MS shows a smaller total disease burden, a greater preponderance of small lesions, fewer gadoliniumenhancing new lesions, and acquisition of fewer lesions per unit time than the secondary progressive form of MS. Gadolinium-diethylcnetriaminepentaacetic acid, a paramagnetic contrast agent that can cross only disrupted BBB, has been used to assess plaque activity. Gadolinium increases signal intensity on T1-weighted images. The accumulation of gadolinium in plaques is associated with new or newly active plaques and has been associated with pathologically confirmed acute inflammation in MS. Gadolinium enhancement usually persists for less than 4 weeks but may persist up to 8 weeks in acute plaques, Gadolinium enhancement diminishes or disappears after treatment with corticosteroids, a therapy thought to restore the integrity of BBB permeability. Allied to the concept of using MRI data as outcome measures of MS therapeutic studies is the notion of following disease burden, which is the total volume of brain affected by plaques as detected on MRI scans. This can be done by measuring the surface area of all plaques and multiplying by the slice thickness. This is most
MULTIPLE Sa.LROSlS AND OTHER !\l I AMMATORY DEMYELtNATING DISEASES
1649
reliable for thin-slice techniques and preferably with threedimensional acquisition. A number of studies have examined the ability to detect lesion burden changes over time and have found that it is possible to detect changes that may not be clinically apparent (Figure 60.10). The extent of cranial MRI abnormalities (and even pathology) does not necessarily correlate with the degree of clinical disability. Patients with small numbers of lesions may be quite disabled, whereas others may function well despite a large burden of disease as detected by MRI. Several possible explanations exist for this. Lesions may occur in areas that are clinically silent; small lesions in the spinal cord can cause major disability. MRI may miss lesions that are clinically relevant such as those in cortex, basal ganglia, and brainstem; and large plaques detected by MRI may not have functional correlates but reflect increased tissue water without impairment of neural function.
progressive and relapsing MS, than is clinically apparent and that MRI is essential to studies of therapy in MS. The utility of cranial MRI in relation to spinal myelopathies was addressed previously in the section on monosymptomatic disease. Spinal MRI is an evolving technology that can detect lesions consistent with demycliuation in some but not all patients. In part, this may be caused by technical limitations of spinal MRI, but also may reflect involvement of small tracts in a relatively small anatomical structure. Many of the pathological lesions extend vertically in the affected tract, and such lesions may be best detected by transverse imaging. Newer technology detects lesions in 7 5 % of patients with definite MS (Kidd et al. 1993). The frequency of abnormal signals in normal individuals is only 3 % , as the non-MS hyperintense T2-weightcd signal seen m older patients mi cranial MRI appears not to occur in the spinal cord.
Several studies have shown that the amount of ongoing MR] activity (new or enlarging lesions, gadoliniumenhancing lesions, or both) exceeds the observed clinical activity by a factor of 2-10. This may reflect not only the factors discussed previously, but also may partly reflect under-re porting of minor symptoms and under-rccogninon of minor signs in patients with MS. It docs, however, suggest that MS is a much more dynamic and active disease, both in
Conventional MRI technology provides excellent images, but makes it difficult to distinguish edema of an acute plaque from gliosis and demyelination of a chronic plaque. Using phosphorus MR specttoscopy, information on phospholipid metabolism can be obtained, whereas proton MR spectroscopy can generate information about other metabolic components, such as N-acetylaspartate (NAA), an exclusively neuronal marker, creatine phosphate
FIGURE 60.10 Changes in MRI scans with duration of disease. The first panels compare three scans from patients with different disease duration, indicating the appearance of atrophy and ventricular dilatation with time. The second panel indicates that as brain atrophy appears it is common to observe that the number of gadolinium-enhancing lesions declines.
1650
NEUROLOGICAL DISEASES
(Cr) (energy marker), choline (membrane component), and lactic acid. Brains of patients with chronic MS have a reduced amount of NAA in comparison with choline and Cr; a reduced NAA to Cr ratio is the common means of expressing such a reduction. This reduced ratio implies loss of neurons or axons, which is consistent with pathological studies and appears to parallel disability in MS {Arnold et a I. 1994) (Figure 60.11). In acute MS lesions studied by MR spectroscopic imaging, the NAA to Cr ratio may be transiently reduced, whereas the levels of choline and lactic iicid i:i;i> lv He" ;iicd, pL.rli;'.ps retaied to myelin membrane disruption and tissue acidosis associated with acute plaque fotmation. Some investigators have found abnormal lipid peaks on MR spectroscopy, suggesting acute demyelination (Davie et al. 1994). The use of these metabolic parameters
may both lead to a better understanding of the evolution of plaques in vivo and be useful as further adjunct measures of disease progression that antedates clinical disability. A number of new technological advances appear likely to enhance yet further the ability to understand the pathogenesis of the disease process. Computed
Tomography
The current utility of CT scans in the evaluation of patients with MS is largely to exclude other treatable or ominous etiologies as the cause of symptoms. Findings on CT of patients with MS include nonspecific atrophy, hypodense lesions often in a periventricular distribution, and contrastenhancing lesions presumed to be active plaques with disruption of the BBB (see Figure 60.10).
Cerebrospinal Fluid
r
1
4
3
D
1
r—
1
2
1
0
(PPm)
FIGURE 60.11 (A, B) Areas of confluent demyelination in a severely affected progressive multiple sclerosis patient. Outlines show volume of interest selected for spectroscopy study. (C) Spectra obtained with proton spectroscopy in this patient (I)) Spectra of normal brain. Note the reduced height of the N-acety I aspartate (NAA} peak with resultant reduction in the ratio of NAA to creatine (Cr). (CHO = choline; LA = lactic acid.)
CSF findings alone cannot make or exclude the diagnosis of MS, but they can be useful adjuncts to clinical criteria. The CSF is grossly normal in MS, being clear, colorless, and under normal pressure. Total leukocyte count is normal in two thirds of patients, exceeding 15 cclls/uL in less than 5% of patients and only rarely exceeding 50 cells/uL (a finding that should raise suspicion of another etiology). The predominant cell type is the lymphocyte, the vast majority of which are T cells. CSF protein (or albumin) level is normal in the majority of patients with MS. Albumin determinations are preferable because albumin is not synthesized in the CNS and thus gives a better indication of BBR disruption than does total protein, some of which may be synthesized within the CNS (i.e., immunoglobulin). Albumin levels are elevated in 2 0 - 3 0 % of patients, although less than 1% of patients have a level twice that of normal (Table 60,8). A common finding in MS is an elevation of CSF immunoglobulin level relative to other protein components, implying intrathecal synthesis. The immunoglobulin increase is predominantly IgC, but the synthesis of IgM and IgA is increased also. The IgG shows an excess of IgGl and • light chains. The IgG level may be expressed as a percentage of total protein (normal
65-80%
OCB
MRI
85-95%
90-97%
BAER = brainstem auditory evoked response; MRI = magnetic resonance imaging; OCB = oligoclonal bands; SSEP = somatosensory evoked potentials; VER = visual evoked response. 'Numbers show the percentage of patients with abnormal study results.
1652
NEUROLOGICAL DISEASES
variants of MS, rather than as separate illnesses, because it is often found, after long follow-up, that the disease has reverted to a more standard variety of MS.
Recurrent Optic Neuropathy There arc patients whose entire clinical illness is confined to the optic nerves. They may have sequential affection of one nerve, then the other, or they may have simultaneous bilateral vision loss, a state that is quite uncommon in classic MS. In some iriM.nuvs VI Is I t IIK- head shows (in addition to lesions of the optic nerves) scattered intracerebral lesions, or a CSF examination shows OCBs, attesting to some degree of dissemination of the lesions. Children and prcadolescent patients are more likely than adults to have recurrent or simultaneous optic neuropathy. Rarely there is slowly progressive optic neuropathy, similar to that seen with optic nerve sheath tumors, such as meningioma. The distinction from an MS variant can be quite challenging. In bilateral ON, sarcoidosis is commonly a diagnostic consideration.
Devic's Disease (Neuromyelitis Optica) A combination of bilateral optic neuropathy and cervical myelopathy make up this condition, which most authorities now classify as a variant of MS. Reported cases indicate that the myelopathy tends to be more severe, with less likelihood of recovery, and that the neuropathological features at autopsy are those of a much more severe necrotic lesion of the cord rather than incomplete dcmyelination. In some patients the optic neuropathy and the myelopathy occur at (In same time, in others on. or the other component is delayed. The longer the interval, the more like typical MS is the pathology. Because the optic nerve and the cervical spinal cord are two of the locations in the nervous system in which the lesions of MS are typically found, many patients could be classified as having Devic's disease, or syndrome. Little is to be gained by this nomenclature, because Devic's syndrome can be a manifestation of ADEM (see Acute Disseminated Encephalomyelitis, later in this chapter), or rarely of other autoimmune disease, such as SLE. This seems to be especially true of patients with relapsing Devic's syndrome, making up approximately one half the patients. In a few patients the distinction between an MS variant and SLE (so-called lupoid sclerosis) is essentially impossible to make, and some of these are patients with neuromyelitis optica.
Slowly Progressive Myelopathy A syndrome of slowly progressive spinal cord dysfunction can present a major diagnostic challenge. If there are no
sensory signs or symptoms, the entity known as primary lateral sclerosis, one ot the group of motor neuron diseases, may be the cause. HTLV-1 infection, vitamin B 1 2 deficiency, and human immunodeficiency virus infection all can be excluded by appropriate tesring. Spinal dural arteriovenous fistula can cause a steadily or stepwise progressive myelopathy, usually in the lower spinal segments. Adrenomyeloneuropathy should be considered. A number of patients remain do not fit into these categories, and their spinal MRI results arc repeatedly negative. VERs, CSF OCBs, and MRI of the head show no sign of demyelination elsewhere. No firm diagnosis is possible. Minor clues that MS is present may be furnished by a Lhermitte's sign that has come and gone or by undue sensitivity to elevated temperature. The degree of compression of the cervical cord by intervertebral disc disease is often an issue in the middle-aged patient, because a majority of persons have some degtee of disc disease, and following trauma there may be a T2 bright signal within the cord due to contusion. There is little doubt that some laminectomies have been carried out for cervical spondylosis where MS was the final correct diagnosis. Progressive myelopathy caused by MS is part of the primary progressive MS group and carries the poor prognosis typical of that group. The choice of therapy is difficult. Some patients do better for a time with monthly intravenous corticosteroid therapy.
Acute Tumor-like Multiple Sclerosis (Marburg Variant) Some patients with demyelinating disease present with a large acute lesion of one hemisphere (Figure 60.12) or rarely other locations, such as the spinal cord. Mass effect may occur, with compression of the lateral ventricle and shift across the midline. The clinical abnormalities in such patients are variable: They may be slight even in a patient with a massive lesion, whereas confusion, hemiparesis, or neglect syndrome may be seen in another patient with a lesion that appears no different. Much of the T2 bright lesion volume is often caused by edema and may be rapidly responsive to corticosteroids. {This change with corticosteroids also may occur with glioma or CNS lymphoma and is therefore not a useful diagnostic criterion.) Biopsy is often required. In one series of 31 patients, the prognosis was good, most patients recovered well clinically, and their lesion volume rapidly cleared. In 24 of the patients the demyelinating lesion was solitary, whereas in the others one or more satellite nodules existed. Six of the patients were older than 57. In follow-up, 28 of the patients did not develop additional evidence of demyelinating activity during a period of 9 months to 12 years. Other authorities have reported a higher rate of recurrent disease, in particular a conversion to more ordinary types of MS, both clinically and by MRI scan criteria.
MULTIPLE SCLEROSIS AND OTHER LNFLAMMATORY DEMYELINATING DISEASES
1653
FIGURE 60.12 (A) Magnetic resonance sain showing a large white matter lesion initially without mass effect in a young woman with right hemiplegia developing over 5 days. (B) Marked increase in size of lesion with associated edema and mass effect 1 month later while on corticosteroids and at a time when clinical deficits wen- improving. Biopsy showed evidence of demyelination.
TREATMENT AND MANAGEMENT In prior decades, treatment of this often progressive disease of young adults was judged to be ineffective, and many clinicians and patients adopted a nihilistic and pessimistic attitude. The advent of more effective symptomatic therapy, and the widely publicized U.S. Food and Drug Administration (FDA) approval of five agents capable of modifying the disease course have drastically changed that view. There remain many problems, particulatly the treatment of progressive MS, yet there arc clearly reasons for hope. Treatment of MS should be directed toward these basic goals: 1. Relief or modification of symptoms 2. Shortening the duration or limiting the residual effects of an acute relapse 3. Preventing progression or slowing its pace 4. Supporting family and patient, alleviating social and economic effects, and advocating fot the disabled ot handicapped
Monitoring Disease Activity Magnetic Resonance Imaging A surrogate marker fot disease activity in MS is badlyneeded. It is now clear from several of the completed interferon therapy trials that there is far more activity in MRI scans of patients than is apparent clinically. Some
authors estimate a ratio of new MRI lesions to clinical events as 10 to 1 in patients with active telapsing-remitting MS. New MR! lesions may be measured by change in total T2 visible lesion load, by new or enlarging lesions, or by gadolinium enhancement. All three criteria have been used with success in one trial or another. Several therapies are known to reduce the accumulation of MRI lesions in clinical trials; these include intetfeton-^i a , interferon-/fit,, and mitoxantrone. Unpublished data suggest that cyclophosphamide blocks the appearance of new gadolinium-positive lesions. The MRI data have been strong indicators of clinical effectiveness in clinical trials and are clearly now a cornerstone of therapeutic investigations in MS. Nevertheless, problems exist. In the care of patients who ate not enrolled in large-scale trials, MRI plays only a doubtful role in monitoring the progress of treatment. Data from the National Institutes ot Health ttials of relapsing MS demonstrate that frequent scanning of an individual patient is required to obtain reliable information, possibly as often as once a month. Infrequent scans can miss lesions that have come and gone. In patients with progressive MS, the lesion load in the head MRI scans can remain unchanged while the patient steadily worsens. Often this state of affaits is caused by ptogressive spinal disease, which cannot be imaged well. A minority of patients with MS, possibly as many as 5 % , have no MRI lesion characteristic of MS at all. Advantages exist in some instances for single or relatively infrequent scans. In the eatly stages of illness, aftet a monosymptomatic relapse, many patients wish to know their risk of developing MS, which can often be defined hy MRI (see previous sections). In patients under rreatment in
16>4
NEUROLOGICAL DISEASES
whom disease activity develops and a change of therapyis contemplated, additional evidence, for or against the change, can sometimes be derived from an MRI scan. Immunological
Data
Thus far, little relevant data exist about levels of cytokines or T-ccll subsets as measurements of disease activity. The expression of different T-cell subsets is not relevant. Levels in blood of the inflammatory cytokine 11,-12 appear to correlate \\ ith activin of relapsing MS and ma] functioE as a surrogate marker. Interferon-)', a cytokine that can itself provoke relapses in patients with MS, may decrease in blood levels when MS is treated successfully. Many investigators are in the process of measuring IL-2, TNF-D, IL-10, and other cytokines (see Chapter 46 for more details). Clinical
Examination
The eventual gold standard of success in MS treatments is the clinical condition of the patient. Every clinical trial includes these data as a primary or secondary outcome. Yet the difficulties of clinical measurement are exemplified by the number of scales and indices that are used. The problems of the EDSS were noted previously. A one-point increase or decrease in the EDSS is often taken as an endpoint; this may require special training of observers, and even rhen variability of observations occurs. The Air.bufuiun liiiKx, :i direct a^essrneiu ol walk MIL;, is useful in most patients. MRI is increasingly considered as the primary endpoint.
Relief or Modification of Symptoms Spasticity Spasticity slows voluntary movement, impairs balance and gait, and may cause painful flexor or extensor spasms. Partial control is often possible, although recovery of motor power is rare. Baclofen is a y- amino butyric acid agonist that can effectively relieve spasms and has modest effects in improving performance. Daily divided doses of 20-120 mg and occasionally more are used. Too large a dose may produce drowsiness or sufficient hypotonicity as to increase the degree of weakness. Intrathecal baclofen via an implanted pump can be effective against spasticity in suitable patients. The pump can be electronically regulated to deliver small doses of baclofen in pulses or a varied dose at different times over 24 hours to increase efficacy and decrease side effects. Its effectiveness has been demonstrated in several controlled trials, and the side effects are few. Tizanidinc (Zanaflcx), a centrally active ^-noradrenergic agonist, may be used alone or in combination with baclofen because the mechanism of action is different. The
medication, available in 4-mg tablets, must be gradually increased starting with 2 mg at bedtime. The side effects are similar to baclofen; however, a blind prospective trial in patients with MS showed that although it relieved spasticity, it did not affect strength. Benzodiazepines contribute to the control of spasticity, although sedation and possible drug dependency are limiting factors. Dantrolene sodium (Dantrium), an agent that acts within muscles on excitation-contraction coupling, is rarely used because of the risk of liver damage. If used, the medication must be titrated from 25 mg daily up to 100 mg three times
a day. 4-Aminopyridinc and 3,4-diaminopyridine (3,4-DAP) are compounds that block potassium channels in the axolemma, and a double-blind trial showed improvement in motor strength. The risk of seizure and hepatitis has limited the use of these compounds. Botulinum toxin type A (Botox) also has been shown to be effective in selective cases. Tremor One of the most disabling and hard to treat symptoms in MS is tremor. Appendicular tremors are usually seen in action or intention and may limit activities of daily living. Weighted wrist bracelets and specially adapted utensils are a nonpharmaccutical option. lsoniazid, 800-1200 mg per day, with pyridoxine, 100 mg per day, may have marginal success. Anticonvulsants also have been reported to be helpful with tremor. Primidone (Mysoline), 125-250 mg two to three times per day, is recommended. Dizziness, somnolence, and nausea are the primary side effects. Carbamazepinc (Tegretol) in divided doses up to 800 nig per day has been used also. Gabapentin (Neurontin) in daily divided doses up to 3600 mg has shown some benefit. Clonazepam (Klonopin), 0.5-2.0 mg one to four times daily, is effective. However the side effects, including ataxia, behavioral changes, confusion, and respiratory depression, must be kept in mind when treating patients. Propranolol (Inderal), 20-40 mg two to three times daily, is another option. Caution must be taken in patients with concomitant cardiac, circulatory, or respiratory disorders. Ondansetron (Zofran), 4-8 mg once or twice daily, has been reported effective in case studies of patients with MS. Side effects include diarrhea, headache, and elevated liver enzymes. Surgical thalamotomy or deep brain stimulation may be used in patients with refractory disease. Fatigue Fatigue is seen in as many as 7 8 % of patients and interferes with daily activities. Fatigue must be separated from
MULTIPLE SCLEROSIS AND OTHER INFLAMMATORY DEMYELINATING DISEASES
depression, medication side effects, or physical exhaustion from gait alterations. Amantadine (Symmetrel), 100 mg twice a day, has relatively few side effects and is well tolerated by most patients. Caution must be taken in patients with renal insufficiency or seizure disorders. Studies have found an efficacy rate of 4 0 % . Modafinil (Provigil) is a wake fulness-promoting agent that is chemically and pharmacologically distinct from CNS stimulants, although the precise mechanism of action is unknown. Modafinil was recently approved for use in narcolepsy. There are open-labeled studies showing that Modafinil is effective for fatigue in MS patients. Oral dosage srarts at 200 mg in the morning and can be increased to 400 mg. Pemoline (Cylcrt) is an alternative medication if no response to amantadine is seen. The starting dose is 18.75 mg twice daily and can be increased to a maximum of six tablets per day. The risk of hepatic failure is an obstacle to using this drug as first-line therapy. Some patients also may respond to methylphenidate (Ritalin), 10-60 mg per day in two to three divided doses. Selective serotonin reuptake inhibitors, in addition to treating the depressive symptoms associared with MS, have been used to treat fatigue. Fluoxetine (Prozac), 10-20 mg once or twice daily, has a side effect profile including nausea, headache, extrapyramidal effects, hypotension, and mania. There is now a once weekly oral dosage of fluoxetine available. Bladder
Dysfunction
Symptomatic bladder dysfunction can be identified at some time during the course of MS in 5 0 - 8 0 % of patients. The severity of bladder symptoms is unrelated to the duration of the disease but parallels the severity of othet neurological symptoms. Differentiating between bladder spasticity and hypotonia is important before initiating therapy because different medications are employed for each condition. Common disorders such as urinary tract infections, prostate and bladder cancer, and benign prostatic hypertrophy may mimic symptoms of neurological dysfunction and should be excluded. Initial steps in managing bladder dysfunction include fluid management, timed voiding, and bedside commode. Oxybutynin (Ditropan) is a first-line medication for l:vpi.T ivlli'\ii bladder without outlet obstruction. Dosage
ranges from 2.5-5.0 mg one to three times daily. An extended release formulation is now available. General precautions and side-effect profiles of the anticholinergics must be observed. Propantheline (Pro-Banthine), 15 mg three to four times per day, is another anticholinergic option for bypcr-reflcxic bladders without outlet obstruction. Imipramine (Tofranil), a tricyclic antidepressant, 50-300 mg in divided daily doses, is also helpful, especially with
1655
enuresis. Side effects are similar to the anticholinergics. This medication has the dual effect of treating concomitant depression. Desmopressin is also effective with hyper-re flex ic bladder without outlet obstruction. Doses of 20-40 ug daily are suggested. Adverse effects include nausea, flushing, and headache. Toltcrodine (Detrol) is a muscarinic receptor antagonist with fewer side effects than anticholinergic medications. This medicine, given at 2 mg twice daily, was shown to reduce bladder frequency and urgency as well as urge incontinence. A long-acting formulation is now available. Detrusor hypcr-reflexia with outlet obstruction may respond to Crede's maneuvers, antispasticity medications, or anticholinergics in combination with alpha-sympathetic blocking agents such as terazosin hydrochloride (Hytrin). The maintenance dose is 2-10 mg daily. Adverse effects include tachycardia, dizziness, syncope, headache, and asthenia. Detrusor areflexia may respond to Crede's maneuvers, alpha-sympathetic blocking agents, or bethanecbo! chloride (Urecholine). The usual dose is 10-50 mg three to four times a day with a side-effect profile including diarrhea, excessive lacrimation, and flushing of the skin. This medication is also contra indicated in many common medical conditions. Catheterization may be employed if the previously mentioned measures are ineffective; however, the long-term effects of catheterization must be considered. Squamous metaplasia of the bladder was significantly greater in patients who had been catheterized for more than 10 years (80%) in comparison with those catheterized for less than 10 years (42%) and those without catheters (20%). Surgical correction, such as augmentation of bladder capacity with an exteriorized loop of bowel, for appropriate patients is another alternative. Depression Prevalence rates for depression in patients with MS range from 14-57% as compared with 1.3-3.7% in the general population. The lite time prevalence of depression in a group of patients with chronic medical disorders was 12.9%. The nature of a chronic debilitating neurological disorder contributes to depressive symptoms and coping problems. Patients taking multiple medications arc prone to depression, and the side-effect profile of the interferon-/) medications includes depression. Selective serotonin reuptake inhibitors are the medication of choice for depressive symptoms in patients with MS. In addition to the previously mentioned fluoxetine, any of the other medications in this class may be used. Amitriptyline (Elavil), 25-100 mg daily (or other tricyclic antidepressants in equivalent dosage), is a second-line
16.S6
NEUROLOGICAL DISEASES
choice because of anticholinergic side effects. However, anticholinergic properties may be helpful to patients with symptoms of bladder spasticity or chronic pain, thus avoiding polypharmacy.
Baclofen, acetazolamide (Diamox), ibuprofen, and bromocriptine are cited as potentially beneficial with these paroxysmal symptoms.
Sexual
Treatment Strategies
Dysfunction
Studies suggest that 4 5 - 7 4 % of women with MS experience sexual dysfunction. These symptoms have been associated with depression, bowel dysfunction, fatigue, spasticity, and pelvic floor weakness. There was no association between duration of disease, type of disease, recent exacerbations, or disability scores. Erectile dysfunction in men is common, especially in patients with spinal cord involvement. Symptoms also may be caused by medications or psvchnio;;ie;i] issues.
Sildenafil (Viagra) has supplanted traditional approaches to erectile dysfunction in men, which used to include intra cavernous papaverine, prostaglandin E, phentolamine, vacuum devices, and penile prostheses. Doses of 2 5 100 mg 1 hour before sexual intercourse arc used with minimal side effects, which include headache, flushing, dyspepsia, and musculoskeletal pain. Reports suggest caution in patients with cardiovascular disease. Sildenafil is probably also effective in women. Cognitive
Impairment
Problems with cognition are increasingly being recognized as an important deficit affecting patients with MS. Studies have found a correlation between dementia and lesion burden on MR1 as well as atrophy of the corpus callosum. In a study of patients with chronic progressive MS who underwent MRI scans and a neuropsychological screening battery, those who were impaired according to the neuropsychological screening battery had significantly more cerebral lesions than those who were judged unimpaired. Treatment of cognitive deficits consists of support, improvement of coping strategies, and treatment of depression. Paroxysmal
Symptoms
A variety of paroxysmal symptoms consist of brief, almost stereotypical, events occurring frequently and often triggered by movement or sensory stimuli. They are likely caused by ephaptic transmission of nerve impulses at sites ot previous dise.ise activity. These s y m p t o m s include, but
are not limited to, trigeminal neuralgia, pain, paresthesia, weakness, tonic seizures, dysarthria and ataxia, pruritus, diplopia, akinesia, and hemifacial spasm and dystonia. Anticonvulsants, especially carbamazepine and valproate (Depakote], have been used in their usual doses with some benefit. Newer anticonvulsants, such as gabapentin, have been used in small case studies. Benzodiazepines also have been effective in some patients.
For some patients MS is a disease with one or two acute neurological episodes with no further evidence of disease activity. In others it is a chronic, relapsing, or progressivedisease with an unpredictable clinical course that generally spans 10-20 years, during which time neurological disability accumulates. Treatment of MS, as with diseases in other branches of medicine, has come to rely on prospective clinical trials. Most such trials have been designed to establish efficacy but do not last longer than 2 or 3 years and give only hints about long-term results of treatment. Patients may differ markedly from those who have been treated in clinical trials, yet therapeutic decisions must be made. Table 60.10 outlines the treatment paradigm used at our institutions. Class I—Prospective, randomized, controlled clinical trial with masked outcome assessment and requires the following: Primary outcomes are clearly defined. Inclusion/exclusion criteria are clearly defined. Adequate accounting of dropouts and crossovers wirh numbers sufficiently low to have minimal potential for bias. Relevant baseline characteristics are presented and substantially equivalent between groups or there is appropriate statistical adjustment. Class II—Prospective matched group cohort study with masked outcome assessment that meets a-d or a randomized controlled trial that lacks one criteria a-d. Class III-—A11 other controlled trials where outcome assessment is independent of patient treatment. Class IV—Evidence from uncontrolled studies, case series, case reports, or expert opinion.
Treatment of Acute Attacks Acute attacks are typically treated with corticosteroids. Indications for treatment of a relapse include functionally disabling symptoms with objective evidence of neurological impairment such as loss of vision and motor, cerebellar, or both kinds of symptoms. Thus mild sensory attacks arc typically not treated. In the past, adrenocorticotropic hormone and oral prednisone were primarily used. More recently, treatment with short courses of intravenous methylprednisolone, 500-1000 mg daily for 3-7 days, with or without a shorr prednisone taper is commonly used. ON may occur anytime during the course of MS or be one of
MULTIPLE SCLEROSIS AND OTTIFR INFLAMMATORY DEMYF.I.INATINt; DISEASES Tabic 60.10:
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Multiple sclerosis treatment strategies Evidence
Disease course/stage
Treatment
Monosymptomatic (e.g., optic neuritis)— Acute attack Rciapsing-remitting, no disease activity for so , T.I I VIM:-,. a ml/or no activitj on MR] Relapsing-remitting, current disease
IV methylprednisoione, 1000 mg for .5 days, without oral taper IV corticosteroids if acute attack occurs
a t t l \ l l v : l l k i (PI
. K i l l l l v ••••
\1U!
Relapsing-remitting, disease activity while on interferon or Copaxone Relapsing-remitting, accumulating disability (interferoii/Copaxoric/corticostcroid non res ponders) Rapidly progressing disability
Very rapidly progressing disabiliry Secondary progressive
Primary progressive
options
IV corticosteroids for acute attacks, plus for prevention (1) interferon iS-lb (Avonex), 30 pg 1M weekly; or (2) interferon p-lb (Betaseron), 1 ml SC qod; or (3) interferon /?-1a (Rebif), 22 or 44 micrograms SC three times/week; or (4) glatiramer acetate (Copaxone), 20 ug SC daily Add monthly bolus of IV methylprednisoione OR oral immunosuppressants IV monthly cyclophosphamide and pulse therapy OR IV mitoxantrone (Novantrone) IV cyclophosphamide and corticosteroid 8-day induction, followed by pulse maintenance Plasma exchange IV corticosteroid monthly pulses IV cyclophosphamide/corticosteroid monthly pulses Methotrexate, oral or SC, 7.5-20 mg/wk, with or without monthly corticosteroid pulses IV corticosteroid monthly pulses Methotrexate, oral or SC, 7.520 mg/wk, with or without monthly corticosteroid pulses Clcidribine, IV or SC Consider mitoxantrone
the initial s y m p t o m s . A r a n d o m i z e d therapeutic trial in ON demonstrated t h a t patients treated with oral prednisone alone were m o r e likely to suffer recurrent episodes of ON as c o m p a r e d with those treated with i n t r a v e n o u s methylprednisoione followed by oral p r e d n i s o n e (Beck et at. 1993). F u r t h e r m o r e , definite MS developed in 7 . 5 % of the intravenous methylprednisoione g r o u p , 1 4 . 7 % of the oral prednisone g r o u p , and 1 6 . 7 % of the placebo g r o u p over a 2-year period (Beck et al. 1993). Five-year data from the same study s h o w e d t h a t C D M S developed in 1 6 % of patients with no M R I lesions at basel ine a n d 5 1 % in patients with 3 or m o r e M R I lesions at baseline. Development of disability, even w h e n the diagnosis of MS had been m a d e , w a s very r a r e , reemphasizing the need for follow-up periods of decades and the benign nature of MS presenting with O N . These data s u p p o r t the use of highdose intravenous methylprednisoione for acute MS a t t a c k s . High-dose intravenous m e t h y l p r e d n i s o i o n e a p p e a r s to be accompanied by relatively few side effects in m o s t patients, a l t h o u g h mental changes, u n m a s k i n g of infections, gastric disturbance'., and an increased incidence of fractures have been reported. Baseline a n d yearly b o n e density scans are
Class I evidence Class I evidence Class I evidence for Avonex, Betaseron Rebif and Copaxone, All four are FDA approved
Class I and 11 evidence Class I evidence for Novantrone, which is FDA approved Class III evidence
Empiric Empiric Class 111 e\ ideuce Class I evidence
I'.nipiric ] ;.m pi vie
F.mpiric Empiric
r e c o m m e n d e d for patients u n d e r g o i n g repeated courses of corticosteroid t h e r a p y . A n a p h y l a c t o i d reactions a n d a r r h y t h m i a s a r e r a r e , but m a y also occur. T h e i m m u n o logical m e c h a n i s m s of high-dose corticosteroids include reduction ot C I ) 4 " cells, decrease in cytokine release from lymphocytes a n d cytokines including T N F , inter feron-y, and decreased class II expression (Kupersmith 1994). Corticosteroids h a v e been s h o w n to decrease IgG synthesis in the C N S a n d reduce CSF a n t i b o d i e s to M B P a n d O C B s . I n t r a v e n o u s m e t h y l p r e d n i s o i o n e m a y decrease the entry of cells into the brain and m a y affect cytokine p a t t e r n s also. T w o o t h e r trials h a v e focused on oral corticosteroid use. A double-blind, ptacebo-controlled trial of oral methylp r e d n i s o i o n e use in acute a t t a c k s involving 51 patients followed over 8 weeks s h o w e d a statistically significant beneficial effect of oral corticosteroids. Patients received a total of 3 6 7 6 mg of oral m e t h y l p r e d n i s o i o n e over 15 days with no serious adverse events. A second r a n d o m i z e d trial of 80 p a t i e n t s evaluated oral versus i n t r a v e n o u s methylp r e d n i s o i o n e in acute relapses. T h e results showed no statistical difference between the t r e a t m e n t g r o u p s .
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NEUROLOGICAL DISEASES
Disease-Modifying Treatments The first meditation approved by the FDA for use in MS was recombinant interferon /t-lb (Betaseron), which has been shown in a double blind, placebo-controlled trial of 372 patients to decrease the frequency of relapses by 34% after 2 years in relapsing-remitting patients receiving 8 mlU every other day (IFNB MS Study Group 1993). In treated patients, the MRI T2 lesion burden went up only 3.6% over 5 years, compared with 30.2% in the placebo group (Paty ct al. 1993). No significant change in disease progression was seen over 5 years. Bclasm>n is administered every other day under the skin by self-injection. Side effects include influenza-like symptoms, depression, and reaaions at the injection site, but these tend to diminish with time. Elevated liver enzymes, leukopenia, and anemia were seen, and blood monitoring is suggested every 3 months. Also 34% of patients developed neutralizing antibodies that may reduce the clinical efficacy of the drug. The mechanism of action of interferon ,8-1 b is currently unknown. A second double-blind, placebo-controlled study in 301 patients with relapsing-remitting disease investigated the efficacy of weekly intramuscular injections of 6 million U (30 ug) of interferon /J-la (Avonex), a glycosylated recombinant interferon-/* (Jacobs et al. 1996). Over 2 years the annual exacerbation rate decreased 2 9 % . After 2 years the MRI data revealed a lesion volume of 122.4 (mean) in the placebo group compared with 74.1 (mean) in the Avonex group. The number of enhancing lesions on MRI over 2 years was 1.65 (mean) in the placebo group and 0.80 (mean) in the Avonex group. The proportion of patients progressing by the end of 104 weeks of the trial was 34.9% in the placebo group and 21.9% in the Avonex group representing a 3 7 % reduction. Adverse events included mild influenza-like symptoms and mild anemia. No skin reactions occurred. Laboratory monitoring is suggested, but not mandatory because no serious liver toxicities occurred. Also, 2 2 % of patients on treatment developed neutralizing antibodies. Glatiramer acetatc/copolymer 1 (Copaxone) is a daily subcutaneous injectable synthetic polymer. In a large double-blind trial in relapsing-remitting MS involving 251 randomized patients (Johnson et al. 1998), the patients receiving Copaxone bad a 2 9 % reduction in the relapse rate over 2 years. Extension data shows that over 140 weeks 4 1 % of patients receiving placebos experienced worsening of their disability by greater than or equal to 1.5 HDSS steps, whereas only 21.6% of Copaxone-treated patients had worsening (Johnson et al. 1998). Side effects included local injection site reactions and transient systemic postinjection reactions including chest pain, flushing, dyspnea, palpitations, and anxiety. No laboratory monitoring is necessary. No neutralizing antibodies were detected in the study. The mechanism by which copolymer 1 may work in humans is unknown.
A randomized, double-blind, placebo-controlled study of interferon fi-& in higher doses was conducted in Europe (European Study Group 1998). This involved 560 patients with relapsing-remitting disease given subcutaneous interferon fi-a (Rebif). Patients were randomized to placebo, 22 pg, or 44 ug of Rebif three times a week for 2 years. There was a 2 7 % reduction in the relapse rate in the group receiving 66 ug per week and a 3 3 % reduction in the group receiving 132 ug per week. The MRI lesion burden showed a decrease of 1.2% in the group receiving 66 pg per week, a decrease of 3.8% in the group receiving 132 ug per week, and an increase of 10.9% in the group receiving a placebo. The side-effect profile was similar to the other interferons. Of note, 23.8% of the group receiving 66 pg per week and 12.5% of the group receiving 132 pg per week were positive for neutralizing antibodies. Rased on this data and a recent comparison trial of Avonex versus Rebif (EVIDENCE), Rebif was approved by rhe FDA in March 2002. Both the EVIDENCE trial and a trial in Europe comparing high- and low-dose interferon (INCOMIN) were short-term trials and do not address the important question of which of these agents, if any, truly suppress the development of long-term disability. It docs appear that there is a detectable dose-response in the use of beta interferons. Another factor to consider is that all four medications (Betaseron, Avonex, Copaxone, Rebif) are contraindicated in pregnancy. With al! three agents, when pregnancy occurs, treatment should be discontinued, and if relapses occur during pregnancy they are treated with intravenous corticosteroids. In addition, the safety of symptomatic medications for pregnancy must be kept in mind when managing these patients (see Table 60.6). Much controversy has arisen since the introduction of the four approved medications for RR-MS. Analysis and comparison of these trials has been difficult because each trial used slightly different statistical, clinical, laboratory, and MRI measures. No direct comparison can be made because in each of the pivotal trials the drug was tested only against placebo. The neutralizing antibody issue is another point of contention. Current consensus does not recommend the routine testing of neutralizing antibody and does not recommend switching between interferons if neutralizing antibodies are in the high titer range. As a general rule, all patients with relapsing forms of MS should be receiving one ol the immunonujJulamry agents indefinitely.
Treatment of Progressive Disease Treatment directed at the progressive phase is the most difficult because the disease may be harder to affect once the progressive stage has been initiated. Immunosuppressive agents such as total lymphoid radiation, cyclosporinc, methotrexate, 2-chlorodeoxyadenosinc, cyclophosphamide
MULTIPLE SCLEROSIS AND OT1 ILK INFLAMMATORY DEMYF.I.INATING DISEASES
1659
(Cytoxan), mitoxantrone, and azathioprine have shown some positive clinical effects in progressive disease. All of these nonspecific immunosuppressive agents suffer from the same basic defect: They may temporarily halt a rapidly progressive downhill course, but it is difficult, or dangerous, to employ them for more than a few months. MS is an illness of decades, not months. Therefore nonspecific immunosuppression often is a temporary solution, even if effective. Total lymphoid irradiation has potent immunosuppressive effects, and a double-blind study of lymphoid irradiation reported benefit in patients with progressive MS. The ahsolute lymphocyte count appeared to be an indicator of therapeutic efficacy, with greater efficacy in patients with lower counts. Many patients began progressing again after initial therapy, and a major limitation of the use of total lymphoid radiation is that it may preclude the use of other treatments that affect the immune system at a subsequent time.
use in MS showed only a small difference in favor of azathioprine after 2 years. Interferon fl-b was studied in patients with secondary progressive MS in 32 centers in Europe. In this study 358 patients received placebo and 360 patients received interferon fi-b every other day subcutaneously for up to 3 years (European Study Group 1998). In the group receiving interferon fi-b a relative reduction of 21.7% occurred in the proportion of patients with progression. The rime to becoming wheelchair-bound was also significantly delayed, equivalent to 12 months (p < 0.01). The mean relapse rate was reduced overall by approximately 3 0 % in the treatment group. In terms of MRI lesion volume, the group receiving placebo showed a mean increase of 8% compared with the group receiving interferon fi-b, which showed a mean decrease ot 5 % . This study has major implications for the treatment of the largest single category of MS, and the effects on the cost of medical care and the search for other treatments arc obvious.
Large multicenter trials of cyclosporine indicate that cyclosporine has a beneficial, albeit modest, effect in ameliorating clinical disease progression, but it has not found clinical use because of the narrow benefit-to-risk ratio. Weekly low-dose oral methotrexate (7.5 mg) was studied in a randomized, double-blind, placebo-controlled trial in 60 patients with chronic progressive disease and has been reported to positively affect measures of upper extremity function in progressive MS. Lower extremity function was not affected (Goodkin et al. 1995). Cyclophosphamide (Cytoxan) has been in use for treatment of patients with MS, despite conflicting data, since the early 1980s. When used, the drug is now given in monthly bolus injections and maintained over a year or more, usually with intravenous cotticostcroids. Effects often can be observed in patients younger than age 40 and especially in those who have been in the progressive phase for less than a year. The drug appears to be ineffective for primary progressive MS. Duration of treatment is limited by the risk of bladder cancer, which appears to increase with time and may depend on total accumulated drug dose.
Monthly bolus intravenous corticosteroids, typically 1000 mg of methylprednisolone, arc used at many institutions for treatment of primary or secondary progressive MS. This use remains empiric because no relevant studies have been reported. Immune globulin may help a number of autoimmune diseases and has been tried in MS. A randomized, placebocontrolled trial of monthly intravenous immunoglobulin in relapsing-remitting MS involved 150 patients over 2 years (Fazekas et al. 1997). In the group receiving placebo there were 11 6 relapses compared with 62 in the group receiving intravenous immunoglobulin, and 3 6 % of the group receiving placebo were relapse-free compared with 5 3 % of the group receiving intravenous immunoglobulin, with a significant p value of 0.03.
A trial of mitoxantrone in 42 patients with active MS was published (Edan et al. 1997), in which patients were treated monthly with cither intravenous mcthytprednisolone plus intravenous mitoxantrone or intravenous methylprcdnisolone alone over 6 months. Although the numbers were small, a statistically significant reduction occurred in the number of relapses and an increase in the number of patients tree of attack. Also, 9 0 % of the group receiving intravenous methyl prednisolone/intra venous mitoxantrone showed no new enhancing lesions on MRI versus only 3 1 % in the group receiving intravenous methylprcduisolone. The risk of cardiotoxicity prevents prolonged usage. Azathioprine has been studied in both relapsingremitting and chronic progressive MS since 1971. A metaanalysis of the results of five double-blind and two single-blind, randomized, controlled trials of azathioprine
Other therapeutic strategies that are in [he process of trial are antibodies against inregrin, which block entry of immune cells into the CNS, antibodies against 11-2 receptor, T-cell vaccination, and other interferons. Accepting the limitations of monothetapy with the interferons or glatiramet, many investigators are attempting combinations with other agents, such as corticosteroids or chemotherapeutic drugs.
ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM) History ADEM is a monophasic demyelinating syndrome that occurs in association with an immunization or vaccination (postvaccination encephalomyelitis) or systemic viral infection (parainfectious encephalomyelitis). It is characterized pathologically by perivascular inflammation, edema, and demyelination within the CNS and clinically by rapid development of focal or multifocal neurological
1660
NEUROLOGICAL DISEASES
Table 60.11: Acute disseminated encephalomyelitis and related disui di'i's Acute disseminated encephalomyelitis Uniphasic parainfectious or postvaccination inflammatory demyelmating disorder of the central nervous system Acute hemorrhagic leukoencephalitis Hyperacute form of acute disseminated encephalomyelitis, usually occurring after upper respiratory infections, with more tissue-destructive pathology Site-restricted forms of monophasic acute inflammatory demyelinating disorders that ma}1 occur after viral illness or vaccination Transverse myelitis Optic neuritis Cerebellitis Brainstem encephalitis Chronic or recurrent forms of parainfectious or post vaccination encephalomyelitis Relationship with multiple sclerosis? Combined peripheral and central nervous system inflammatory demyelinating disorders Post vaccination: rabies, influenza? Postinfectious: measles
dysfunction. The most precise clinical and pathological observations regarding ADEM are derived from case studies in which there has been a close link between the specific virus infection or vaccine and the syndrome. The syndromes arising after acute measles infection or rabies vaccine administration can be considered the prototypes of the illness. When cases with the clinical features of the syndrome occur with viral infections or vaccine administration linked by weak epidemiological data, problems arise (Table 60.11). Postvaccination
Acute
Disseminated
non-neural, human diploid cell vaccine has virtually eliminated neuroparalytic complications of rabies vaccinations. Reports have associated ADEM with other vaccines, including pertussis, rubella, diphtheria, and measles. The association of influenza vaccination, particularly the swine influenza vaccine, with ADEM has been the subject of medicolegal conti nvei s\ . In i..i, (, Al 'I'M is not known in Inassociated with any vaccine currently used in the United States, and the administration of influenza vaccine to people with MS does not induce relapse. ADEM developing after drug administration has been reported with sulfonamides and para-aminosalicylic acid/streptomycin. The aforementioned associations can only be substantiated by strong epidemiological evidence or by the development of a pathognomonic laboratory finding for ADEM, neither of which yet exists. Measles-induced
Acute
Disseminated
Encephalomyelitis
Descriptions of cerebral and cerebellar abnormalities after measles appeared in the mid- to late nineteenth century. By 1928, Ford summarized more than 100 cases and delineated subgroups of cases including those with diffuse cerebral features, focal ot multifocal cerebral findings, cerebellar dysfunction, and spinal cord abnormalities. The overall experience suggests that neurological sequelae complicate 1 in 400 to 1 in 1000 cases of measles infection, and that patients do not develop peripheral nerve damage, nor do relapses occur. The introduction of measles vaccination has greatly reduced the incidence of measles and its neurological complications, but the disease continues to occur in large epidemics in specific geographic areas with at-risk populations.
Encephalomyelitis Idiopathic
The occurrence of neuroparalytic accidents as a consequence of the Pasteur rabies vaccine prepared from spinal cords of rabbits inoculated with fixed rabies virus was recorded soon after introduction of the treatment. Similar neurological complications were observed as a consequence of the Jenner vaccine used for the prevention of smallpox. The concern regarding the presence of neural tissue in vaccines as the majot factor in predisposing to neuroparalytic accidents has led to attempts to develop vaccines devoid of CNS tissue in the case of rabies and to the discontinuation of routine smallpox vaccination because the natural disease has been eradicated. The incidence of encephalomyelitis associated with the original Pasteur rabies vaccine prepared in rabbit brain has been estimated at 1 per 3000-35,000 vaccinations. An incidence rate of 1 per 25,000 vaccinations occurred with duck embryo rabies vaccine, a preparation containing minimal amounts of neural tissue; many of the complications with this vaccine involved the PNS. Introduction of the
Acute
Disseminated
Encephalomyelitis
Cases of acute encephalomyelitis occurring in the setting of nonspecific viral illness arc difficult to diagnose with certainty and to distinguish from episodes of MS. Cases occurring in children at an age too young to overlap with MS are perhaps the most readily delineated. Features deemed characteristic of ADEM include simultaneous bilateral ON, loss of consciousness, meningismus, loss of deep tendon reflexes and retained abdominal reflexes in the presence of Babinski's reflexes, central body temperature of greater than 100"F, and severe shooting limb pains, Recovery from ADEM is more rapid compared with MS (days versus weeks) and usually more complete. Tentative associations with ADEM have been made with a wide array of viral and bacterial infections: rubella, mumps, herpes zoster, herpes simplex, influenza, Epstein-Barr virus, coxsackievirus, Borrelia burgdorferi. Mycoplasma, and Leptospira. IAtvpl III children, an ia'i.il . r u c k •:>I MS is r u i n hundreds of times nunc common than is ADEM.
MULTIPLE SCI.F.ROSIS AND OTHER INFLAMMATORY DEMYELINATINC DISEASES
1661
The hallmark clinical feature of the disorder is the development of a focal or multifocal neurological disorder following exposure to virus or receipt of vaccine. In some, but not all, cases, a prodromal phase of several days of fever, malaise, and myalgias occurs. The onset of the CNS disorder is usually rapid (abrupt or up to several hours), with peak dysfunction within several days. Initial features include encephalopathy ranging from lethargy to coma, seizures, and focal and multifocal signs reflecting cerebral (hemiparesis), brainstem (cranial nerve palsies), and spinal cord (paraparesis) involvement. Other reported findings include movement disorders and ataxia. Each of these findings may occur as an isolated feature or in various combinations. Recovery can begin within days, with complete resolution noted on occasion within a few days, but more often over the course of weeks or months. The mortality varies between 10% and 3 0 % , with complete recovery in 5 0 % . Poor prognosis is correlated with severity and abruptness of onset of the clinical syndrome. In the postrabies vaccine case series, a mortality of 18% was recorded. At a mean follow up of 17 months, 68% "1 survivors were complexly recovered, and 3 2 % were partially recovered, most with minimal deficits. In three patients in the series, a relapse of neurological deficits occurred during the recovery period. No patients were recorded as having relapses after complete recovery had occurred. Measles virus-associated ADEM may carry a worse prognosis than vaccine-associated disease. In earlier series, the occurrence of acute hemiplegia, which was intetprctcd as vascular occlusion and akin to the syndrome of acute hemiplegia of childhood, carried a particularly unfavorable prognosis with respect to recovery. Relapses are rare.
Laboratory Features The hallmark lesions of ADEM are perivascular inflammation and surrounding demyclination within the CNS (Figures 60,13 and 60.14). Vessel necrosis is frequently observed. The demyclinating aspect may be minimal or widespread, with coalescence of the multiple lesions. Some meningeal reaction may be apparent also. Reports of MRI studies, largely from apparent sporadic cases of ADEM, describe multifocal CNS lesions initially indistinguishable from those observed in MS. In ADEM, after several weeks lesions show at least partial resolution without the appearance of new lesions; this is unlike MS. In some cases lesions ean [HTSIM, MKI in ADF.M. .is with MS, is more sensitive than CT scanning, which may in some cases show enhancing lesions. The usual CSF formula is normal pressure, little or no increase in cell count (M:ioxic voituimse patients develop a vegetative state. They begin to open their eyes within a few days
1667
but make no apparent contact with the environment. Motor responses continue to be decorticated or decerebrate posturing. Triple-flexion leg withdrawal may be seen, along with spontaneous clonus, flexor or extensor thrusting of the legs, or shivering, Brainstem reflexes recover quickly; sleep-wake cycles appear. With eye opening, other behaviors emerge such as yawning, bruxism, spontaneous smiling or crying, sneezing, and blinking to threat. Absolutely no consistent nonreflexive response to stimulation can be established with the patient. These patients do not consistently follow moving people or objects with their gaze. They meet the criteria for being called vegetative. If this condition persists for a month after resuscitation, it is considered a persistent vegetative state (PVS) (Ashwal et al. 1995). Pathologically, there is virtually complete forebrain necrosis with preservation of the brainstem. The electroencephalogram (EEG) is diffusely abnormal. Arousal changes may be seen in the EEG record with stimulation of the patient but normal reactive alpha activity is absent. Serial brain scans demonstrate diffuse and multifocal cerebral damage; severe cerebral atrophy develops during ensuing months of survival. These patients must be distinguished from those with central pontine infarctions, who are "locked in" or de-efferented but have normal cognition with preserved awareness. Other comalike states should be distinguished from TVS (American Neurological Association Committee on Ethical Affairs 1993) as well (see Chapter 5).
Cerebral Edema The mechanisms for the development of cerebral edema in hypoxia are discussed in Chapter 65, but the role of edema in A1E remains uncertain. Patients with AIE do not develop papilledema, although ischemic papillopathy may be observed rarely. Measurements of intracranial pressure (ICP) yield equivocal results. In small reported series, some—but not all—postresuscitation patients have had either elevated ICP or evidence of diffuse cerebral edema on imaging studies. Intracranial hypertension may be more likely to occur after cardiac arrest due to respiratory failure. The effects of prearrest hypercapnia and acidosis are unclear. Autopsies of patients in coma due to AIE have revealed the presence of gross brain edema and cerebral liquefaction when there had been both a deep level of coma and prolonged survival (5 days or more). Patients who died within 24 hours of cardiopulmonary arrest (CPA) in deep coma do not show cerebral edema or liquefaction, suggesting that brain swelling is a postnecrotic phenomenon in these patients. In the setting of global anoxic ischemia, the presence of high ICP may portend a poor prognosis related to antecedent widesptead tissue death. There is no established indication for the use
1668
NEUROLOGICAL DISEASES
of corticosteroids, osmotic diuretics, barbiturate-induced coma, hyperventilation, or ventriculostomy.
Delayed Postanoxic Deterioration Occasionally, patients seem to arouse early and begin to recover well from anoxic coma, only to relapse with the appearance of apathy, confusion, gait disturbance, spasticity, incontinence, movement disorders, and dysarthria. Pathologically, there are varying degrees of demyclination in the centrum semiovale, bilateral pallidal necrosis, and patchy cortical necrosis, especially in the hippocampi. With supportive care, these patients may recover but are often left with residua] deficits. This unusual disorder is most often seen after carbon monoxide poisoning, in which the clinical picture is frequently that of parkinsonism. Indu ulimls older than 50 years are at greater risk !ur delayed deterioration. The overall frequency of delayed neurological degeneration in several series of cases of carbon monoxide intoxication approximates 2.75% (Gottfried ct al. 1997). An oligodendroglial injury resulting in delayed demyelination is a speculation.
Other Sequelae Recovery of cognitive functions generally proceeds rapidly during the first several weeks after anoxic injury and seems to plateau by 3 months. Moderate to severe biparietal dysfunction (acalculia, apraxia) occurs in one of every three survivors. Almost one half of patients are left with moderate to severe memory impairment. Problems with planning and organizational skills, as well as depression, arc common. It remains unclear whether these patients may show some continued cognitive recovery in the first several years after their AIE. Movement disorders frequently emerge during recovery from severe hypoxic events. Bilateral hemiparesis, pseudobulbar palsy, parkinsonism, tremor, choreoathetosis, and dystonia may appear as the patient awakens from coma or may develop weeks to months later (Govaerts et al. 1998). Features of different disorders may coexist in a given patient. Treatment is often unsatisfactory, and medications that seem to benefit one problem may well worsen others. Epilepsy is uncommon in surviving postanoxic patients, although one syndrome deserves mention: delayed-onset action sensitive myoclonus (Lance-Adams syndrome) can be extremely disabling and may occur in patients who have made good cognitive recoveries from AIE, Intractable stimulus- and action-sensitive, asynchronous, distal limb myoclonus occasionally emerges days to weeks after recovery from anoxic coma. These patients often improve over the course of years after onset of myoclonus (Werhahn et al. 1997). Clonazepam and valproic acid may be therapeutically effective.
Prognosis of Anoxic Coma after Cardiopulmonary Arrest ("PA is associated with a high rate of morbidity and mortality and is rhe most common cause of severe anoxic injury. Of patients who survive until hospital admission, in-hospital mortality rates range from 54% to 8 8 % . Of those surviving to hospital discharge, 2 0 % die in 1 year, and 4 0 % within 3 years; of the remaining patients, 7 5 % have severe neurological impairment (Mullner et al. 1998), often with severe memory deficits (Mecklinger et al. 1998). Statistics describing the outcome for patients in anoxic coma have varied somewhat in different clinical scries, largely because of patient selection criteria. Some investigators reported series of consecutively tcsuscitated patients, whereas others have selected those who remain in deep coma for some specified period. The clinician must be aware of the differences in selection criteria when attempting to apply a specific set of published statistics to a given patient. The use of sedatives, analgesics, muscle relaxants, or anticonvulsants may weaken the applicability of published statistics to a specific case. Survival after CPA is closely correlated with the duration of coma. Individuals who are either arousablc or fully alert within 12 hours of resuscitation tend to do well neurologically, although they still experience a 2 5 % mortality rate, related primarily to their underlying cardiac disease. In a series of consecutive patients with an overall 4 0 % survival rate, the presence of initial postanoxic unarousability was a negative prognostic sign, with only 2 8 % of that group surviving. The level of consciousness or motor responsiveness to stimulation may fluctuate after resuscitation; a decline within 48 hours is generally associated with a fatal outcome. A declining level of consciousness at any time during hospitalization also is associated with a reduced survival rate and poorer outcome. Prognosis in the first few hours of resuscitation remains uncertain. Patients making reflex responses to pain (decorticate or decerebrate posturing) within 1-3 hours of CPA still have a 2 0 - 3 0 % possibility of survival with good outcome. Patients who achieve arousal within 72 hours of resuscitation may do well. Such arousal, however, does not guarantee either survival or independent functioning. The clinician should be cautiously optimistic while continuing vigorous life support in such situations. Occasional patients do not achieve full alertness for up to 10 days after CPA (Snyder et al. 1980; Snyder et al. 1980). The delay may relate to some superimposed or associated metabolic factor, in which case outcome may still be quite good. A meta-analysis of published work rating prognosis after CPA led to the following conclusions: when evaluated 3 days after CPA, the absence of pupil light reflexes, the absence of any motor response to pain, and the absence of cortical evoked responses (SSEP) to median nerve stimulation were each 100% predictive of a poor outcome or death (Zandbergen et al. 1998).
HYPOXIC/ANOXIC AND ISCHEMIC ENCEPHALOPATHIES Table 61,2: Cranial nerve reflex abnormalities and survival after cardiopulmonary arrest Time after Number of cranial Survivors cardiopulmonary arrest nerve reflex abnormalities* (%) i yet available in the United States, it may have some advantages over lactulose because it can be prepared in a crystalline form that may make it more acceptable to patients who' may object to the taste of lactulose preparations.
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Severe hepatic coma carries a substantial risk of death. Fulminant hepatic failure is usually the result of massive necrosis of hepatocytcs and is defined as a syndrome in which the signs of encephalopathy develop within 8 weeks of the onset of the symptoms of liver disease in a patient with a previously normal liver. This condition has been desctibed as "metabolic chaos," because of coexisting acid-base, renal, electrolyte, cardiac, and hematological abnotmalities, usually culminating in GI bleeding, ascites, sepsis, and death frequently caused by cerebral edema. In spite of intensive treatment, patients who become comatose have an 8 0 - 8 5 % mortality. Improvements in liver transplantation have led to better treatment and improved survival for these patients. Transplantation is associated with its own spectrum of neurological problems (see Chapter 55A).
Uremic Encephalopathy Amino Acids. The hypothesis that altered plasma amino acid ratios (discussed earlier), especially the (valine + leucine + isoleucine) to (phenylalanine + tyrosine) ratio, affect brain neurotransmitter pools has led to attempts to treat encephalopathy by normalizing the blood-amino acid profile with branched-chain amino acids. After preliminary open trials suggested a possible therapeutic benefit, a number of controlled trials were undertaken. Although they failed to show a clear beneficial effect, amino acid solutions (oral and parenteral) are still used. Complications and
Prognosis
The incidence of HE is probably underestimated, mainly because n on-neurologists are usually the primary physicians of these patients and may miss early, subtle signs of cerebral dysfunction. It is important to establish the diagnosis of Lib promptly and proceed with vigorous treatment. Although HE is potentially completely reversible, prolonged or repeated episodes risk transforming this reversible condition into non-Wilsonian hepatocerebral degeneration, a severe disease with fixed or progressive neurological deficits, including dementia, dysatthria, gait ataxia with intention tremor, and chorcoathetosis. Other patients may develop evidence of spinal cord damage, usually manifested by a spastic paraplegia. This complication may be a part of the spectrum of hepatocerebral degeneration. Differentiating correctly between early myelopathy or hepatocerebral degeneration and the motor abnormalities that characterize reversible encephalopathy may not always be possible. Because of the high sensitivity of MRI, M -. ]io-.-.iNr i i.ii rhi-n recln:n In t:ic dcvL-liipruciil of uremic encephalopathy. Disordered water balance is, however, a major factor in the syndrome of dialysis disequilibrium (see Syndromes Related to Dialysis, later in this chapter). Many patients complain of headache, fatigue, and other relatively nonspecific symptoms at the time of dialysis that are attributable to the removal of free water and solutes from the vascular compartment and a lag in re-establishing a new steady-state osmotic equilibrium with the brain. More severe forms of dialysis disequilibrium arc now rare. Before the current level of sophistication in equipment, membranes, and schedules for dialysis was developed, severe abnormalities of the EEG, epileptic seizures, coma, and even death occurred as the result of this syndrome. Calcium and Parathyroid Hormone. Abnormal calcium metabolism and abnormal control of the parathyroid glands are common in uremic patients, including those receiving dialysis. Experimental studies have shown a doubling of the brain calcium content and serum parathyroid hormone levels within days of the onset of acute renal failure. EEG slowing correlates with elevations in the plasma content of the N-terminal fragment of parathormone. Treatment with 1,25 dihydroxyvitamin D leads to improvements in the KEG and reductions in N-reniniial fragment parathyroid hormone concentrations. Brain calcium concentrations may be related to the activity of an ATP-dependent sodium-calcium transporter protein. Neurotransmitters, Disorders of plasma amino acids, most notably glutaminc, glycine, aromatic and branchedchain amino acids, and potential relationships to GABA, dopamine, and serotonin, have led to speculations that neurotransmitter function may be abnormal in patients with uremic encephalopathy. Others have suggested that brain calcium abnormalities may exert an effect on neurotransmitter release. These hypotheses remain unproven. Treatment and Its
Complications
Dialysis is the primary treatment for uremic encephalopathy. This may be preceeded by a period of peritoneal dialysis, which can be administered ro ambulatory patients. Many patients ultimately require transplantation. Epileptic seizures occur in up to one third of all uremic patients. In evaluating patients with seizures, it is essential
to determine whether the seizure is the result of uremia or the consequence of some other coexisting or causative illness, such as malignant hypertension with encephalopathy, intercurrent infection, dialysis disequilibrium syndrome, or cerebral infarction. Usually, the seizures caused by uncomplicated uremia arc generalized, but focal motor seizures and epilepsia partialis continua occur. Treatment of uremic seizures is complicated by abnormalities of anticonvulsant metabolism and plasma binding encountered in patients with renal failure; phenytoin, a mainstay in seizure treatment, is affected particularly. Regardless of the route of phenytoin administration, uremic patients have lower drug levels than do normal controls, and plasma levels ot the metabolite 5-phenyl-5para-hydroxylphenylhydantoin are higher. The half-life of phenytoin is shortened in uremia and unrelated to the binding of phenytoin to plasma proteins or to the volume of distribution. Plasma protein binding studies of phenytoin in normal and uremic patients show that normal people have approximately 8% unbound, or free, whereas uremic patients have between 8% and 2 5 % in the unbound state. The unbound fraction correlates well with both the blood urea nitrogen and the creatinine concentration in Moo J, will1 Ix'lui cnnylaiion with ovar.niiic :h.in blond urea nitrogen. In regulating phenytoin doses in uremic patients, it is critical to use the free drug level rather than the more commonly used total drug level. As a general rule, the free level should be kept between 1 and 2 ug/ml,, roughly 10% of the therapeutic level for total phenytoin. Phenytoin toxicity is difficult to manage in uremic patients because the drug is not removed by dialysis. Phcnobarbital is also a useful drug for treating seizures in uremic patients in spite of the fact that it is excreted by the kidneys. Plasma phcnobarbital levels are unaffected by uremia and may be used to monitor therapy. Orher abnormalities detected on examination of uremic patients include asterixis, tremor (which may appear before asterixis), and myoclonus. These signs do not require specific therapy and usually clear as the mental status responds to dialysis or transplantation. Tetany and spontaneous carpopedat spasms also may occur. Treating renal failure by dialysis and transplantation has given rise to a number of neurological syndromes. Because of the large number of patients being treated by these modalities, especially dialysis, it is important to recognize currently described complications and to be alert to the possibility that new syndromes will emerge as treatment modalities evolve. Although dialysis is clearly an important life-sustaining treatment modality for patients with renal failure, two important neurological syndromes related to this modality are recognized: dialysis disequilibrium syndrome and dialysis dementia syndrome. The former is an acute syndrome that may be seen during or after a single dialysis treatment; the latter is a chronic condition that emerges subacutely or chronically after prolonged treatment by
TOXIC AND METABOLIC ENCEPHALOPATHIES dialysis. The treatment and prophylaxis of these syndromes have become much more successful as our understanding of their pathophysiology has improved. Dialysis disequilibrium syndrome occurs during or immediately after treatment by either hemodialysis or peritoneal dialysis. Symptoms range from subtle signs to death, and include seizures (usually grand mal, although focal seizure's may occur), coma, and death. Other symptoms that may be encountered include disorientation, headache (often associated with nausea, restlessness, or fatigue), muscle cramps, and tremulousness. During the acute syndrome, disorganization and KEG slowing may be seen, and CSF pressure is elevated. EEGs recorded during chronic maintenance hemodialysis show that there is usually some abnormality during the treatment of stable patients, with the most significant abnormalities seen in patients reporting symptoms such as fatigue. The symptoms of dialysis disequilibrium are probably caused by the development of cerebral edema. Uremic patients have increased serum and brain osmolality because of the accumulation of urea and idiogenic osmoles. When rapid hemodialysis is compared with slow hemodialysis, the water and osmole content of brains of the animals treated by rapid dialysis is found to be greater than in those treated by slow dialysis. Urea concentration in the CSF and the brain exceeds the plasma urea concentration in both treatments. Rapid hemodialysis also is associated with the development of CSF acidosis and a significant osmotic gradient between blood and brain not explained by sodium, potassium, chloride, or urea concentration. These conditions result in the obligatory water retention by the brain relative to blood, which causes the brain to swell. Idiogenic osmoles are probably of critical importance in the development of this syndrome. Presumably under conditions of slower dialysis, the brain has an opportunity to rid itself of idiogenic osmoles and is less susceptible to the development of edema during dialysis. The presence of acidosis in the central nervous system also may be important. Recognizing these mechanisms has led ro a rcducuoii in the severity and incidence of this potentially fatal disorder. Dialysis dementia syndrome is now rare and is a more serious syndrome. It is a subacute syndrome of impaired memory with personality changes, apractic dysarthric speech, myoclonus, seizures {usually multifocal), and an abnormal EEG characterized by slowing with multifocal bursts of more profound slowing and spikes. Aluminum levels in the brains of patients with the syndrome are higher than the levels in controls, in uremic patients not receiving dialysis, and in uremic patients on dialysis but without the syndrome. Epidemiological studies of the relationship of the syndrome to the aluminum content of dialysate fluid have established the latter as the probable source of rhe aluminum and the most likely cause of the syndrome. In general, all areas with large numbers of cases of the dialysis dementia syndrome had high aluminum concentrations in dialysis fluid (100-500 pg/liter). Cases occurred most
1 683
frequently in areas with a high aluminum content in the municipal water supply; removal of aluminum from dialysis baths, preferably by deioni/ation, has markedly reduced the incidence of the syndrome. Although it seems clear that the majority of cases of dialysis dementia can be related to aluminum in the dialysate, there are unexplained sporadic cases occurring in centers with low aluminum levels. In these patients, blood aluminum levels appear to be high, suggesting that CI aluminum absorption may be of occasional importance in the pathogenesis of the disorder, Treatment of the syndrome has been difficult, and linksuccess has been reported.
METABOLIC DISTURBANCES Disorders of Glucose Metabolism Under normal conditions, glucose is the exclusive fuel for the brain. The brain, unlike other organs such as rhe liver and skeletal muscle, is able to store only trivial quantities of glucose as glycogen. Because brain glucose concentrations are normally low, approximately 2 5 % of the plasma concentration, and the cerebral metabolic rate for glucose is high, [he brain is highly vulnerable in interruptions in the supply of glucose. Hyperglycemia is tolerated by the brain better than hypoglycemia, but it, too, produces neurological symptoms, largely because of osmotic effects. Physiology Glucose Homeostasis. After ingesting food, blood glucose levels begin to climb, wbich, in concert with a number of complex factors, leads to the release of insulin from the pancreas. Insulin has the combined effects of suppressing hepatic glucose production and fostering the storage of glucose, particularly as glycogen in the liver. After carbohydrate absorption is complete, homeostasis is maintained by hepatic glveogeunlysis. Normally, the liver contains sufficient glycogen stores to maintain the blood glucose concentration at 80-90 mg/dE for 24-36 hours. After this time, glue oncogene sis becomes the principal mechanism for maintaining adequate plasma glucose levels. Alanine and glutamine are the amino acids that, along with lactate and pyruvate, are the most important glucose precursors. Initially, most glue oncogenes is takes place in the liver, but with extended starvation, the kidney begins to produce glucose, accounting for roughly one half of the glucose produced. Approximately one half of the glucose produced in the postabsorptive state is metabolized by the brain. Because the metabolic processes of glucose homeostasis, including insulin release, glycogen break down, and gluconeogenesis, arc complex and involve the pancreas, liver, and other organs, it is not surprising that an extensive list of conditions may present as hypoglycemia.
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NEUROLOGICAL DISEASES
Cerebral Glucose Metabolism. Under normal conditions with a mean CBF of 50 mL/100 g of brain per minute and a glucose concentration of approximately 5 mmol/liter, large amounts of glucose are presented to the brain at all times. Approximately 10% of this total is transported across the BBB by a glucose transporter enzyme that exhibits Michaelis-Mentcn kinetics. Once in the brain, the majority of the glucose is metabolized by the glycolytic pathway and then by the tricarboxylic acid cycle to generate the ATP needed to maintain brain function. Normally, approximately 8 5 % of the glucose that enters the brain is metabolized in this fashion. The remaining glucose is metabolized by the hexose monophosphate shunt and converted to glycogen. After the administration of uniformly labeled glucose, label appears in carbon dioxide in the venous blood in less than 1 minute and eventually appears in a variety of amino acids, proteins, and other compounds. Measuring cerebral glucose metabolism was revolutionized by the development of PET using an 18F-labcled glucose analogue, fluorodeoxyglucose (FDG). FDG PET scans of the brain are an important aspect in the preoperative investigations of patients with intractable seizure disorders. Clinical Aspects
of Hypoglycemia
Diagnosing hypoglycemia on the basis of clinical symptoms is ftaught with hazards. Although the majority of symptoms are attributable to nervous system dysfunction, they are extremely varied, nonspecific, and not always present, even when blood glucose levels are very low. Because of the close link between the symptoms of hypoglycemia and the brain, some authors use the term neuroglycopenia to refer to symptomatic hypoglycemia. There arc three syndromes: acute, subacute, and chronic. The acute syndrome most commonly develops as the result of the action of short-acting insulin preparations or oral and hyperglycemics and begins with vague symptoms of malaise, feeling detached from the environment, restlessness associated with hunger, nervousness that may lead to panic, sweating, and ataxia. Patients may recogni/.e these symptoms. The symptoms respond quickly to oral or parenteral glucose. An EEG during this period may reveal nonspecific abnormalities. Attacks may end spontaneously or proceed rapidly to generalized seizures and coma, with the attendant risk of permanent brain injury. These patients may arrive in the emergency department m coma with no history. The subacute syndrome is the most common form and occurs in the fasting state. Most of the symptoms listed for the acute syndrome are absent. In their place is a slowing of thought processes and a gradual blunting of consciousness with a retention of awareness, although amnesia for the episode is common. The diagnosis may be difficult to establish until the possibility of hypoglycemia is considctcd or routine testing uncovers the abnormality. Hypothermia
is encountered frequently in this form of the disorder, and unexplained low body temperatures always should be followed by a blood glucose measurement. Chronic hypoglycemia is rare and, if confirmed, suggests a probable insulin-secreting tumor or obsessively good control by a diabetic. Plasma hemoglobin A lt . levels arc helpful in making this differential diagnosis. This syndrome is characterized by insidious changes in personality, memory, and behavior that may be misconstrued as dementia. Unlike those of the acute and subacute forms of hypoglycemia, these symptoms are not relieved by administering glucose, suggesting the presence of neuronal injury. Clinical improvement after removal of the source of the exogenous insulin is gradual, extending over periods as long as a year. The symptoms of sweating, tremor, and the sensation of warmth may be attributed to activity of the autonomic nervous system. The inability to concentrate, weakness, and drowsiness arc attributable to neuroglycopenia. Hunger, blurred vision, and other symptoms are of uncertain cause. Diabetics may develop hypoglycemia without being aware of the usual warning symptoms, a condition known as hypoglycemia unawareness, which may occur in a complete or partial form in up to 17% of all episodes in patients with type 1 diabetes (MacLeod et al. 1993). The underlying mechanisms appear to be related to the occurrence of prior episodes of hypoglycemia, altered neuroendocrine responses that regulate blood glucose levels, and central nervous system dysfunction that may interfere with symptom detection and analysis (Lingenfclser et al, 1993). There are special problems associated with detecting hypoglycemia in neonates and children that center on the various nonspecific symptoms {e.g., pallor, irritability, and feeding difficulties) and on the variable sensitivities of individual children to a given plasma glucose concentration. As with adults, the diagnosis is most likely to be made when the physician consciously keeps his or her index of suspicion high and when glucose measurement is done routinely when there is any doubt about a diagnosis. The risk of missing the diagnosis and having irreversible neuronal injury develop in the patient justifies liberal use of screening measures and, in some cases, presumptive treatment with parenteral glucose. Because of the complexity of glucose homeostasis, the causes of hypoglycemia arc many and varied, and a detailed discussion is beyond the scope of this chapter. In general, most authors present a physiological classification as shown in Table 62.3. Drugs are frequently cited as an important cause of hypoglycemia. In some cases the effect of a drug may be pnk'ruiak'i.: by .i l v s n v t i n n of food intake. Ai;i'-v;iyving
causes have been found and should aid in the diagnosis of the disorder. In the newborn period, administration of sulfonylureas to the mother dominated as a cause of
TOXIC AND METABOLIC ENCEPHALOPATHIES, Table 62.3:
Causes of hypoglycemia
Postprandial hypoglycemia (reactive) Postoperative rapid gastric emptying (alimentary hyperinsulinism) Fructose in tolerance Galactosemia I r l k l l i : - intolerance
Idiopathic Fasting hypoglycemia Overuse of glucose Elevated insulin levels Exogenous insulin (therapeutic, factitious) Oral hypoglycemic (therapeutic, factitious) Islet cell disorders (adenoma, nesidioblastosis, cancer) Excessive islet cell function (prediabetes, obesity) Antibodies to endogenous insulin Normal to low insulin levels Kctotic hypoglycemia Hypermetabolie state (sepsis) Rare extra pancreatic tumors Carnitine deficiency Antibodies to endogenous insulin Underproduction of glucose Hormone deficiencies (growth hormone, glucagon, hypoad renal ism) Enzyme disorders Glycogen metabolism (glycogen phosphorylase, glycogen synthetase) Hexosc metabolism (glucose-6-phosphatase, fructose-1,6-bi phosphatase) Glycolysis, Krebs cycle (phosphoenolpyruvate carboxykinase, pyruvate carboxylase, malate dehydrogenase) Alcohol and probably other drugs Liver disease (cirrhosis, fulminant hepatic failure) Severe malnutrition
hypoglycemia. From 0-2 years, salicylate ingestion dominates. Surprisingly, alcohol predominated as a cause in the 2- to 7-year age group. Alcohol-containing cough syrups and alcoholic beverages were responsible. Sulfonylureas again dominate in the 11- to 30-ycat and 50 and older age groups. Alcohol predominated between the ages of 30 and 50 years. Significant numbets of patients in most age groups were encountered in whom beta blockade with propranolol was a factor in masking the symptoms of developing hypoglycemia. The use of beta blockers in patients receiving insulin or oral hypoglycemic agents therefore should be avoided. A number of risk factors have been recognized that predispose to the development of hypoglycemia. These include (in addition to diabetes) decreased caloric intake (usually related to severity of some illness or disruption of dietary routines), uremia, livet disease, infection, shock, pregnancy, neoplasia, and burns. Hypoglycemia is associated with a substantial morbidity. A study of 600 patients with diabetes showed that the frequency of severe hypoglycemia was 1.60 episodes pet patient per year and that it occurred twice as often in patients with the type 1 form of the disorder (MacLeod et al. 1993). Among patients with severe episodes of
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hypoglycemia, injuries and convulsions occurred at rates of 0.04 and 0.02 episodes per patient per year. Five patients had automobile accidents caused by hypoglycemia. Patients with episodes of severe hypoglycemia were more likely to have had priot sevete episodes, were on insulin longer, and had lower hemoglobin A ] c concentrations. A southern California medical examiner found 123 deaths caused by hypoglycemia in a series of 54.S.50 autopsies. The risk of death is highest in patients with the most sevete hypoglycemia and the largest number of risk factors. Among hospitalized patients, whites have the lowest mortality (approximately 6%), whereas black and Hispanic patients have mortalities of 3 0 % and 4 6 % , respectively. Hypoglycemia is a medical emergency, and all patients suspected of being hypoglycemic, including all patients with coma of unknown cause, should be treated with parentetal glucose after adequate blood samples ate obtained fot laboratory testing. It is prudent to dtaw extra blood so that insulin and hemoglobin A| e levels can be measured if indicated by the patient's subsequent coutse. These measures are particularly important in patients with obscure histories and in whom factitious hypoglycemia may be present. The total amount of glucose administeied may be of little consequence if the patient is found to have a notmal or elevated plasma glucose concenttation. Exogenous glucose is harmful to the brain during hypoxia or ischemia, and caution must be exercised in administering glucose to this group of patients. Clinical Aspects
of Hyperglycemia
Although thetc ate many causes of hyperglycemia, diabetic ketoacidosis (DKA), nonketotic hyperosmolar coma, and iatrogenic factors, such as parenteral hyperalimentation, are the most important. DKA is a relatively common disorder affecting patients with type 1 diabetes. It is frequently precipitated by an infectious process in a patient who has been otherwise stable, develops ovet sevetal days, and is heralded by polyuria and polydipsia caused by the osmotic diuresis produced by glucosuria. These symptoms ate followed by anorexia, nausea, disorientation, and coma. On physical examination, sustained hyperventilation is common, especially in patients with severe acidosis. The diagnosis is frequently suspected on the basis ot clinical findings, but labotatory data, including the plasma glucose, arterial blood gases, electrolytes, and an appropriate test for ketone bodies, ate essential fot confirming the diagnosis and management. Nonketotic hyperosmolar coma, by contrast, is a feature of type 2 diabetes and is thus encountered in older patients, commonly as the first manifestation of the disease. This syndiome evolves more slowly than DKA, and the period of polyuria is more prolonged, leading to much mote severe dehydration. Because glucose is a less effective dipsogen than other solutes, watet-sceking behavior is not as strong in this group of patients as it is in patients with
16S6
NEUROLOGICAL DISEASES
hypematremic hyperosmolality, thus promoting the development of dehydration. Suppressed water-seeking behavior, combined with the inhibitory effect of hypertonicity on insulin release, can lead to severe dehydration and hyperglycemia that can be in excess of 2000 mg/dL. The disorder's signs and symptoms are those of hyperosmolality, hypovolemia, and cerebral dysfunction, with epileptic si'i/LLivs inYiirnns! in MUHC individuals. Precipitating factors include infection, gastroenteritis, pancreatitis, and, occasionally, treatment with glucocorticoids or phenytoin. Because many total parenteral nutrition protocols use solutions with high glucose contents, hyperglycemia is a potential complication of their use. DKA is an insulin-deficient state, and insulin is the cornerstone of therapy. In the absence of insulin, peripheral glucose uptake and glycogen formation are reduced, and glycogenosis and lipblysis are accelerated, leading to the formation of acidic ketone bodies and hyperglycemia. When plasma glucose levels exceed the renal threshold (usually approximately 180 mg/dL), glucosuria and a forced osmotic diuresis ensue. The treatment of DKA is designed to reverse these pathophysiological abnormalities and consists of administering insulin to enhance glucose uptake, enhance glycogen formation by nonccrchral tissues, and reduce the rate of ketone body formation that occurs during low-insulin, high-glucagon states that promotes the entry of fatty acids into mitochondria, where they are converted to ketones. Replacing fluid and electrolytes also is required, as is treatment of precipitating factors. It is important to remember that overly vigorous treatment with rapid restoration of plasma osmolality to normal levels can lead to the development of cerebral edema (see Complications of Treatment, later in this chapter). Neurologists may become involved in the diagnosis and management of patients with nonketotic hyperosmolar coma when a patient has no prior history of diabetes and is brought to the emergency department with unexplained coma or seizures. Because hyperosmolality and the associated hypovolemia are usually much more severe in this condition than in DKA, maintaining an adequate blood pressure and cardiac output are the first priorities in treatment. One or two liters of normal saline should be given rapidly to restore blood volume and to begin to reduce plasma osmolality. Additional fluid and insulin therapy then can be initiated as indicated by laboratory and clinical data. These patients may require intensive monitoring with arterial and Swan-Ganz catheters to monitor the circulatory system status and avoid inducing a volume overload; at the same time, adequate amounts of fluid should be given to restore osmolality to normal levels. The exact mechanisms leading to the development of the syndrome, particularly the absence of ketosis, are not fully explained. ComplicationsofTreatment. AlthoughtreatmentofDKA has improved, the mortality rate is still appreciable. The majority of patients who succumb do so because of
FIGURE 62.4 Blood glucose and intracranial pressure during treatment of diabetic ketoacidosis. The untreated hyperosmolar state leads to the intracerebral accumulation of idiogenic osmoles. As blood glucose and osmolality levels decrease during treatment, free water niters the brain more rapidly than idiogenic osmoles arc shed, leading to an increase in intracranial pressure from the swollen brain. This mechanism presumably operates in all cases in which hyperosmolality is corrected rapidly. CSF = cerebrospinal fluid. (Reprinted with permission from Clements, R. S. Jr, Blumenthal, S. A., Morrison, A. D., et al. 1971, "Increased cerebrospinal fluid pressure during treatment of diabetic kcroses," Lancet, vol. 2, pp. 671-675.)
cardiovascular collapse or from complications of the precipitating factor. A small number of patients die unexpectedly when laboratory and clinical indicators all show initial improvement, Clinically, patients with DKA who die experience rapid neurological then cardiovascular deterioration. Postmortem examinations of the brains show lesions similar to those seen in acute asphyxia, including capillary dilation with perivascular and pericellular edema. Death is heralded by a rapid evolution of signs and symptoms indicating an increase in intracranial pressure. Approximately one half of patients die during the initial episode of DKA. The rate and degree to which the plasma glucose level is lowered is not a major risk factor for death. Some degree of cerebral edema attends the treatment of most patients with DKA, occasionally to the high level of 600 mm CSF pressure, as shown in Figure 62.4. The data suggest that at least mild, clinically silent cerebral swelling may be much more common than is realized in cases of DKA. Rare, unknown factors appear to trigger a malignant increase in intracranial pressure in a small number of patients, producing a syndrome characterized by rapid neurological deterioration and death caused by neurological and circulatory collapse. Published experience suggests that if this diagnosis is made, prompt, aggressive treatment of cerebral edema is indicated, preferably using intracranial pressure monitoring as a guide to therapy. Nevertheless, there is still a high mortality. Glucose and Cardiopulmonary Resuscitation. A number of studies suggest that hyperglycemia is associated with an
TOXIC AND METABOLiC ENCEPHALOPATHIES
1687
were less likely to awaken than patients with lower blood glucose levels, they concluded that it is appropriate to restrict the amount of glucose administered during cardiopulmonary resuscitation.
Disorders of Water and Electrolyte Metabolism
FIGURE 62..S Neurochemical consequences of decapitation. Experimental animals were decapitated and then frozen at various times thereafter. Brains were assayed for metabolites, as shown in the figure. As can lie seen, high-energy phosphates are depleted rapidly. Glucose and glycogen also are consumed, generating lactate, as metabolism changes from the normal aerobic condition to an anaerobic state. The changes shown in this figure are analogous to those following acute hypoxia or cerebral infarction. ATP = adenosine triphosphate; P-Crcat = phosphocreatine. (Reprinted with permission from Lowry, O. H. & Pasonneau, J, V. 1964, "The relationships between substrates and enzymes of glycolysis in brain," / Biol Chem} vol. 239, pp. 31-42.)
Patients with abnormalities of water and electrolyte metabolism frequently exhibit signs and symptoms of cerebral dysfunction. Typically, these patients have altered states of consciousness or epileptic seizures that herald the onset of the abnormality. The vulnerability of the nervous system to abnormalities of water and electrolyte balance arises from changes in brain volume, especially the brain swelling that may be associated with water intoxication; the abnormalities are symptomatic almost immediately because the brain is enclosed by the rigid skull. The role played by electrolytes is also important in maintaining transmembrane potentials, neurotransmission, and a variety of metabolic reactions, such as those involving the role of calcium and calmodulin. Although most clinicians are aware of the importance of water and electrolyte disturbances as a cause of brain dysfunction, the importance of the brain in the control of water and electrolytes is less well appreciated. Disordered
increase in the severity of complications of cerebral ischemia and hypoxia. The presumption is that blood, and hence brain, glucose levels are higher in hyperglycemic individuals and that this glucose produces more lactate during the hypoxic-ischemic insult. This sequence is shown in Figure 62.5, in which the metabolic consequences of decapitation in animals are shown. Glucose is metabolized anaerobically to lactate, which, with the hydrolysis of ATP, causes acidosis. A large number of experimental studies suggest that cerebral acidosis is an important determinant of brain injury, including acidosis associated with lactate production during ischemia. The results of these studies have been extended to humans, in whom a less favorable outcome was suggested for stroke patients with diabetes and hyperglycemia compared with euglycemic diabetic stroke patients. A number of animal studies have shown that the risk of neurological injury during resuscitation from cardiopulmonary arrest increases if exogenous glucose is administered. This issue has been investigated in humans by Longstretch et al. (1993), who randomly administered 5% dextrose in water or half-normal saline while treating outof-hospital cardiopulmonary arrest. These treatments did not produce significant differences among three measures of outcome: awakening, survival to admission to the hospital, or discharge from the hospital. However, because patients with ventricular fibrillation or asystole with high blood glucose levels at the time of admission to the hospital
Osmolality
Osmotic Homeostasis. The serum, and hence whole-body osmolality, are regulated by complex neuroendocrine and renal interactions that control thirst and water and electrolyte balance. When serum osmolality increases, the brain loses volume; when osmolality falls, the brain swells, Events related to water loss are illustrated in Figure 62.6. The brain has little protection in terms of volume changes when an osmotic stress is acute. Examples of acme osmotic stress may be found in patients with heat stroke, inadvertent solute ingestion (particularly in infants), massive ingestion of water (which may be psychogenic), hemodialysis, and diabetics with nonketotic coma. When osmotic stress is applied more slowly over a longer period, the predicted volume changes arc smaller than would be expected. The mechanisms that underlie these protective adaptations are not known completely but involve the gain of amino acids in the case of the hyperosmolar state and the loss of potassium in the hypo-osmolar state. Experimental studies have failed to identify all of the osmotically active particles that must exist in the brain after a given osmotic stress is applied. These unidentified molecules are called idiogenic osmoies. Hypo-osmolality and Hyponatremia. Hypo-osmolality almost always is associated with hyponatremia. The diagnosis usually is made by laboratory testing. Conditions associated with hyponatremia are shown in
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NEUROLOGICAL DISEASES Table 62.5: Causes of the syndrome of inappropriate antidiuretic hormone secretion
FIGURE 62.6 Water balance and tlie brain. A reduction in water (or an increase in water loss or solute gain) stimulates tbirst and vasopressin release, leading to increased water conservation and intake, which in turn reduces vasopressin levels and ends thirst. Excessive water intake or excessive water loss leads to hypoosmolality or hyperosmolality and the loss or gain of osmotically active particles in the brain, respectively. Excessively rapid treatment of these conditions may lead to the development of neurological symptoms. ADH = antidiuretic hormone,
T a b l e 6 2 . 4 . W h e n h y p o n a t r e m i a is encountered, a measurement of serum osmolality should be performed to differentiate true from p s c u d o hypo-osmolaliry, which may be encountered in patients with lipemic serum or in neurological patients treated w i t h m a n n i t o l . A large and diverse g r o u p of neurological c o n d i t i o n s is associated with h y p o n a t r e m i a as a result of S I A D H ,
Table 62,4:
Causes of hyponatremia
Combined water and sodium depletion (hypovolemia) Renal loss Primary renal disease Osmotic diuresis (glucose, mannitol) Adrenal insufficiency Nonrenal loss Gastrointesfinal (diarrhea, suction, vomiting) Transcutaneous (sweating, burns) Sequestration (ascites, peritonitis) Hyponatremia without water loss Edema with water and sodium retention Dilutional (iatrogenic, psychogenic)
Malignant neoplasms Small cell carcinoma of lung Pancreas Thymoma Mesothelioma Lymphoma (lymphosarcoma, reticulum cell sarcoma, Hodgkin's disease) Bladder, ureter, prostate Duodenum Ewing's sarcoma Central nervous system disorders Infections (meningitis, encephalitis, abscess, Rocky Mountain spotted fever) Trauma Subarachnoid hemorrhage Infarction Guillain-Barre syndrome Acute intermittent porphyria Hydrocephalus Neonatal hypoxia Shy-Drager syndrome Delirium tremens Systemit lupus erythematosus Drugs Vasopressin Oxytocin Vine a alkaloids Thiazides Chlorpropamide Phcnothia zincs Carbamazepine Clofihratc Nicotine Monoamine oxidase inhibitors Tricyclic antidepressants Cyclophosphamide Narcotics Pulmonary diseases Tuberculosis Other pneumonias Abscess or cavity Empyema Cystic fibrosis Obstructive airway disease Pneumothorax Asthma Positive pressure ventilation Miscellaneous causes Hypothyroidism Acute psychosis Postoperative state Idiopathic
SILA .ell ss ndrome
Hyperosmotic (hyperglycemia or mannitol administration) Syndrome of inappropriate antidiuretic hormone secretion (see Table 62,5) Artifact (laboratory error, hyperlipemia)
as s h o w n in T a b l e 6 2 . 5 . S I A D H is characterized by h y p o n a t r e m i a in the face of n o r m a l or increased blood v o l u m e , n o r m a l renal function, and the absence of factors t h a t n o r m a l l y operate t o p r o d u c e antidiuretic h o r m o n e
TOXIC AND METABOLIC ENCEPHALOPATHIES release. The syndrome may be relatively asymptomatic, in which case water restriction is the treatment of choice. In more severe cases, hypertonic saline combined with a diuretic may be required. Overly zealous treatment may produce central pontine myclinolysis (sec Therapy, later in this chapter). Chronic syndromes have been treated successfully with a variety of drugs, including the tetracycline dcmeclocycliue, which interferes with the action of antidiuretic hormone on the renal tubules. Great care must be taken when considering the diagnosis of SIADH in patients with subarachnoid hemorrhage. Patients with subarachnoid hemorrhage, hyponatremia, and reduced blood volume may not have true SIADH. In these patients fluid restriction may lead to further volume reduction and cerebral infarcts during the period of the highcsi risk for vasospasm, The mechanisms underlying this phenomenon are not clear, but may be related to the complexity of the peptidergic neurotransmitter systems in the vicinity of the third ventricle and to the possibility that they are damaged by the ruptured aneurysm. Damage is especially likely with an aneurysm on the anterior communicating artery. Hyponatremia occurs in approximately 1 % of patients with recent surgical procedures. Because the symptoms are frequently mild or attributed to the surgery itself, this diagnosis may be missed. Typically, these patients seem to do well in the immediate postoperative period and then develop symptoms and signs of encephalopathy. Men and postmenopausal women are less likely to develop postoperative hyponatremia than women who are still menstruating. Complications, such as respiratory arrest, are particularly likely to occur in menstruating women and occur at higher serum sodium concentrations than in men or menopausal women. Thus it is important to be particularly vigilant when evaluating younger women with postoperative encephalopathy. Therapy. The treatment of hyponatremia always has been controversial and has become more so since the link between hyponatremia and the subsequent development of central pontine myclinolysis was recognized and experimental replication of the syndrome achieved. Harris et al. (1993) reviewed this problem. They were not able to identify rite rue a I which sera m sodium was con,.., led, the absolute magnitude of the correction, or the type of solution infused as a factor that predisposed to the development of central pontine myelinolysis. They noted that there are undoubtedly thousands of patients with symptomatic hyponatremia who have been treated successfully using a large number of protocols but who have not been reported. This makes it impossible to estimate the risk of central pontine myclinolysis associated with any given treatment regimen. However, because they were unable ro identify any cases of central pontine myelinolysis among the 185 published examples of symptomatic hyponatremia (published since 1954) in which patients were allowed to "self-correct" during a period of water
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restriction (as opposed to the infusion of saline solutions of varied concentrations), they suggested that the preferred therapy of hyponatremia might be water restriction and discontinuing diuretics. Fraser and Arieff (1997) recommend the use of hypertonic sodium chloride for the treatment of symptomatic hyponatremia. Infusions should be adjusted to increase the plasma sodium concentration at a rate of 1 mmol/liter per hour. Complicating factors such as evidence for cerebral edema or seizures require more rapid correction of the deficit. A rate of 4-5 mmol/ liter per hour was suggested. Hypertonic saline therapy may he discontinued when patients become asymptomatic, when the serum sodium reaches 120-125 mmol/liter, or when the plasma sodium has increased by a total of 20 mmol/liter. Protection of the airway and ventilatory support may he required. Diuretics acting at the loop of Henle, such as furosemide, may be required. It is important to monitor electrolytes at frequent intervals (every 2 hours) and to avoid the administration of excessive amounts of sodium and the production of hypemarremia. Hyperosinoiality. Hyperosmolality is less common than hypo-osmolality but may present with similar symptoms or evidence of intracranial bleeding caused by the tearing of veins that bridge the space between the brain and dural sinuses. Usually, hyperosmolality is diagnosed by laboratory findings of an elevated scrum sodium or, perhaps more commonly, hyperglycemia in diabetics. The syndrome frequently is caused by dehydration, especially in hot climates; by uncontrolled diabetes with or without ketosis; and, less frequently, by central lesions that reset the osmotically sensitive regions of the brain. As with hypoosmolality, cautious correction of the defect is important. Replacement should be given orally, if possible. The first half of the deficit can be given rapidly, but the second half must be given with much more caution to avoid producing iatrogenic brain swelling as the whole-body osmotic pressure decreases. Chronic hyperosmolality is associated with relative brain volume preservation as a result of the production of idiogenic osmoles, as described earlier. Administering free water at a rate that exceeds the rate at which the brain is able to rid itself of idiogenic osmoles is associated with the development of paradoxical brain edema that occurs at a time when serum glucose and electrolyte concentrations are normalized. This is illustrated by the data in Figure 62.4, in which the CSF pressure was measured continuously as hyperglycemia caused by diabetes mellitus was corrected. The increase in intracranial pressure is undoubtedly caused by adapted brain cells imbibing free water as serum osmolality decreases in response to therapy. If patients undergoing treatment for hyperosmolar states develop new neurological signs, including altered consciousness and seizures, rhe diagnosis of brain swelling should be considered, Mannitof treatment to restore osmolality to the
•
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NEUROLOGICAL DISEASES
prior elevated level may be required to prevent death caused by brain swelling. Disorders of Calcium Hypercalcemia and hypocalcemia both have diverse causes associated with disordered parathyroid gland function and a variety of oilier conditions. Under normal circumstances, approximately one half of the total serum calcium is bound to proteins, mainly albumin, and one half is in the ionized form, the only form in which it is active. When there is doubt about the ionized calcium concentration, as in patients with hypoalbuminemia, direct measurement of ionized calcium with ion-sensitive electrodes may be required. Hypercalcemia is associated with hyperparathyroidism; granulomatous diseases, especially sarcoidosis; treatment with drugs including thiazide diuretics; vitamin D; calcium itself; tumors that have metastasized to bone; and thyroid disease. Many cases are idiopathic. The symptoms and signs of hypercalcemia may be protean. Severe hypercalcemia affects the brain directly, causing coma in extreme cases. In this group of patients, metastatic tumors are common, especially multiple myeloma and tumors of the breast and lung. Cancer patients seem to be particularly vulnerable to developing hypcrcaleemia after a change in therapy. Less severe hypercalcemia may cause altered consciousness with a pseudodementia syndrome and weakness. GI, renal, and cardiovascular abnormalities also may be present. Severe hypercalcemia is life threatening. Initial treatment consists of a forced diuresis using saline and diuretics. Because the volumes ol saline thai are required ma\ helarge, a central venous or Swan-Ganz catheter may be needed lo monitor thcrap-.. OIKC the initial phase ol treatment is accomplished, further management is determined by the cause of the hypcrcaleemia. f lypocalcemia usualh is associated with hypoparathyroidism. The neurological symptoms are caused by the enhanced excitability of the nervous system. Symptoms include paresthesias around the mouth and fingers, cramps caused by tetanic muscle contraction, and, in more extteme cases, epileptic seizures. In more chronic hypocalcemia, headache caused by increased intracranial pressure may occur, and extrapyramidal signs and symptoms such as chorea or parkinsonism may be encountered. These patients may have calcification of the basal ganglia, evident on computed tomographic scans of the brain. The physical examination should include attempts to elicit Chvostek's and Trousseau's signs. Cataracts and papilledema may be seen. Severe hypocalcemia should be treated with infusions of calcium to treat or prevent epileptic seizures or laryngeal spasms, both of which are life-threatening but unusual complications. Chronic therapy usually involves the administration of calcium and vitamin D. Care must be taken to
avoid hypercalcemia and hypercalciuria. Consultation with an endocrinologist is prudent, but continued neurological care may be necessary, especially in patients with extrapyramidal syndromes, who may require specific treatment. Disorders
of Magnesium
Hypermagnesemia is an unusual condition because ol unease with which normal kidneys act to preserve magnesium homeostasis. The most frequent cause of hypermagnesemia is infusions given to treat symptoms of eclampsia, in which its effect to lower blood pressure and inhibit the nervous system is desirable. Care must be observed in administering magnesium to patients with renal failure. This group of patients is the most vulnerable and the most likely to develop hypermagnesemia because the kidneys' homeostatic function is impaired. Hypocalcemia potentiates the effects of excess magnesium. Severe hypermagnesemia is life threatening, and concentrations in excess of 10 mEq/liter must be treated. Discontinuation of magnesium preparations usually suffices. When cardiac arrhythmias are present or circulatory collapse is possible, calcium must be infused, especially when hypocalcemia is present. Isolated Hypomagnesemia is unusual. Magnesium deficiency usually occurs in patients with deficiencies of other electrolytes. Hypomagnesemia may result from a diet deficient in magnesium, including prolonged parenteral alimentation with insufficient or no magnesium replacement, malabsorption, and alcoholism. Excess magnesium loss from the GI tract or the kidneys also can lead to calcium deficiency. Magnesium deficiency is usually part of a complex electrolyte imbalance, and accurate diagnosis and management of all aspects of the state are necessary to ensure recovery. Pure magnesium deficiency has been produced experimentally and is expressed primarily through secondary reductions in serum calcium levels in spite of adequate dietary calcium intake. Ultimately, anorexia, nausea, a positive Trousseau's sign, weakness, lethargy, and tremor develop but are rapidly abolished by magnesium repletion. Balance studies indicate that magnesium deficiency causes a positive sodium and calcium balance and a negative potassium balance. Magnesium is necessary for proper mobilization and homeostasis of calcium and the intracellular retention of potassium. Some of the effects of magnesium depletion are secondary to abnormalities of potassium and calcium metabolism. Disorders
of Manganese
Manganese poisoning occurs primarily in manganese ore miners and causes parkinsonism. As presented in the section on HE, there is increasing evidence rhat accumulation of this metal in the brain causes the Tl MR! hyperintensities and may be associated with disorders of dopaminergic neurotransmission.
TOXrC AND METABOLIC ENCEPHALOPATHIES DRUG OVERDOSE AND TOXIC EXPOSURES The tentative diagnosis of intentional or accidental drug overdose must be considered during the course of the evaluation of almost all emergency department patients with altered behavior (see Chapter 64B). Most overdoses are attributable to drugs in one of six groups that account for more than 8 0 % of all positive laboratory results. They are, in order of decreasing frequency, ethanol, benzodiazepines, salicylates, acetaminophen, barbiturates, and tricyclic antidepressants. Table 62.6 classifies dtugs into four groups based on the usefulness of toxicotogieal information and the relationships between drug levels and symptomatology. Regional poison control centers usually are staffed by well-informed, helpful personnel and should be consulted when further information is needed or there is uncertainty about the contents of specific products. Reported patterns of drug overdoses vary among communities and with time. Illicit drug availability varies substantially by region and evolves constantly. So-called designer drugs arc unpredictable. As benzodiazepine use has increased and replaced barbiturates used as sleeping pills, barbiturate intoxications have declined. The prevalence of overdose varies as a function of the numbet of prescriptions written.
Miscellaneous Disorders Neurologists may be asked to evaluate patients with vague complaints such as headache, poor concentration and memory, and other symptoms to determine whether toxin exposure is a contributing factor. These requests may occur during the coutsc of ordinary patient care, litigation, or more systematic population-based investigations, hi some instances, the doctor-patient relationship is clouded by political or legal ramifications of the questions asked and the possible answers. Concerns about Gulf War syndrome
Tahlc 62.6:
Characteristics of drug overdose
1. Toxicity predicted by drug level—specific therapy determined by toxicology Acetaminophen, digoxin, ethylene glycol (not detected by most systems), lithium, salicylates, theophylline 2. Toxicity parallels drug level—supportive care required Barbiturates, ethanol, phenytoin 3. Toxicology confirms only clinical impression—clinical decisions determined by direct patient evaluation Cyanide, narcotics, organophosphates, tricyclic antidepressants 4. Toxicity correlates poorly with drug level—clinical decisions determined by direct patient evaluation Amphetamines, benzodiazepines, cocaine, hallucinogens, neuroleptics, phencyclidine, phenylpropanolamine Source: Based on Mahoney, J. D., Gross, P. L., Stern, T. A., et al. 1930, "Quantitative scrum toxic screening in the management of suspected drug overdose," Am} Emer Med, vol. 8, pp. 16-22.
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typify this dilemma. Many veterans of the Persian Gulf conflict contend that a variety of problems ranging from the complaints outlined previously to more definitive problems, such as amyotrophic lateral sclerosis, a variety of cancers, birth defects among their children, and others, are the consequence of exposure to chemicals, including insecticides, pytidostigmine bromide, and nerve agents. This anxiety was heightened by the revelation in the summer of 1997 that the destruction of a munitions depot in Khamisiyah, Iraq, in March 1991 released a cloud of sarin that exposed almost 100,000 troops to this nerve agent. Kven though there were no documented acute effects of sarin on the exposed combatants, suspicion and distrust of the federal authorities charged with evaluating the Gulf War veterans were heightened by the chatges of cover-up that were inevitable because of the delay in acknowledging the exposure. In spite of investigations that have failed to show excess mortality in Gulf War veterans, increases in birth defects in their children, or more frequent hospitalizations, this issue is far from settled. The findings of a Presidential Advisory Council and an independently chartered commirtce appointed by the National Academy of Sciences Institute of Medicine also have failed to satisfy those who believe that Gulf War syndrome is a real entity. A similar and parallel situation has arisen among some who complain that pesticide exposure has affected their health. Because many pesticides are organophospbate cholinesterase inhibitors (OPCIs; differing from nerve agents in potency), links between exposure and a variety of complaints have been claimed or sought. "Worldwide, OPCIs are a common cause of death in agricultural workers, particularly in underdeveloped nations. In Western countries, death is less common, but accidental or intentional exposure may occur (ingestion by children, overdose among adults and agricultural workers). OPCIs may cause peripheral neuropathy, as described in Chapter 64B, and a subacute condition characterized by proximal weakness and respiratory failure known as intermediate syndrome. Comparisons among control populations and OPCIexposed subjects have shown differences in performance on certain neuropsychological tests, buttressing claims of disability and distress among exposed individuals. Epidemiological, case control, and animal model studies all suggest that pesticide exposure may be related to the subsequent development of Parkinson's disease (Lockwood 2000). Efforts to redefine pesticide tolerances, the maximal permissible concentration of pesticides in food, arc complicated by predictable disagreements between pesticide manufacturers and public lie,l till groups. Recently [he pesticide industry has sponsored experiments that appear to be designed to raise tolerances. In these studies, pesticides have been administered to volunteers who are monitored for adverse effects. Ethical challenges to these studies arc unresolved. The clinical neuroscience community faces a major challenge in aiding regulatory bodies as they develop
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NEUROLOGICAL DISEASES
rules that govern e x p o s u r e to potential toxins t h a t respect the b o u n d a r i e s of science while providing a d e q u a t e protection for the public a n d social accountability.
KLH'RIiNCLS Adams, R. D. & Foley, J. M. 1953, "The neurologicil disorder associated with liver disease," Res Pub! Assoc Res Nerv Ment Ms, vol. 32, pp. 198-237 Blci, A. T. Be Cordoba, J. 2001, "Practice guidelines: Hepatic encephalopathy," Am J Gastroenterol, vol. 96, pp. 1968-1975 Ferenci, P., Lockwood, A., Mullen, K., et al. 2002, "Hepatic encephalopathy—Definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11 World Congress of Gastroenterology, Vienna, 1998," Hepatology, vol. 35, pp. 716-721 Frascr, C. L. & Arieff, A. I. 1997, "Epidemiology, pathophysiology, and management of hyponatremia encephalopathy," Am } Med, vol. 102, pp. 67-77 Harris, C. P., Townscnd, J. J., & Baringer, J. R. 1993, "Symptomatic hyponatremia: Can myclinolysis be prevented by treatment?" / Neurol Neurosurg Psychiatry, vol. 56, pp. 626-632
I.ingenfelscr, T., Rcnn, W., Sommerwerck, U., et al. 1993, "Comprised hormonal counterrcgnlation, symptom awareness, and neurophysiology;a I function after recurrent short-term episodes i>! insulin induced hypoglycemia in ID DM patients," Diabetes, vol. 42, pp. 610-618 Lockwood, A. H. 2000, "Pesticides and parkinsonism: Is there an etiological link?" Ciirr Opin Neurol, vol. 13, pp. 687-690 Lockwood, A. H., Weissenborn, K., Bokcmeyer, M., et al. 2002, "Correlations between cerebral glucose metabolism and neuropsychological test performance in non-alcoholic cirrhotics," Metabo Brain Ms, vol. 17, pp. 259-270 Lockwood, A. H., Weissenborn. K., & Rutterworth, R. F. 1997, "An image of the bram in patients with liver disease," Curr Op'm Neurol, vol. 10, pp. 525-533 Longstreteh, W. T„ Jr., Copass, M. K., Dennis, C. K., et al. 1993 "Intravenous glucose after out-of-hospital cardiopulmonary arrest: A community-based randomized trial," Neurology, v o l . 4 3 , no. 12, pp. 2534-2541 MacLeod, K. M., Hepburn, D. A., & Frier, B. M. 1993, "Frequency and morbidity of severe hypoglycemia in insulin-treated diabetic patients," Diabetic Med, vol. 10, pp. 238-245 Norenberg, M. D. 1998, "Astroglial dysfunction in hepatic encephalopathy," Metab Brain Dis, vol. 13, no, 4, pp. 319-335
Chapter 63 Deficiency Diseases of the Nervous System Yuen T. So and Roger P. Simon Vitamin B^ Deficiency t 1iniv.il
I ' .iliiivs
Laboratory Studies Physiology lliih. herniary Pathology Pathogenesis and Etiology Course and Prognosis Treatment and Management Folate Deficiency and Homocysteine Clinical Features Laboratory Studies Pathogenesis and Etiology Treatment and Management Vitamin F. Deficiency Clinical Features Laboratory Studies Physiology and Biochemistry Pathology Pathogenesis and Etiology Treatment and Management Pellagra (Nicotinic Acid Deficiency) Clinical Features Treatment and Management Vitamin B6 (Pyridoxine) Deficiency
1694 1694 1694 1695 1696 1696 1696 1697 1697 1697 1697 1698 1698 1698 1698 1698 1698 1699 1699 1699 1699 1699 1700 1700 1700
Undernutrition causes a wide spectrum of neurological disorders. Although deficiency of almost any nutrient can lead to some kind of neurological symptoms, the B vitamins (thiamine, pyridoxine, nicotinic acid, and vitamin B12), vitamin E, and perhaps folic acid are the most important to the nervous system. Despite great advances since the turn of the twentieth century, nutritional deficiency is still a serious worldwide problem. Kwashiorkor and marasmus arc endemic in many underdeveloped countries. The problem in Western countries is usually the result of dietary insufficiency from chronic alcoholism or malabsorption states from gastrointestinal (GI) diseases. Drugs such as isoniazid and hydralazine also interfere by altering vitamin metabolism. Most causes of nutritional deficiency, whether dietary or malabsorptive, do not selectively deplete a single vitamin. This is especially true among the malnourished populations in underdeveloped countries, in which the diet may lack more than one vitamin, and overlapping neurological syndromes are the result. One exception is pernicious anemia, in which malabsorption is restricted to vitamin Bu-
History Clinical Features Treatment and Management Beriberi (Thiamine Deficiency Polyneuropathy) Clinical Features Laboratory Studies ['livsi(>loi;\ .uitl Biiifbcmistry Pathology Epidemiology Course and Prognosis Treatment and Management Infantile Beriberi Wernicke-Korsakoff Syndrome Wernicke's Encephalopathy Korsakoff's Syndrome Other Nutritional Diseases Associated with Alcoholism Alcoholic Neuropathy Tobacco-Alcohoi or Nutritional Amblyopia Marchiafava-Bignami Disease Alcoholic-Nutritional Cerebellar Defeneration Miscellaneous Deficiency Diseases Strachan's Syndrome and Related Disorders Vitamin A Vitamin D Protein-Calorie Malnutrition
1700 1700 1701 1701 1701 1701 1701 1702 1702 1702 1702 1702 1702 1702 1704 1704 1705 1705 1706 1706 1706 1706 1707 1707 I 708
Individual vitamin requirements are influenced by many factors. The daily need of thiamine and nicotinic acid, important compounds in energy metabolism, increases proportionally with increasing caloric intake and energy need. For example, symptoms of thiamine deficiency often occur in at-risk patients during periods of vigorous exercise and high carbohydrate intake. Other factors, such as growth, infection, and pregnancy, may worsen deficiency states, although the relationship is not precisely known. Vitamin requirement is genetically determined in some cases, as in some infants dependent on unusually large doses of pyridoxine to prevent seizures. Low scrum levels of vitamins in many individuals do not necessarily correlate with the occurrence of symptoms, and laboratory data should always be interpreted in light of clinical findings. The most frequent neurological deficits fall into several categories (Table 63.1). Peripheral neuropathy, the most common, occurs with the deficiency of many vitamins. Cerebral dysfunction, ranging from mental dullness to acute encephalopathy, may occur with deficiency of vitamin B] 2 or in Wernicke-Korsakoff syndtome. Myelopathy usually suggests a deficiency of vitamin iil2, although vitamin E 169.1
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NEUROLOGICAL DISEASES
Tabic 63.1:
Neurological manifestations in deficiency diseases
Neurological manifestations
Associated nutritional deficiencies
Peripheral neuropathy
Thiamine, vitamin B ] ; , vitamin E, pyridoxine, folate Vitamin B|>, nicotinic acid, thiamine, folate Pyridoxine Vitamin B12, vitamin E, folate Vitamin D, vitamin E Vitamin B12, thiamine, folate, and probably others Vitamin ¥.
Dementia, encephalopathy Seizures Myelopathy Myopathy Optic neuropathy Spinocerebellar degeneration
and folate have been implicated in rare instances. A spinocerebellar degeneration may occur with severe vitamin E deficiency.
results from pyramidal tract dysfunction and is most sevete in the legs, ranging from mild clumsiness and byper-reflexia to spastic paraplegia and extensor plantar responses. Visual impairment occasionally is encountered and may antedate other manifestations of vitamin deficiency; ophthalmological examination reveals bilateral visual loss, optic atrophy, and centrocecal scotomata. Brainstem or cerebellar signs, or even reversible coma, may occur.
Laboratory Studies As most patients present with clinical features suggesting a myelopathy or encephalopathy, imaging studies are necessary to exclude structural causes. Magnetic resonance imaging (MRI) abnormalities may be seen in tin- lateral or posterior columns in patients with subacute combined degeneration (Figure 63.1). Both treatment-reversible T2
VITAMIN B ] 2 DEFICIENCY The terms vitamin B\2 and cobalamin are used interchangeably in the literature. Cobalamins are abundant in meat, fish, and most animal by-products. Although vegetables are generally devoid of the vitamin, strict vegcranu:^ alnu.M ik'\cr develop a clinical deficiency, because only 1 ug of vitamin B | 2 is needed per day, and an adequate amount is available in legumes. Intestinal absorption of vitamin R !2 requires the presence of intrinsic factor, a binding protein secreted by gastric parietal cells; inadequate availability7 of intrinsic factor is probably the most common cause of vitamin Bi 2 malabsorption. The transport protein transcobalamin II binds Bj 2 and is important in transporting it to the liver. Deficiencies may also occur with derangement of this transport process.
Clinical Features The onset of symptoms is insidious, with paresthesias in the hands or feet in the majority of patients. Weakness and unsteadiness of gait are the next most frequent complaints. Lhermitte's sign may be present, and a myelopathy may develop. Cerebral symptoms, such as mental slowing, depression, confusion, delusions, and hallucinations, are quite common, and occasionally patients present with only cognitive or psychiatric symptoms. Many patients also complain of dyspepsia, flatulence, altered bowel habits, or other GI symptoms. On examination, most patients show signs of both peripheral nerve and spinal cord involvement, although either can be affected first in the early stage of the disorder. Loss of vibration or joinr position sense in the legs is the most consistent abnormality. If impaired position sense is severe, Romberg's sign may be present. Tendon reflexes often are decreased or absent in the legs, although the effect on reflexes is quite variable. Motor impairment, if present,
FIGURE 63.1 Vitamin B| 2 deficiency myelopathy. Gadolinium enhanced, Tl-weighted cervical and upper thoracic MRI image •Jiriv-.Ty. iin:ki'd ailiancc-mc-nt ol pnstcrioi i> instances were methodologically flawed. Furthermore, workers performing the same basic tasks in different companies have highly variable levels of solvent exposure, complicating the interpretation of published studies (Horstman et al. 2001). Because of these factors, the existence of so-called "painter's encephalopathy" in those
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NEUROLOGICAL DISEASES
exposed to low levels of organic solvents for a prolonged period remains uncertain.
Styrene Styrene is used for manufacturing reinforced plastic and certain resins. Occupational exposure occurs by the dermal or inhalation routes and is typically associated with exposure to a variety of other chemicals, thereby making it difficult to define the syndrome that occurs from styrene exposure itself. Acute exposure to high concentrations of styrene has led to cognitive, behavioral, and attentional disturbances. Less clear are the consequences of exposure to chronic low levels of styrene. Abnormalities in psychomotor performance have been reported, but there is little compelling evidence of persisting neurological sequelae in this circumstance. Visual abnormalities (impaired color vision and reduced contrast sensitivity) have also been described (Castillo et al. 2001).
Toluene Toluene is used in a variety of occupational settings. It is a solvent for paints and glues and is used to synthesize benzene, nitrotoluene, and other compounds. Exposure occurs among workers laying linoleum, spraying paint, and working in the printing industry, particularly in poorly ventilated locations. Chronic high exposure may lead to cognitive disturbances and to central neurological deficits with upper motor neuron, cerebellar, brainstem, and cranial nerve findings and tremor. An optic neuropathy may occur, as may ocular dysmetria and opsoclonus. Disturbances of memory and attention characterize the cognitive abnormalities, and subjects may exhibit a flattened affect. M,I::IH'IK K-MJIUIKV ::ii;i;;i:u:. :MRI) shows
cerebral atrophy and diffuse abnormalities of the cerebral white matter; symmetrical lesions may be present in the basal ganglia and thalamus and the cingulate gyri. Thalamotomy may ameliorate the tremor (Miyagi et al. 1999). Lower levels of exposure lead to minor neurobeksvior.il disUirhina-..
Tricliloro ethylene Trichloroethylene is an industrial solvent and degrcaser that is used in dry cleaning and the manufacture of rubber. It also has anesthetic properties. Recreational abuse has occurred because it may induce feelings of euphoria. Acute low-level exposure may lead to headache and nausea, but claims that an encephalopathy follows chronic low-level exposure are unsubstantiated. Higher levels of exposure lead to dysfunction of the trigeminal nerve, with progressive impairment of sensation that starts in the snout area
and then spreads outward. This has been particularly associated with rebreathing anesthetic circuits where the trichlorcthylcnc is heated by the carbon dioxide absorbent. With increasing exposure, facial and buccal numbness is followed by weakness of the muscles of mastication and facial expression. Ptosis, extraocular palsies, vocal cord paralysis, and dysphagia may occur also, as may an encephalopathy, but occurrence of a peripheral neuropathy is uncertain. The clinical deficit relates to neuronal loss in the cranial nerve nuclei and degeneration in related tracts. With discontinuation of exposure, the clinical deficit generally resolves, sometimes over 1-2 years, bur occasional patients are left with residual facial numbness or dysphagia.
Vacor Vacor, a rodenticide, has led to severe autonomic dysfunction accompanied by a usually milder sensorimotor axonopathy following its ingestion. The mechanism by which this develops is unclear, but it may relate to an impairment of fast anterograde axonal transport. Acute diabetes mellitus also resulrs from necrosis of the beta islet cells of the pancreas.
METALS Aluminum Aluminum exposure is responsible for dialysis encephalopathy, which is characterized by speech disturbances, cognitive decline, seizures, and myoclonus.
Arsenic Arsenic poisoning can result from ingestion of the trivalent arsenite in murder or suicide attempts. Large numbers of persons in areas of India, Pakistan, and certain other countries are chronically poisoned from naturally occurring arsenic in ground water (Hall 2002). Traditional Chinese medicinal herbal preparations may contain arsenic sulfide and mercury and arc a source of chronic poisoning. Uncommon sources of accidental exposure include burning preservative-impregnated wood and storing food in antique copper kettles. Exposure to inorganic arsenic occurs in workers involved in smelting copper and lead ores. With acute or subacute exposure, nausea, vomiting, abdominal pain, diarrhea, hypotension, tachycardia, and vasomotor collapse occur and may lead to death. Obtundation is common, and an acute confusion a 1 state may develop. Arsenic neuropathy takes the form of a distal axonopathy, although a demyelinating neuropathy is found soon after acute exposure. The neuropathy usually
EFFECTS OF OCCUPATIONAL TOXINS ON THE NERVOUS SYSTEM develops within 2-3 weeks of acute or subacute exposure, although the latent period may be as long as 1-2 months. Symptoms may worsen over a few weeks despite lack of further exposure, but eventually stabilize. With low-dose chronic exposure, the latent period is more difficult to determine. In either circumstance, systemic symptoms arc also conspicuous. With chronic exposure, similar but less severe gastrointestinal disturbances develop, as may skin changes such as melanosis, keratoses, and malignancies. Mees' lines are white transverse striations of the nails (striate leukonychiae) that appear 3-6 weeks after exposure (Figure 64A.1). As a nonspecific manifestation of nail matrix injury, Mees' lines can be seen in a number of other conditions, including thallium poisoning, chemotherapy, and a variety of systemic disorders. The neuropathy involves both large- and small-diameter fibers. Initial symptoms are typically of distal, painful dysesthesias and are followed by distal weakness. Proprioceptive loss may be severe, leading to marked ataxia. The severity of weakness depends on the extent of exposure. The respiratory muscles are sometimes affected, and the disorder may simulate Guillain-Barre syndrome both clinically and electrophysiologically. Elcctrodi a gnostic studies may initially suggest a demyelinating polyradiculoneuropathy, but the changes of an axonal neuropathy subsequently develop. Arsenic levels in hair, nail clippings, or urine may be increased, especially in cases of chronic exposure. Detection of arsenic in urine is diagnostically useful within 6 weeks of a single large-dose exposure or during ongoing low-level exposure. Inorganic arsenic values over 25 ug per 24 hours are abnormal. Methods are available in reference laboratories to distinguish between inorganic (toxic) and organic (sea food-derived) arsenic compounds. Arsenic bound to keratin can be detected in hair or nails
FIGURE 64A.1 Mees' lines in arsenic neuropathy.
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months to years after exposure. Pubic hair is preferable to scalp hair for examination because it is less liable to environmental contamination. Levels exceeding 10 ug/g of tissue arc abnormal. Other abnormal laboratory features include aplastic anemia with pancytopenia and moderate cerebrospinal fluid protein elevation. Nerve conduction studies in chronic arsenic neuropathy reflect the changes of distal axonopatby with low-amplitude or unelicitable sensory and motor evoked responses and preserved conduction velocities. Electromyography typically shows denervation in distal extremity muscles. In the subacute stages, however. Mime clectropl'.\ siolnejcil v.mnv-., such .is partial motor conduction block, absent F responses, and slowing of motor conduction velocities are suggestive of demyelinating polyradiculoneuropathy. Progressive slowing of motor conduction velocities sufficient to invoke consideration of segmental demyelination has been reported in the first three months after massive exposure. Biopsies of peripheral nerves show axonal degeneration in chronic cases. Arsenite compounds react with protein sulfhydryl groups, interfere with formation of coenzyme A and several steps in glycolysis, and are potent uncouplers of oxidative phosphorylation. These biochemical reactions are responsible for the impaired neuronal energy metabolism, which in turn results in distal axonal degeneration. Chelation therapy with either water-soluble derivatives of dimercaprol (DMSA or DMPS) or penicillamine is effective m controlling the systemic effects of acute arsenic poisoning and may prevent the development of neuropathy if it is started within hours of ingestion (Graeme and Pollack 1998). There is little evidence that chelation in the later stages of arsenic neuropathy promotes clinical recovery. The neuropathy itself often improves gradually over the course of many months, but depending on the
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NEUROLOGICAL DISEASES
severity of the deficit when exposure is discontinued, a substantial residual neurological deficit is common.
Lead Occupational exposure to lead occurs in workers in smelting factories and metal foundries and those involved in demolition, ship breaking, manufacturing of batteries or paint pigments, and construction or repair of storage tanks. Occupational exposure also occurs in the manufacture of ammunition, bearings, pipes, solder, and cables. Nonindustrial sources of lead poisoning are home-distilled whiskey, Asian folk remedies, earthenware pottery, indoor firing ranges, and retained bullets. Lead neuropathy reached epidemic proportions at the end of the nineteenth century because of unfcontrolled occupational exposure but now is rare because of strict industrial regulations. Exposure also may result from ingestion of old paint in children with pica and consumption of illicit spirits by adults. Absorption is commonly by ingestion or inhalation but occasionally occurs through the skin. The toxic effects of inorganic lead salts on the nervous system commonly differ with age, producing acute encephalopathy in children and polyneuropathy in adults. Children typically develop an acure gastrointestinal illness followed by behavioral changes, ^HIIUMHM. drowsiness, reduced alertness, focal or generalized seizures, and {in severe cases) coma with intracranial hypertension. At autopsy, the brain is swollen, with vascular congestion, perivascular exudates, edema of the white matter, and scattered areas of neuronal loss and gliosis. In adults, an encephalopathy is less common, but behavioral and cognitive changes are sometimes noted. In adults, lead produces a predominantly motor neuropathy, sometimes accompanied by gastrointestinal disturbances and a microcytic, hypochromic anemia. The neuropathy is manifest primarily by a bilateral wrist drop sometimes accompanied by bilateral footdrop or by more generalized weakness that may be associated with distal atrophy and fascieulations. Sensory complaints are usually minor and overshadowed by the motor deficit. The tendon reflexes may be diminished or absent. Older reports describe a painless motor neuropathy with few or no sensory abnormalities and distinct patterns of weakness affecting wrist extensors, finger extensors, and intrinsic hand muscles. Preserved reflexes, fascieulations, and profound muscle atrophy may simulate amyotrophic lateral sclerosis. A rare sign of lead exposure is a blue line at the gingival margin in patients with poor oral hygiene. Hypochromic microcytic anemia with basophilic stippling of the red cells, hyperuricemia, and azotemia should stimulate a search for lead exposure. Lead intoxication is confirmed by c lev a red blood and urine lead levels. Blood levels exceeding 70 j.iu, pet 100 mL are considered harmful, but even levels greater than 40 tig per 100 mL have been correlated with minor
nerve-conduction abnormalities. Lead inhibits erythrocyte ^-aminolevulinic acid dehydratase and other enzymatic steps in the biosynthctic pathway of porphyrins. Consequently, increased red cell protoporphyrin levels emerge together with increased urinary excretion of 5-aminolevulinie acid and coproporphyria Excess body lead burden, confirming past exposure, can be documented by increased urinary lead excretion aftet a provocative chelation challenge with calcium ethylenediaminetetraaceric acid. Only a few electrophysiological studies have been reported in patients with overt lead neuropathy. These investigations indicate a distal axonopathy affecting both motor and sensory fibers. These observations corroborate changes of axonal degeneration seen in human nerve biopsies, Contrary to the findings in humans, lead produces segmental demye11nation in animals. Lead is known to cause early mitochondrial changes in cell-culture systems, but the biochemical mechanisms leading to neurotoxicity remain unknown. Lead encephalopathy is managed supportively, but corticosteroids arc given to treat cerebral edema, and chelating agents (dimercaprol or 2,3-dimercaptopropane sulfonate) are prescribed also. No specific treatment exists for lead neuropathy other than prevention of further exposure to lead. Chelation therapy does not hasten recovery.
Manganese Manganese miners may develop neurotoxicity following inhalation for prolonged periods (months or years) of dust containing manganese. Headache, behavioral changes, and cognitive disturbances ("manganese madness") are followed by the development of motot symptoms such as dystonia, parkinsonism, retropulsion, and a characteristic gait called "cock-walk" manifested by walking on the toes with elbows flexed and the spine erect. There is usually no tremor and the motor deficits rarely improve with l.-dopa therapy. Manganese intoxication has been reported in miners, smelters, welders, and workers involved in the manufacture of dry batteries; after chronic accidental ingestion of potassium permanganate, and from incorrect concenttation of manganese in parenteral nutrition. Welders with Parkinson's disease (PD) were found to have their onset of PD an average of 17 years earlier than a control population of PD patients, suggesting that welding, possibly by causing manganese toxicity, is a risk factor for PD (Racette et al. 2001). In addition to welding and manganese mining, manganese toxicity may occur with chronic liver disease and long-term parenteral nutrition. Manganese intoxication may be associated with abnormal MR imaging (abnormal signal hyperintensity in the globus pallidus and substantia nigra on'11-weighted images). In contrast to PD, fluorodopa positron-emission tomography (PET) scans arc usually normal in patients with manganese-induced parkinsonism,
EFFECTS OF OCCUPATTONAI TOXINS ON THE NERVOUS SYSTEM
and raclopride (D2 receptor) binding is only slightly reduced in the caudate and normal in the putamen. Neuronal loss occurs in the globus pallidus and substantia nigra pars reticularisj as well as in the subthalamic nucleus and striatum. There is little response to L-dopa of the extrapyramidal syndrome, which may progress over several years (Huang et al. 1998). Myoclonic jerking may occur, sometimes without extrapyramidal accompaniments (Ono, Komai, and Yamada 2002),
Mercury The toxic effects of elemental mercury (mercury vapor), inorganic salts, and short-chain alkyl-mercury compounds predominantly involve the central nervous system and dorsal root ganglion sensory neurons. Inorganic mercury toxicity may result from inhalation during industrial exposure, as in thermometer and battery factories, mercury processing plants, and electronic applications factories. In the past, exposure occurred particularly in the hat-making industry. No evidence exists that the mercury contained in dental amalgam imposes any significant health hazard. Differences in health and cognitive function between dentists and control subjects cannot be attributed directly to mercury (Ritchie et al. 2002), Clinical consequences of exposure include cutaneous erythema, hyperhidrosis, anemia, proteinuria, glycosuria, personality changes, intention tremor ("hatter's shakes"), and muscle weakness. The personality changes ("mad as a hatter") consist of irritability; euphoria; anxiety; emotional lability; insomnia; and disturbances of attention, with dtowsiness, confusion, and, ultimately, stupor. A variety of other central neurological deficits may occur but are more conspicuous in patients with organic mercury poisoning, The effects of methyl mercury (organic mercury) poisoning have come to be widely recognized since the outbreak that occurted in Minamata Bay (Japan) in the 1950s when industrial waste dischatged into the bay led to contamination of fish that were then consumed by humans. Outbreaks have occurred also following the use of methyl mercury as a fungicide, because intoxication occurs if treated seed, intended for planting, is eaten instead. Methyl and ethyl mercury compounds have been used as fungicides in agriculture and in the paper industry. Methyl mercury and elemental mercury are potent neurotoxins that cause neuronal degeneration in the cerebellar granular layer, calcarine cortex, and dorsal root ganglion neurons. The primary molecular target of methyl mercury is probably sulfhydryi ligands in enzyme complexes or critical membrane sites. The characteristic features of chronic methyl mercury poisoning are sensory disturbances, constriction of visual fields, progressive ataxia, tremot, and cognitive impairment. Electrophysiological studies have shown that these symptoms relate to central dysfunction. Sensory disturbances result from dysfunction of sensory cortex or dorsal root
1717
ganglia rather than petipheral nerves, and rhe visual complaints also relate to cortical involvement. Pathological studies reveal neuronal loss in the cerebral cortex, including the parietal and occipital regions, as well as in the cerebellum. A few cases presenting with peripheral neuropathy or a predominantly motor neuronopathy resembling amyotrophic lateral sclerosis have been described in association with intense exposure to elemental mercury vapors. The diagnosis of elemental or inorganic mercury intoxication usually can be confirmed by assaying mercury in urine. Monitoring blood levels is recommended for suspected organic mercury poisoning. Chelating agents increase urinary excretion of mercury, but insufficient evidence exists to substantiate the claim that chelation increases the rate or extent of recovery.
Tellurium Tellurium is used in the manufacture of various alloys; the coloring of glass, ceramics, and metalware; the production of rubber; and the manufacture of thermoelectric devices. Inhalation of volatile tellurium compounds may lead to headache, drowsiness, a metallic taste, hypohidrosis, skin rashes and discoloration, and a curious odor resembling garlic on the breath. Recovery generally occurs spontaneously.
Thallium Thallium salts cause severe neuropathy and central nervous system degeneration that has led to their discontinued use as rodenticides and depilatories. Most intoxications result from accidental ingestion, attempted suicide, or homicide. After consumption of massive doses, vomiting, diarrhea, or both occur within hours. Neuropathic symptoms, heralded by limb pain and severe distal paresthesia, are followed by progressive limb weakness within seven days. Cranial nerves, including optic nerves, may be involved. Ptosis is common. In severe cases, ataxia, chorea, confusion, and coma as well as ventilatory and cardiac failure may ensue. Alopecia, which appears 2-4 weeks after exposure, provides only rerrospective evidence of acute intoxication. A chtonic progressive, mainly sensory neuropathy develops in patients with chronic low-level exposure. In this form, hair loss is a helpful clue. Electrocardiographic findings of sums tachycardia, U waves, and T-wave changes of the type seen in potassium depletion are related to the interaction of thallium and potassium ions. Electrophysiological findings are characteristic of distal axonal degeneration. Autopsy study results confirm a distal axonopathy of peripheral and cranial nerves. Studies in animals show accumulation of swollen mitochondria in distal axons before wallcrian degeneration of nerve fibers. The diagnosis is confirmed by the
1718
NEUROLOGICAL DISEASES
demonstration of thallium in urine or bodily tissues. High levels are found m central nervous system gray matter and myocardium. The toxic effects of thallium may be related to binding of sulfhydryl groups or displacement of potassium ions from biologic membrane systems. With acute ingestion, gastric lavage and cathartics artgiven to remove unabsorbed thallium from the gastrointestinal tract. Oral potassium ferric ferrocyanide (Prussian blue), which blocks intestinal absorption, together with intravenous potassium chloride, forced diuresis, and hemodialysis, has been used successfully in acute thallium intoxication.
Tin Although ingested inorganic tin usually produces little or no systemic and neurological complications, organic tin compounds used in various industrial processes have definite neurotoxicity. Intoxication with trimethyl tin leads to multifocal central dysfunction with conspicuous behavioral disturbances, emotional lability, confusion, disorientation, cognitive disturbances, sleep dysfunction, headaches, and visual disturbances. Triethyl tin may lead to severe cerebral edema with headache, papilledema, and behavioral abnormalities that generally resolve some weeks after discontinuation of exposure.
REFERENCES Castillo, L., Baldwin, M., Sassine, M. P., & Mergler, D. 2001, "Cumulative exposure to styrenc and visual functions," Am ] Ind Med, vol. 39, pp. 351-360 Glynn, P., Holton, J. L., Nolan, C. C, et al. 1998, "Neuropathy target esterase: immu no localization to neuronal cell bodies and axons," Neuroscience, vol. 83, pp. 295-302 Gobba, F, 2000, "Color vision: a sensitive indicator of exposure to neurotoxins," Neurotoxicology, vol. 2 1 , pp. 857-862 Graeme, K. A. & Pollack, C. V. Jr. 1998, "Heavy metal toxicity, part I: Arsenic and mercury," j Emerg Med, vol. 16, pp. 45-56 Guadarrama-Naveda, M., de Cabrere, L. C, & Matos-Bastidas, S. 2001, "Intermediate syndrome secondary to ingestion of chlorpinphos," Vet Hum Toxical, vol. 4 3 , p. 34 Hall, A. H. 2002, "Chronic arsenic poisoning," Toxicol Lett, vol. 128, pp. 69-72
Hampson, N. B. & Hampson, L. A, 2002, "Characteristics of headache associated with acute carbon monoxide poisoning," Headache, vol. 42, pp. 220-223 Hawkins, M., Harrosin, j . , &c Charters, P. 2000, "Severe carbon monoxide poisoning: Outcome after hyperbaric oxygen therapy," Br J Anaestb, vol. 84, pp. 584-586 Horstman, S. W., Browning, S. R., Szeluga, R., et al. 2001, "Solvent exposure in screen printing shops," / Environ Sri Health Part A Tax Hazard Subst Environ Eng, vol. 36, pp. 1957-1973 Huang, C. C, Chu, N. S., Lu, C. S., et al. 1998, "Long-term progression in chronic manganism: ten years of follow-up," Neurology, vol. 40, pp. 698-700 Huang, C. C, Chu, C. C, Chu, N. S., & Wu, T. N. 2001, "Carbon disulfide vascuiopathy: A small vessel disease," Cerebrovasc Dis, vol. 11, pp. 245-250 LoPacbin, R. M., Ross, J. F., & Lehning, H. J. 2002, "Nerve terminals as the primary site of acrylamide action: A hypothesis," Neurotoxicology, vol. 2 3 , pp. 43-59 Lotti, M. 2002, "Low-level exposures to organophosphoms esters and peripheral nerve function," Muscle Nerve, vol, 25, pp. 492-504 Miyagi, Y., Shima, F., Lshido, K., et al. 1999, "Tremor induced by toluene misuse successfully tteated by a Vim thalamotomy," / Neurol Neurosurg Psychiatry, vol. 66, pp. 794-796 Ono, K., Komai, K., &c. Yamada, M. 2002, "Myoclonic involuntary movement associated with chronic manganese poisoning," / Neurol Sci, vol. 199, pp. 93-96 Pilkington, A., Buchanan, D., Jamal, G. A., et al. 2001, "An epidemiological study of the relations between exposure to orga no phosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers," Occup Environ Med, vol. 58, pp. 702-710 Racettc, B. A., McCcc-Minnich, L., Moerlein, S. M., et al. 2001, "Welding-related parkinsonism. Clinical features, treatment, and pathophysiology," Neurology, vol. 56, pp. 8-13 Ritchie, K. A., Gilmour, W, H., Macdonald, E. B., et al. 2002, "Health and neurological functioning of dentisrs exposed to mercury," Occup Environ Med, vol. 59, pp. 287-293 Spencer, P, S., Kim, M. S., & Sabri, M. I. 2002, "Aromatic as well as aliphatic hydrocarbon solvent axonopathy," Int ] Hyg Environ Health, vol. 205, pp. 131-136 Stone, J. D., Peterson, A. P., Eyer, J., et al. 2001, "Neutofilaments are nonessential to the pathogenesis of toxicant-induced axonal degeneration," / Neurosci, vol. 2 1 , pp. 2278-2287 Yamano, Y., Kagawa, J., Ishizu, S., & Harayama, O. 2001, "Three cases of acute methyl bromide poisoning in a seedling farm family," Ind Health, vol, 39, pp. 353-358
Chapter 64 Effects of Toxins and Physical Agents on the Nervous System B. EFFECTS OF DRUG ABUSE ON THE NERVOUS SYSTEM Yuen T. So Pharmacological Effects Opioid Analgesics Sedatives and Hypnotics Psychomotor Stimulants Other Substances of Abuse
1720 1720 1721 1722 1723
Drug abuse occurs in several different forms. The use of drugs such as heroin or cocaine may be termed abuse simply because they are illegalal or are obtained illegally. Legal prescription drugs, such as the opioid analgesics and benzodiazepines, also may be abused if taken in excessive amounts or used solely for recreational purposes. Drug dependence refers to either a psychological dependence or a physical dependence. In the former, drugcraving or drug-seeking behavior emerges when the drug is not available. Physical dependence, on the other hand, implies the appearance of physiological symptoms and signs during drug withdrawal. Drug tolerance is defined as a diminished response to the same dosage of a drug and reflects either increased metabolism of the drug or reduced physiological response to the drug at its normal cellular target. Of the abused drugs that result in emergency room visits, cocaine is the most commonly encountered. This is followed in frequency by heroin, marijuana, and methamphctamine. The so-called club drugs have risen in popularity in recent years. They are frequently used in dance clubs and include GHB (gamma hydroxybutyrate), kern mine, MDMA (3,4-rnethyleiiedioxymcthamphcraminc or ecstasy), LSD (lysergic acid diethylamide), and methamphetamine. All these drugs have been implicated in causing deaths in one way or another. Aside from the biological effects to be discussed in this chapter, forensic data link these drugs to many vehicular accidents, blunt trauma, and gunshot and other penetrating injuries and deaths. All the substances of abuse have potent acute and chronic .•tlirr- (in t'le nervous -.ystern. h i-- helpt.k lt> divide flic neurological consequences of drug abuse into three
Indirect Neurological Complications Stroke Myelopathy Rhabdomyolysis and Myopathy Neuropathy and Plexopathy
1724 1724 1725 1725 1725
broad categories according to the mechanism of action (Table 64B.1). First, acute intoxication or overdose often leads to delirium, stupor, or coma, sometimes accompanied by myoclonus, seizures, or serious systemic consequences such as respiratory depression and cardiovascular collapse. Second, chronic use of most of these agents often leads to drug tolerance or dependence. With abrupt abstinence of a habitually used drug, a patient may present for emergency care with an acute withdrawal syndrome. Third, drug abuse may affect the nervous system indirectly via infectious and embolic consequences of intravenous drug use, hypersensitivity ot immunological mechanisms, or some other manner that is not yet understood. Urine screening of drugs of abuse is widely used in the diagnostic evaluation of patients (Table 64B.2). The detection times listed in Table 64B.2 are rough estimates at best, as detection is dependent on the time, dose, and route of administration, a subject's metabolism, and the characteristics of the screening assay. Negative test results are difficult to interpret, and detection is particularly problematic for the designer amphetamines (see MDMA, latet in this chapter). Positive results may be confirmed by an alternative method such as gas chromatography and mass spectroscopy. The urine test provides only qualitative information of recent drug use. Because urinary levels are dependent on time and clearance, they often do not correlate with toxic symptoms, The first part of the following discussion reviews the pharmacological effects of commonly abused drugs, wirh emphasis on the acute effects and the withdrawal syndromes. The second part discusses the indirect effects of drug abuse on the nervous system. 1719
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NEUROLOGICAL DISEASES
Tabic 64B.1:
Neurological complications of drug abuse
for all agonists and antagonists with morphine-like activities as well as the naturally occurring and synthetic opioid peptides. These compounds act on the three opioid receptor subtypes, /*, S, and K, and have a wide spectrum of activities as analgesics, psychotomimetics, miotics, and suppressants of respiration, cough, and gastric motility. Development of drug tolerance and dependence is an almost unavoidable physiological consequence of repeated use of opioids. For example, when used in prolonged treatment of pain, increasingly higher doses of opioids are often required to maintain the same degree of pain control. The pharmacological basis of this phenomenon is poorly understood, although the N-methyl-d-aspartatc (NMDA) receptor may play an important role. Neither tolerance nor dependence predicts drug abuse; thus the fear that tolerance may develop should not interfere with the appropriate use of opioids.
Acute intoxication and overdose Drug withdrawal syndrome Indirect complications of drug abuse Infectious endocarditis Cerebral or spinal cord abscess Meningitis or encephalitis Myelopathy Strokes Cerebral or spinal cord infarct Postanoxic encephalopathy Hemorrhage Brachial plexitis Nerve compression Rhabdomyolysis
PHARMACOLOGICAL EFFECTS Opioid Analgesics The name opium came from the Greek word for juice because the drug was derived from the juice of the poppy. Its medicinal uses were discovered as early as the third century BC. Opium contains more than 20 alkaloids. Morphine was the first to be isolated, in 1806, and was named after Morpheus, the Greek god of dreams. Other alkaloids, such as codeine, were discovered soon afterward. By the middle of the nineteenth century, the use of these compounds was widespread in medicine. Pharmacology Opiates refer only to those drugs derived from opium and include the naturally occurring alkaloids as well as semisynthetic derivatives. Kndorphins are endogenous opioid peptides and encompass the enkephalins, dynorphins, and jS-endorphins. The term opioid is more inclusive and is used
Table 64B.2: Common drugs of abuse: maximum time interval after last drug use when drugs and their metabolites are still detectable by enzyme immunoassay of urine Drug Amphetamine Cocaine Benzodiazepines* Barbiturates, long-acting Barbiturates, short- or intermediate-acting Heroin* Methadone Morphine Phencyclidine* Propoxyphene
Maximum detection after last use
time
48 hrs 48 hrs 5 to 7 days 7 days 1 to 2 days 4 ro 5 days 3 days 48 hrs 2 wks 48 hrs
'Maximum detection times given for chronic users. Single dose in nonhabitual users is cleared considerably more rapidly.
Drug Abuse A prescription opioid analgesic may be abused. A typical patient may seek multiple physicians for prescription, present with exaggerated complaints, or engage in other drug-seeking behavior. A second group of abusers are the street addicts, typified by use of the illegal drug heroin. Heroin crosses the blood-brain barrier rapidly. Heroin's effect on the brain is identical to that of morphine. Three milligrams of heroin is roughly equivalent to 10 mg of morphine. Heroin may be snorted (sniffed up the nose), smoked, injected subcutaneously {"skin-popping"), or administered intravenously ("mainlining"). Heroin is sold in the streets in varying degrees of purity, and it is sometimes combined with cocaine ("spcedball"). Acute
Effects
Aside from the analgesic effects, morphine and heroin acutely produce a sense of rush, accompanied by either euphoria or dysphoria. Hallucinations may occur also. Other effects include pruritus, dry mouth, nausea and vomiting, constipation, and urinary retention. Examination may show pupillary constriction so marked that it may be difficult to discern the light reflex. Overdose of heroin leads to coma and respiratory suppression. Hypotension and hypothermia also occur, but seizures are rare. Acute treatment of opioid overdose should include close monitoring of vital signs and, if necessary, support of blood pressure and respiration. Naloxone is a safe and effective opioid antagonist and should be used immediately in any suspected opioid overdose. Naloxone is also useful for diagnosis, because it induces immediate reversal of coma and respiratory depression in a patient with opioid overdose. For treatment of respiratory depression, 2 mg of naloxone is given parenterally, and the dose is repeated as needed up to a total of 10-20 mg. Because the half-life of
EFFECTS OF DRUG ABUSE ON THE NERVOUS SYSTEM
naloxone (1—4 hours) is shorter than most opioid agonists, it should be given in repeat boluses and the patient should be monitored closely through the at-risk period, With careful titration of the dose, respiratory depression can be reversed without precipitating acute opioid withdrawal. Drug Dependence and
Withdrawal
With development of drug dependence, symptoms and signs of withdrawal appear hours after the last opioid use. Drug craving appears first, followed by restlessness and irritability. Autonomic symptoms such as sweating, Inclination, and rhinorrhea then emerge. Still later, piloerection, aching, nausea, abdominal cramps, diarrhea, and
coughing
develop.
Tin-
time
ol
tile
appearance
of withdrawal symptoms depends on the duration of action of the drugs. With morphine and heroin, withdrawal symptoms appear within 6-9 hours of rhe last dose, peak at 24-72 hours, and last approximately 10 days. With methadone, symptoms appear within approximately 12-24 hours, peak at 6 days, and last approximately 3 weeks. Opioid withdrawal in adults, although unpleasant, is usually not life threatening. In contrast, opioid withdrawal in neonates is sometimes accompanied by myoclonus, seizures, or even status epilepticus. This occurs typically in newborns of opioid-dependenr mothers. Naloxone used during the treatment of respiratory depression sometimes precipitates withdrawal reactions. Acute administration of paregoric or methadone is an effective treatment. Phcnobarbital may be used if there has been prenatal exposure to other drugs such as barbiturates and alcohol. Oral methadone, a long-acting opiate, is used to relieve opioid withdrawal symptoms. A dose of 10 to 20 mg once or twice a day is sufficient in most patients. The dose is then gradually reduced, w i n the hope of eventually achieving detoxification. Clonidine, an a 2 -adrenergic agonist, suppresses the autonomic disturbances of opioid withdrawal and is useful when combined with methadone. Methadone is becoming a primary drug of addiction.
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use benzodiazepines and barbiturates in conjunction with heroin. Alcoholics also sometimes use them to alleviate symptoms of alcohol withdrawal. Benzodiazepin es All the benzodiazepines share similar effects on the central nervous system, and the differences among individual drugs are largely those of dosage and duration of action. The benzodiazepines with rapid onset of action, such as diazepam, are among the most likely to be abused. Acutely, the recipient experiences varying degrees of lassitude, drowsiness, confusion, amnesia, euphoria, and impairment of other psychomotor functions. Even in conventional dosages, these neurological effects are potentially dangerous, especially in elderly people. Falls, for example, may result from drowsiness and motor incoordination. Sufficiently severe overdose leads to coma, although benzodiazepines arc less likely than barbiturates and opioids to cause respiratory or cardiovascular depression. Thus benzodiazepine overdose is rarely fatal unless other drugs are used concurrently. Still, treatment of comatose patients should be directed to immediate assessment and management of cardiovascular and respiratory functions. Flumazenil is a specific antagonist for benzodiazepines. It reverses rapidly the stupor or coma of overdose, although its usefulness is limited by its short action of only 30-60 minutes. A dose of 0.2-5.0 mg given intravenously over 2-10 minutes is sufficient to reverse benzodiazepine overdose. A lack of response is strong evidence that another drug is involved. Chronic use of benzodiazepines may lead to tolerance and physical dependence. Withdrawal symptoms typically occur within 24 hours of cessation of use of a short-acting benzodiazepine and approximately 3-7 days after stopping a long-acting agent. Withdrawal symptoms include irritability, increased sensitivity to light and sound, sweating, tremor, tachycardia, headache, and sleep disturbances. In more severe withdrawal states, delirium, hallucinations, and seizures may occur. Withdrawal symptoms may last several weeks. Reinstituting the benzodiazepine, followed by gradual tapering of the dosage, is usually sufficient to treat these withdrawal symptoms.
Sedatives and Hypnotics
Barbiturates
Sedatives and hypnotics as a group have calming effects and are capable of inducing sleep when taken in sufficient dti.vigev The group includes die bcn/.odia/.cpincs. barhitu rates, and various less commonly used agents. As with opioid analgesics, manifestations of abuse include excessive use of prescription drugs, recreational use, drug overdose, drug dependence, and withdrawal symptoms. The benzodiazepines are among the most frequently prescribed medications in Western countries and account for over one-half of the overdoses in the United States. Addicts often
The acute symptoms of barbiturate use are similar to those of alcohol and include euphoria, sedation, slurred speech, and gait ataxia. Severe intoxication leads to coma, hypotension, and hypothermia. Breathing may be slow or rapid and shallow. Cheyne-Stokes breathing, respiratory depression, and eventually apnea occur with sufficient intoxication. Treatment is primarily supportive. The lethal dose varies, but as a general rule, ingestion of more than 10 tunes the hypnotic dose is likely to be dangerous. Gastric lavage may be useful within 24 hours because barbiturates
1722
NEUROLOGICAL DISEASES
may reduce gastric motility. Hemodialysis or hemoperfusion is rarely necessary. Withdrawal symptoms are similar to those seen with alcohol withdrawal. Insomnia, irritability, tremor, tachycardia, nausea, and vomiting are common. With shortacting barbiturates, symptoms usually begin within 36 hours; the long-acting barbiturates are associated with a longci delay of several days. In sevcte cases, delirium tremens and seizures may occur. Treatment of withdrawal consists of reinstitution of the batbiturates, followed by gradual tapeting. Other Sedatives and Hypnotics Othet sedatives and hypnotics are abused much less frequently than barbiturates and benzodiazepines. Mcthaqualone was popular in the 1970s. Overdose is characterized b; delirium, myoclonus, and seizures, sometimes followed by coma and acute congestive heart failure. Glurcthimide overdose leads to coma, hypotension, and, less frequently, respiratory depression. Abuse of this agent is recognized by its anticholinergic effects, which produce dilated unteactive pupils. Other uncommonly abused drugs include paraldehyde, chloral hydrate, meprobamate, and ethchlorvynol. Ethchlorvynol overdose is characterized by its long duration of action, which may last many days. Treatment includes diuresis, perironeal dialysis or hemodialysis, or hemoperfusion with activated charcoal or resin.
Psychomotor Stimulants Psychomotot stimulants all share sympathomimetic effects on the central nervous system. Cocaine is the most commonly abused. It may be administered intranasal!}' or parcntcrally or may be smoked (crack). Amphetamine, dextroamphetamine, methamphetamine, and methylphenidate also have significant abuse potential. Another drug in this group is MDMA or ecstasy, as ir has hallucinogenic effects in addition to its stimulant properties. Other agents such as fenflutamine, phentermine, ephedtinc, and phenylpropanolamine have less liability for abuse. Acute Effects In modetate doses, stimulants produce mood elevation, increased alertness, reduced fatigue, dectcased appetite, and enhanced performance in various tasks. There arc individual differences in the psychic effects of these stimulants. Some patients develop paranoia, delusions, hallucinations, agitation, and violence. Other patients may be depressed or lethargic. Systemic symptoms include palpitation, pupillary dilation, tachycatdia, and hypertension. For patients presenting to the emergency room, systemic complications such as hyperthermia, dehydration, and rhabdomyolysis
are sometimes encountered. An increased risk of myocardial infarction is also especially well documented with cocaine use, Of the neurological symptoms seen in the emergency room, headache is probably the most common and ftequcntly accompanies other more serious symptoms. Some patients may present with encephalopathy, myoclo'nus, or seizures. Seizures are usually self-limiting, although status epilepticus is an uncommon but well-recognized complication of overdose. Of the abused stimulants, cocaine is the most likely to cause seizures (Zagnoni and Albano 2002). Seizures are more likely when cocaine is smoked (crack) or given intravenously than with other modes of administration. The estimate of seizure frequency varies widely from 1^40%, depending on the study population. Typically, seizures occur within 1-2 hours of cocaine use. Other drugs, such as methamphctamine, amphetamine, MDMA (ecstasy), methylphenidate, ephedrine, and phenylpropanolamine also cause seizures. MDMA in particular has been linked to the development of hyponattcmia with resultant seizures and encephalopathy. The mechanism may involve inappropriate secretion of antidiuretic hormone (Hartung et al. 2002). Both acute ischemic and hemorrhagic strokes have been reported in association with stimulant use. This is especially true for cocaine and amphetamine, although other stimulants may also be responsible. Stroke is discussed further later in this chapter (see Indirect Neurological Complications). Movement disorders are sometimes seen after stimulant use (Catdoso and jankovic 199i). Hyperkinetic movement disorders may be exacerbated or may develop de novo in cocaine users. These include vocal and motot tics, chorea, dystonia, and acute dystonic reaction to neuroleptics. Rarely, dyskinesias may persist months after abstinence (Weiner et al. 2001). Otomandibular stereotypies such as teeth-grinding and tongue protrusion are common among amphetamine users. Treatment of overdose should include supportive measures such as oxygen, cardiac monitoring, cooling for hyperthermia, antihypertensives, and blood pressure and ventilatory support as necessary, Sedarives may be used judiciously to treat agitation. Seizures arc managed with benzodiazepines and phenytoin. Forced diuresis and urine acidification promote drug excretion bur should be avoided if myoglobinuria is present. Drug Dependence and
Withdrawal
Aftet repeated use of cocaine or amphetamines, tolerance develops to the euphoric and anorexic effects of these agents. A wide range of psychiattic symptoms have been described in chronic active users. Functional imaging studies have shown altetations of dopamine and serotonin transporters in the brain, although the clinical significance of these findings is unknown. Acute abstinence aftet
EFFECTS OF DRUG ABUSE ON THE NERVOUS SYSTEM
chronic use manifests primarily as fatigue and depression. The withdrawal syndrome is seldom life-threatening, with the exception of those who develop suicidal ideations. Treatment with imipramine or other antidepressant drags may be helpful.
Other Substances of Abuse MDMA Ecstasy
(1,4-methylenedioxymethampketamine)
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and sense of time. A sense of relaxation, subjective slowing of time, euphoria, and depersonalization can occur during its use. Variable degrees of anxiety, paranoia, sedation, and sleepiness may occur also. High doses of tetrahydrocannabinol produce hallucinations, paranoia, or a frank panic reaction. Treatment of such cases generally requires only calm reassurance. Tolerance develops with chronic use. Irritability, restlessness, and insomnia are typical after abrupt discontinuation.
or
MDMA merits a special mention as it has become a very popular club drug internationally, and there is a widely held misconception among users that it is safe. The drug is used commonly on college campuses and at all-night dance parties. As its name implies, MDMA is a derivative of methamphctamine, and it has properties of both a stimulant and a hallucinogen (Kalant 2001). The hallucinogenic effects result from its structural resemblance to mescaline. Complications from MDMA's acute stimulant effects were discussed in the previous section (see Psychomotor Stimulants). Although the incidence of serious complications with MDMA use is low, the unpredictability of these serious and sometimes fatal complications is of great health concern. Adding to the unpredictability is the fact that the street name ecstasy has also been applied by vendors and users to other related compounds: 3,4-merhylenedioxyamphetamine (MDA), N-ethyl-3,4-methylcncdioxyamphetamine (MDF.A), and paramethoxyamphetamine (PMA). These compounds share the biological effects of MDMA and have also been linked to serious complications. These drugs are often referred to as "designer-drugs" or "designer-amphetamines," because they were created by illicit attempts to achieve a blend of amphetamine-like and mcscaline-like pharmacological properties. MDMA has been linked to death from hyperthermia, hyponatremia, seizures, rhabdomyolysis, hepatic failure, coagulopathy, and cardiac arrhythmias. Recent studies also suggest long-term neurotoxicity with MDMA use. MDMA acutely causes massive central serotonergic discharge that is the physiological basis for its pleasurable psychic effects. By contrast, habitual users often report depression or lethargy during the time period between drug binges. Neuropsychological testing reveals impairment in verbal and visual memory in abstinent MDMA users compared to controls. Autopsy study in one patient demonstrated depletion of serotonin level in the striatum (Kish ct al. 2000). Functional imaging studies also suggest a long-lasting alteration of brain function.
Marijuana Tetrahydrocannabinol is the primary active ingredient of marijuana and has effects on mood, memory, judgment,
Pbencyclidine
and Ketamine
Phencyclidine and ketamine were developed as anesthetics. At progressively increasing dosages, analgesia, anesthesia, stupor, and coma develop. At moderate doses, phencyclidine and ketamine produce variable degrees of euphoria, dysphoria, relaxation, paranoia, and hallucinations. Psychosis, agitation, bizarre behavior, and catatonia arc common. These may be accompanied by physical signs of fever, hypertension, sweating, miosis, and horizontal as well as vertical nystagmus. Treatment is largely supportive. Violent behavior may require restraint. Rhabdomyolysis is common with overdose, and myoglobinuria should be looked for and treated if discovered. Anticholinergics The recreational use of anticholinergics includes abuse of prescription drugs as well as use of plants that contain the belladonna alkaloids atropine and scopolamine. These agents are abused for their pharmacological ability to induce delirium and hallucinations. The psychoactive effects are accompanied by mydriasis, dry and flushed skin, tachycardia, urinary retention, and fever. Severe overdose may lead to myoclonus, seizures, coma, and death. Acute treatment employs intramuscular or intravenous injection of 1 mg of physostigmine. This is followed by titrating doses of 0.5-2.0 mg of physostigmine every 30 minutes to 2 hours. inhalants 1'his group ol compounds comprises a wide range ol volatile compounds, including various hydrocarbons, nitrites, and nitrous oxide. Many are present in common household and industrial products. Despite the diversity of chemicals, the acute effects are similar. At low to moderate doses, these chemicals induce a sense of euphoria, relaxation, incoordination, and slurred speech. These effects resemble alcohol intoxication for most practical purposes. Higher doses produce psychosis, hallucinations, and seizures. The duration of action is typically only 15-30 minutes, but the effects may be sustained by continual use. Various complications such as cardiac arrhythmia; suffocation from the use of plastic bags, vomiting, and aspirations; and, rarely, sudden death have been reported.
1724
[\r:i KOI OC.ICAT DTSFASFS
Aside from die acute neuropsychological effects, different systemic and neurological complications may result from chronic abuse of individual agents. Lead intoxication may result from sniffing leaded gasoline. A peripheral neuropathy with disabling weakness and slow nerve-conduction velocities may result from the chronic use of M-hcxane. Nitrous oxide abuse leads to a syndrome of subacute combined defeneration similar to that seen in vitamin ]>L' deficiency. Cerebral and cerebellar dysfunctions are seen after chronic toluene abuse. Mild cognitive dysfunction has been associated with chronic exposures to many volatile hydrocarbons. Systemic complications include renal, hepatic, and bone marrow abnormalities after exposure to benzene and methemoglobinemia after use of alkyl nitrite, Hallucinogens The hallucinogens as a group cause alteration of mood, perception, and thought processes without significantly changing alertness, memory, and orientation. The synthetic ergot LSD is the best-known example and is still popular among drug abusers. In addition, a wide range of plants and mushrooms are known to be hallucinogenic. Acute ingestion leads to rapid onset of dizziness, blurred vision, nausea, and weakness followed by hallucinations that are often visual and complex. There may be depersonalization and a distortion of time. Sometimes the experience is terrifying (the so-called 'Lbad trips"), resulting in injuries to self or others. Physical signs include fever, tachycardia, hypertension, mydriasis, seizures, and coma.
INDIRECT NEUROLOGICAL COMPLICATIONS Stroke Drug abuse increases the risk of strokes. In retrospective studies of stroke patients between 15 and 44 years of age, drug abusers accounted for 1 2 - 3 1 % (Sloan et al. 1998). Drug abuse was the most important risk factor for stroke in those younger than 35 years of age. The relative risk of stroke was 6.5 after controlling for other stroke risk factors. The possible mechanisms are diverse (Table 64B.3) and arc dependent on the route of drug administration and the agents involved. The risk increase does not take into consideration the abuse of alcohol and tobacco, both of which, though legal, also increase stroke risk. The evaluation of patients with drug-related strokes should include a careful search for endocarditis or other source of embolization, a full cardiac evaluation, erythrocyte sedimentation rate, and antiphospholipid antibody assay. Cerebral angiography may be necessary, especially when vasculitis, aneurysms, or vascular malformations are suspected.
Table 64B.3: drug abuse
Probable mechanisms of strokes associated with
Intravenous drug abuse Endocardins, infectious or marantic Embolization of foreign materials Right-tO-left shunt in pulmonary vasculature Mycotic aneurysm Direct effects of drugs Vascular injury: hypertensive changes, arterial dissection Acute severe hypertension Vasoconstriction or vasospasm Impaired auto regulation Indirect effects of drugs Vasculitis Pre-existing vascular malformation or aneurysm Cardiomyopathy and arrhythmia Antiphospholipid antibodies Nephropathy and secondary hypertension Hypotension or hypoxia from overdose Acquired immunodeficiency syndrome or HIV iiiUvnon
Embolism The sources of embolism include valvular disease secondary to infective or marantic endocarditis, mural thrombi of cardiomyopathy, right-to-left shunt, aortic or other arterial dissection, and foreign materials injected during intravenous drug abuse. Strokes occur in approximately 2 0 % of cases of infective endocarditis; many of them are due to intravenous drug abuse. Early recognition is important because prompt antibiotic therapy can markedly reduce the risk of stroke. Mycotic aneurysm complicates 1-3% of cases of endocarditis and may cause intracerebral hemorrhage, Angiography should be considered when mycotic aneurysm is suspected, although the role and timing of surgery are controversial. Kmboli of particulate materials often occur because of the poorly controlled sale and manufacture of these injected drugs. Some intravenous preparations of methyl ph en idate, meperidine, and pentazocine are made by crushing or dissolving drug tablets. Other intravenous preparations may contain insoluble fillers such as talc. Undissolved particles, if injected intravenously, become lodged in the lungs and may cause pulmonary hypertension and arteriovenous fistulae. This in turn provides a path for emboli materials to reach the cerebrovascular circulation. Vasculitis and Other
Vasculopathies
Vasospasm is associated with many drugs of abuse, most notably the psychostimulants such as cocaine, amphetamines, methylphenidatc, and phenylpropanolamine, for poorly understood reasons, some drugs of abuse also lead to the development of vasculitis. This has been best documented in some patients with amphetamine abuse and less convincingly in a few patients who abused
F.FFF.CTS OF DRUG ABUSE ON THF NERVOUS SYSTEM
phenylpropanolamine, cocaine, or heroin. The diagnosis of vasculitis without histological verification is difficult, because the classic angiographic findings of segmental narrowing and beading of intracerebral arteries do not distinguish among vasculitis, vasospasm, arteriosclerosis, and other vasculopathics. Abstinence should be the first step in treatment of patients suspected to have vasculitis. The role of immunosuppressive therapy is undefined. It is not clear if the clinical course and response to treatment of drug-induced vasculitis are different from those of other vasculitis of the nervous system. Hypotension
and Anoxia
Anoxic brain injury often follows drug overdose, most notably overdose from heroin and other opiates. An autopsy series of heroin addicts observed that 2% had ischemic injury to the globus pa Hid us. Delayed postanoxic encephalopathy also rarely occurs. The clinical manifestations are similar to those described after prolonged cardiac arrest, respiratory failure, and carbon monoxide poisoning. Cocaine Cocaine is without question the most important cause of drug-related stroke and accounts for approximately 5 0 % of all cases. Neurological symptoms typically develop within hours of cocaine use, although rarely symptoms may progress gradually for up to a week. Seizures sometimes accompany the strokes. There are reports of transient ischemic attacks or ischemic infarctions of almost any area of the brain or spinal cord. In most series, over half of the ischemic infarcts involve die middle cerebral artery territory. Asymptomatic subcortical white matter lesions are also more prevalent in cocaine users when compared to normal controls. The difference is especially apparent in older subjects, irrespective of the years of cocaine use (Bartzokis et al. 1999). Intraparenchymal or subarachnoid hemorrhage is another common mode of presentation (Aggarwal et al. 1996; Noltc, Brass, and Fletterick 1996). There arc several porential pathophysiologic mechanisms of cocaine-induced stroke. Acute hypertension, vasospasm, and vasoconstriction probably play an important role (Kaufman et al. 1998). Under experimental conditions in cocaine users, modest intravenous doses of 40 mg or less can induce vasospasm of large arteries and reduce cerebral Hood flow by 25 oO'V I'hese doses .ire lower than those habitually consumed by many chronic cocaine users. Preexisting vascular pathology may be a key factor in some patients. Among those who present with intracranial hemorrhages, approximately one-half have underlying cerebral aneurysms or vascular malformations. Endocarditis, myocardial infarction, cardiac arrhythmias, aortic dissection, and anticardiolipin antibodies arc other observed associations.
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Myelopathy An acute myelopathy may develop rarely after drug abuse. The association is best documented in heroin abuse and rarely in cocaine use. For rhe most part, the syndrome resembles an anterior spinal artery syndrome. Paraparesis, urinary retention, and a segmental sensory level appear acutely. On examination, posterior column function is often relatively spared. Myelography, magnetic resonance imaging (MRI), and cerebrospinal fluid findings are usually normal, although mild elevation of cerebrospinal fluid protein may be present. There are several possible causes. Watershed infarct secondary to hypotension may be responsible. Embolic infarct from injected particulate material may account for other cases, as may hypersensitivity or vasculitis.
Rhabdomyolysis and Myopathy It is unclear whether any of the commonly abused drugs are directly toxic to muscles. Evidence of muscle injury ranges from asymptomatic elevation of serum creatine kinase to frank myoglobinuria and renal failure. The observations are made most commonly in the abuse of heroin, cocaine, amphetamine, MDMA, and phencyclidinc. The patients were typically severely intoxicated. Possible mechanisms include trauma, crush :njur>, hypotension, hypertension, fever, seizures, and excessive muscular activities, Repeated intramuscular injections of meperidine, pentazocine, or heroin sometimes lead to focal fibrosis and weakness of the injected muscles. Contractures develop slowly. The affected muscles have a woody and firm quality. Weakness is mild and is limited to the injected muscles. Flccrronv. ogniphic elimination ot affected areas demonstrates reduced insertional activity (suggesting extensive fihrotic replacement of the muscle), short duration, and small-amplitude motor-unit action potentials.
Ncuroparhy and Plexopathy Compressive or stretch injuries ro peripheral nerves and plexuses result from drug abuse of any kind. Focal neuropathies may also develop as a result of compartment syndrome and secondary nerve ischemia. The most commonly affected sites are the brachial plexus, the radial nerve at the upper arm, the ulnar nerve at the elbow, the sciatic nerve in the gluteal region, and the peroneal nerve at the fibular head. Some cases of idiopathic brachial or lumbosacral plexitis have been attributed to heroin use. A potential though tin proven cause is a hypersensitivity reaction to heroin or the accompanying adulterant. Many drug abusers have physical signs of a distal sensory or sensorimotor polyneuropathy, but a causal
1726
NEUROLOGICAL DISEASES
relationship to the ahused drugs is difficult to establish because c o n f o u n d i n g factors such as alcohol a b u s e a n d systemic diseases are often present. An exceptional e x a m p l e is in the chronic use of h y d r o c a r b o n i n h a l a n t s (Smith a n d Albers 1997), in which the n e u r o p a t h y is similar to t h a t observed during industrial o u t b r e a k s caused by e x p o s u r e to ji-hexane or methyl w-butyl ketone. Distal paresthesias and numbness a p p e a r first, followed by d e v e l o p m e n t oi distal weakness. W e a k n e s s w o r s e n s with c o n t i n u i n g a b u s e a n d may progress to involve p r o x i m a l muscles of both u p p e r and lower limbs.
REFERENCES Aggarwal, S, K., Williams, V., Levine, S. R., et al. 1996, "Cocaineassociated intracranial hemorrhage: Absence of vasculitis in 14 cases," Neurology, vol. 46, pp. 1741-1743 Bartzokis, G., Goldstein, I. B., Hance, D. B„ et al. 1999, "The incidence of T2-weighted MR imaging signal abnormalities in the brain of cocaine-dependent patients is agerelated and region-specific," Am / Nexroradiol, vol. 20, PP. i62s 16 ;-> Cardoso, F. E. & Jankovic, J. 1993, "Cocaine-related movement disorders," Mm Diaurti, vol. S. pp. 175 178
Hartung, T. K., Schofield, E., Short, A. I., et al. 2002, "Hyponatraemic states following 3,4-methyiencdioxymethamphetamine (MDMA, 'ecstasy') ingestion." QJM, vol. 95, pp. 431-437 Kalant, H. 2 0 0 1 , "The pharmacology and toxicology of 'ecstasy' (MDMA) and related drugs," CMAj, vol. 16.S pp. 917-928 Kaufman, M. J., levin, J. M., Ross, M. H., er al. 1998, "Cocaineinduced cerebral vasoconstriction detected in humans with magnetic resonance angiography," JAMA, vol. 279, pp. 376-380 Kish, S. J., Furukawa, Y., Ang, L., et al. 2000, "Striatal serotonin is depleted in brain of a human MDMA (F.cstasy) user," Neurology, vol. 55, pp. 294-296 Nolte, K. B., Brass, L. M., &c Fletterick, C. F. 1996, "Intracranial hemorrhage associated with cocaine abuse: A prospective autopsy study," Neurology, vol. 46, pp. 1291-1296 Sloan, M. A., Kittner, S. J., Fecser, B. K., et al. 1998, "Illicit drugassociated ischemic stroke in the Baltimore-Washington Young Stroke Study," Neurology, vol. 50, pp. 1688-1693 Smith, A. G. & Albers, J. W. 1997, "ra-Hexane neuropathy due to rubber cement sniffing," Muscle Nerve, vol. 20, pp. 1445-1450 Weiner, W. J., Rabinstem, A., Levin, B., et al. 2 0 0 1 , "Cocaineinduced persistent dyskinesia," Neurology, vol. 56, pp. 964-965 Zagnoni, P. G. & Albano, C. 2002, "Psychostimulants and epilepsy," Epilepsia, vol. 43 (Suppl 2), pp. 28-31
Chapter 64 Effects of Toxins and Physical Agents on the Nervous System C. NEUROTOXINS OF ANIMALS AND PLANTS Neil E. Schwartz and Yuen T. So Neurotoxins of Animals Snakes Spiders Scorpions Neurotoxins of Plants and Mushrooms Jimson weed {IXituni stramonium) Poison Hemlock [Conatm maculata)
I 27 1727 1728 1729 1729 ! MO 1731
Naturally occurring neurotoxins of animals, plants, and fungi are of great scientific interest in addition to their obvious clinical concern. Many of them serve as important tools used by investigators to probe the workings of the nervous system. One of the oldest and bestknown examples is curare, a plant toxin used in Claude Bernard's classical experiments on neuromuscular transmission over 100 years ago, a-Bungarotoxin, from the venom of the banded krait, is a competitive blocker of the acetylcholine receptor that has proven to be invaluable for studies of the neuromuscular junction and myasthenia gravis. Our understanding of the mechanisms of neurotransmitter release has been enhanced by toxins such as a-latrotoxin, from the black widow spider. Likewise, the toxins from a multitude of plants and fungi have helped advance our knowledge of many aspects of cellular neurophysiology. This chapter highlights some of the more common and clinically relevant neurotoxins that might be encountered by the neurologist in the United States.
NEUROTOXINS OF ANIMALS The neurotoxins of animals serve several essential functions in nature. Reptiles and arthropods use venoms to defend against predators and to immobilize prey. Some venom may contain enzymes that aid in the digestion of consumed food. Many of these agents are among the most potent neurotoxins known to humankind {Table 64C.1) (Markland 1997). Major components of snake and insect
Water Hemlock (Cicitta maculata) Peyote (Lophophora williamsii) Morning Glory {Ipomoea tricolor) Medicinal Herbs Excitatory Amino Acids Mushroom Poisoning
1731 1731 1731 1731 1731 1732
venoms are disulfide-rich small molecules that exhibit phospholipase A 2 activity (Schiavo, Matteoli, and Montecucco 2000). Despite their biological potency, mortality caused by these agents is uncommon. The rarity is in part a result of the healthy respect most people have for snakes, spiders, and scorpions. Moreover, most bites result in a relatively small amount of envenomation that is well below lethal dosage. Mortality tends to occur at the extremes of age.
Snakes The overwhelming majority of venomous snakebites in the United States are inflicted by the pit vipers (subfamily Crotalidac), a group that includes rattlesnakes (genera Crotalus and Sistrurus), fer-dc-lances (genus Bothrops), and the bushmaster (Lachesis muta). Moccasins (genus Agkistrodon), including cottonmouths and copperheads, account for up to half of pit viper envenomations in the United Stares (Litovitz et al, 2002). Pit vipers are so named because of an identifiable heat-sensing foramen "pit" between each eye and nostril; they have a triangular head with elliptical pupils and retractable, canalized fangs (Gold, Dart, and Barish 2002). All but one species of rattlesnake has a characteristic rattle on the tip of its tail. Coral snakes (family Eiapidae) such as Micrurus fulvius tenere (Texas coral snake) and Micrurus fulvius fulvius (eastern coral snake) are the only native venomous snakes that are not pit vipers; they account for less than 5% of envenomations in the United States. Important venomous snakes in other 1727
1728
NEUROLOGICAL DISEASES
Table 64C.1:
Neurotoxins of snakes and arthropods
Source
Toxins
Physiological site of action
Snake (various species) Snake (various species)
a-Bungaroroxin, cobrotoxin 0 Bungarotoxin, crotoxin, notexin, taiposin cr-Latrotoxin
Postsynaptic: competitive blockade of AChR Presynaptic: inhibition of ACh release
Black widow spider (Latrodectus mactans) Scorpion (Tityus serrulatus) Scorpion (Centrtiroides sp.)
Tityustoxin At least two groups of toxins
Presynaptic: facilitation of ACh release, followed by (lerlerion •••• Ac h Presynaptic: facilitation of ACh release Postsynaptic: inhibition of Na"1 channel inactivation Presynaptic: membrane depolarization
Ach = acetylcholine; AchR = acetylcholine receptor; Na + = sodium.
parts of the world include Elapidae such as cobras, mambas, kraits, coral snakes (Maticora sp.), and most Australian venomous snakes. Bites from these non-native species among zoo petsonncl and amateur snake keepers are not unusual. Viperidae (true vipers) include the puff adder, daboon viper, rhinoceros-horned viper, and Russell's viper, Hydrophiidae (pelagic sea snakes) are highly neurotoxic but rarely bite humans. As many as 2 5 % of pit viper bites and half of coral snake bites are "dry" and do not result in envenomation. Signs and symptoms of envenomation may vary. Morbidity and mortality depend on the venom composition of the local snakes and the availability and sophistication of emergency medical care. In the United States, approximately 6400 snake bites were reported in 2001 (about one-fifth of which were from rattlesnakes). Mortality, fortunately, is uncommon (averaging 5.5 deaths/year) and is due mostly to diamondback rattlesnake bites. By contrast, over 10,000 deaths are reported yearly from the Nigerian savannas and apptoximatcly 23,000 from West Africa. Up to 110,000 deaths per year worldwide have been reported, with many more individuals experiencing permanent morbidity. Young male adults are bitten most commonly, with about half of all bites in persons aged 18—28. In many cases of snakebite, the subject is intoxicated with alcohol. Snake venoms are composed of a complex mixture of peptides, many of which have enzymatic activity. Lowmolecular-weight polypeptides in the venom have neurological activities on both presynaptic and postsynaptic elements of the neuromuscular junction (see Table 64C.1). Diverse effects on platelets, endothelial cells, and the coagulation cascade, as well as almost every organ system, are responsible for much of the morbidity and mortality of envenomation. Some of the toxins may be directly myotonic; rhabdomyolysis and compartment syndrome are sometimes seen after envenomation. Considerable species and geographic variations occur in the spectrum of biological activities. For example, snakebites may cause primarily neuromuscular paralysis in one region, whereas bites by the same species in another region may result mainly in coagulopathy and hemorrhage. In general, when weakness is present, the pattern of involvement resembles
myasthenia gravis, with predilection of the neck flexors and ocular, bulbar, and proximal limb muscles. Respiratory paralysis, if severe and untreated, may lead to death, At the time of patient presentation, fear and panic are common symptoms; the accompanying autonomic reactions should not be mistaken for systemic symptoms of envenomation. The cardinal signs of pit viper envenomation are local pain, swelling, and erythema. Early signs of envenomation include tender regional lymph nodes; nausea; and a metallic, rubbery, or minty taste in the mouth. Systemic symptoms appear over the ensuing 12-24 hours and consist of a variable combination of perioral or limb paresthesias, muscle fasciculations, weakness, hypotension, and shock. Ptosis is common following envenomation by some Mojave rattlesnakes. In contrast to pit viper envenomation, little pain or swelling accompanies coral snake bites. After a delay of up to 24 hours, cranial nerve palsies, dysphagia, diffuse weakness, areflexia, and respiratory suppression may develop. Initial laboratory evaluation should include complete blood cell and platelet counts, coagulation panel, fibrinogen, fibrin split products, serum chemistries, creatine kinase, and urinalysis. In patients with significant weakness, nerve-conduction studies with repetitive stimulation testing may reveal a pattern of either presynaptic or postsynaptic blockade. The observed changes consist of reduced amplitude of the compound muscle action potentials, decremental response to lowfrequency repetitive stimulation, and postexercise and post-tetanic facilitation. Treatment includes calming and supportive measures. Even in the absence of life-threatening symptoms, a patient should be monitored for at least 6 hours if bitten by a pit viper and 12 hours if bitten by a coral snake. Appropriate antivenin should be administered as soon as it is certain that significant envenomation has occurred.
Spiders Of the commonly encountered spiders, few produce significant symptoms in humans. Venom is injected via fangs (chelicerae). The female widow spider (Latrodectus sp.)
NEUROTOXINS OF ANIMALS AND PLANTS
is the most important worldwide in terms of morbidity and is the only one commonly found in the United States with significant neurological morbidity. Over 2600 widow spider bites were reported in the United States in 2001,16 of which had major health consequences; there were no fatalities if.mn it/. et .{.. 2l>iUj, In fact, no deaths have bt.rn reported to the Ametican Association of Poison Control Centers since 1983. Vboneutria (banana spiders) from South America and Atrax (funnel web spiders) from Australia also cause neurotoxic lesions. Black widow spider [Latrodectus mactans mactans) venom contains a-larroxin, a neurotoxin capable of inducing neurotransmitter release from presynaptic cholinergic, noradrenergic, and aminergic nerve endings. Re-uptake is hindered as well. Although the toxin itself is fat mote potent than those found in snake venom, most spider bites do not cause many symptoms because only a small volume of venom is injected. Sometimes a characteristic erythematous ring surrounding a paler center (target or halo lesion) develops around the site of the spider bite. Within 30-60 minutes of black widow envenomation, intense pain and involuntary muscle spasms may appear in abdominal muscles, with spread to limb musculature (lactrodeemm); this can be seen as many as 612 houts after the spider bite. Dysautonomia, piloerection, and unique sweating patterns may be present. Respiratory arrest can result from diaphragmatic muscle involvement. Other associated symptoms include priapism, salivation, sweating, bronchospasm,and bronchorrhea. Hypertension is a nearly universal finding in affected individuals (Woestman et al. 1996). Serum creatine kinase may be elevated, Treatment begins with careful monitoring of respiration and vital signs and intensive-care support if necessary, Antivenin shortens the duration of symptoms if administered early but should be reserved primarily for severe disease. Muscle spasms may be treated with slow infusion of calcium gluconate or methocarbamol. Benzodiazepines and opioids are useful for the control of anxiety and pain.
Scorpions Although only a few of the approximately 1400 scorpion species are of neurological importance, bites by poisonous scorpions are generally more dangerous than spider bites. Scorpion envenomation is a public health problem in warm climates. In Mexico alone, there are 100,000-200,000 scorpion bites annually, resulting in 400-1000 fatalities. Small children in particular are prone to developing neurological sequelae; as many as 80% of bites to children are symptomatic. More than 14,500 scotpion bites were reported in the United States in 2001, with no mortality (Litovitz et al. 2002). All potential lethal scorpions ate members of the family Butbtdae, with the exception of Hemiscorpious (family Scorpionidae). They are characterized by a triangular sternal plate, to be distinguished from the pentagonal plate seen in less dangerous species.
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Buthntus tamulus of India, Leiurus quinquestriatus of North Africa and the Middle East, Tityus serrulatus of Brazil, Centmroides suffusus of Mexico and Androctonus a us tralis of Africa and Asia are among the most toxic species. The Arizona bark scorpion {Centmroides exilicauda) is found in southwestern United States and Mexico. Venom from C. exilicauda is relatively low in toxicity, with only one death reported in the United States since 1964 (Boyer et al. 2001). Other species of medical importance include Butbus, Mesobuthus, Parabutbus, and Nebo. The venoms of these scorpions contain a wide range of polypeptides that have a net excitatory effect on autonomic and skeletal neuromuscular systems. Effects are exerted through alteratior. ol voluj^- g.m-d ion uunnu's, panicu larly sodium ionophores (see Table 64C.1). Venom is delivered from glands located on the lateral tip of the scorpion's tail stinger. Presenting symptoms are highly variable, from local pain (which may be secondary to serotonin found in scorpion stings) to a general state of intoxication. Paresthesias are common and are usually experienced around the site of bite but also may be felt diffusely. Autonomic symptoms of sympathetic overdrive (tachycardia, hypertension, and hyperthermia) are often present, but parasympathetic symptoms, including the SLUD syndrome (salivation, /acrimation, wrination, and defecation), may be present as well. Muscle fasciculations, spasms, dysphagia, and other cranial nerve signs arc sometimes seen, as well as dy scon jugate roving or rotary ocular movements (Bond 1999). With severe envenomation, encephalopathy may result from direct central nervous system (CNS) toxicity or secondary to uncontrolled hypertension. The constellation of symptoms has led to the misdiagnosis of seizures, particularly in infant victims of scorpion stings; although seizutes can occur, they have never been proven in Centruroides envenomation. Treatment is often limited to symptomatic control. Severe cases should be monitored and treated in an intensive care setting, with attention to a secure airway. Use of scorpion antivenin is controversial, but the consensus is that it should be used for significant envenomations.
NEUROTOXINS OP PLANTS AND MUSHROOMS Pharmacologically active agents arc present in thousands of plants and mushtooms species. Many of these have been known since antiquity. Although fatal poisoning is relatively rare, some of the commonly encountered species are capable of inducing serious neurological symptoms. In the United States, 105,560 cases of plant poisoning and 8483 cases of mushroom poisoning were reported in 2001; only two fatalities occurred (Litovitz et al. 2002). Clinically significant toxicity happens under several circumstances. Approximately 7 5 % of cases occur in children under the age of six, most as a result of accidental ingestion. Adult poisoning may occur when toxic plants or mushrooms are
1730
NEUROLOGICAL DISEASES
mistaken for edible species. Undoubtedly an under-reported category is the intentional consumption among some adolescents and young adults who attempt to get "high" from so-called "natural" botanical sources. Common names of plants are entirely inadequate for their identification; botanical names should be used whenever possible. Identification is neither easy nor accurate, even with the aid of current computer software (Lawrence 1998). Naming the plant or mushroom involved in a botanical exposure should be left to a trained botanist or mycologist. Even without a definitive identification, the history of exposure and the recognition of a characteristic syndrome are often sufficient to establish a tentative diagnosis. The best treatment is usually empiric, including gastric lavage or catharsis, supportive measures, and control of symptoms. With the exception of anticholinergic poisoning, there are few specific antidotes. Several of the important neurological syndromes are discussed in the following sections. A comprehensive review of the many botanical toxins is impossible, and only a small selection is presented. Table 64C.2 lists several major categories and the commonly associated plants in each category. Omitted are plants that do not have direct toxicity on the nervous system, such as those containing cardiac glycosides, cournarin, oxalates, taxines, andromedotoxin, colchicine, and phytotoxins. Secondary neurological disturbances may result from these toxins because
Tabic 64C.2:
some can cause severe electrolyte abnormalities, cardiovascular dysfunction, or coagulopathy.
Jimson Weed
(Datura stramonium)
Jimson weed, first grown by early settlers in Jamestown from seeds brought from England, was initially used to treat asthma. It is now found throughout the United States. Intoxication is not uncommon, especially among young recreational users in rural areas. The chief active ingredient is the alkaloid hyoscyamine, with lesser amounts of atropine and scopolamine. Among the 1144 intoxications by anticholinergic drugs reported in 2001, the single fatality was attributed to Datura ingestion (Litovitz ct al. 2002). Symptoms of anticholinergic toxicity appear within 30-60 minutes after ingestion and often continue for 24-48 hours because of delayed gastric motility (Centers for Disease Control 1995). The clinical picture can include hyperthermia, delirium, hallucinations, seizures, and coma. Autonomic disturbances such as mydriasis, cycloplegia, tachycardia, dry mouth, and urinary retention are often present. Treatment includes gastrointestinal decontamination with or without the induction of emesis. Supportive measures and symptom relief should be provided, and physostigmine should be reserved for severe or lifethreatening intoxications.
Neurotoxicity of plants
Principal Toxins
Plants (representative examples)
Main Clinical Features
Tropane alkaloids (belladonna)
Mydriasis, cycloplegia, tachycatdia, dry mouth, hyperpyrexia, delirium, hallucinations, seizures, coma
Cicu toxin
Jimson weed (Datura stramonium), Deadly nightshade (belladonna, Atropa belladonna), Matrimony vine (Lycium halimifolium), Henbane (Hyoscyamus niger), Mandrake (Mandragoran officinarum), Jasmine [Cestrum sp.) Woody nightshade (bittersweet, Solanum dulcamara), Black nightshade {Solanum nigrum), Jerusalem cherry (Solanum pseudocapsicum), Wild tomato {Solanum gracile), Leaves and roots of the common potato {Solanum tuberosum) Tobacco (Nkotiana sp.}, Golden chain {Laburnum anagyroides), Mescal bean (Sophora sp.), Scotch broom (CyrisHs sp.), Poison hemlock (Conium maculatum) Water hemlock (Cicuta maculata)
Triterpenc
China berry {Melia azedarach)
Anthracenones Excitatory amino acid agonists
Buckthorn {Karwinskia humboldtiana) Chickling pea and others [Lathyrus sp.), Cycad (Cycas rumpbii), False sago palm (Cycas circinalis)
Solanine alkaloids
Nicotine-like alkaloids (e.g., Cytisine)
Mydriasis, cycloplegia, tachycardia, dry mouth, hyperpyrexia, delirium, hallucinations, seizures, coma
Variable sympathetic and parasympathetic hyperactivity, hypotension, drowsiness, weakness, hallucinations, seizures
Diarrhea, abdominal pain, salivation, seizures, coma Confusion, ataxia, dizziness, stupor, paralysis, seizures Ascending paralysis; polyneuropathy Neurodegenerative diseases
NEUROTOXINS OF ANIMALS AND PLANTS
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Poison Hemlock (Cortiutn maculata)
Medicinal Herbs
The dangers of poison hemlock have been known since ancient times. It was reportedly used to execute Socrates. The Old Testament describes rhabdomyolysis in Israelites who ate quail fed on hemlock (coturnism). The highest concentration of toxin is in the root of this ubiquitous plant, which may be mistaken for wild carrots. Alkaloid toxins structurally similar to nicotine initially cause CNS activation and general autonomic stimulation. In severe cases, a depressant phase may then ensue, presumably secondary to acetylcholine receptor tachyphylaxis. Death is usually secondary to respiratory paralysis.
Treatment of illness with herbal remedies, either purchased over-the-counter at health food stotes or procured from practitioners of traditional medicine, has become increasingly popular in the United States. Potentially harmful ingredients may be included in products as contaminants or intentionally added to increase a desired effect. The labels, if present, often do not fully represent the myriad of compounds contained within. Many of these can have potential GNS effects of varying severity. Gomamination of products with Atropa belladonna (deadly nightshade), Datura sp., and Mandragora officinarum (mandrake) have been reported. Common herbal preparations such as kava-kava (Piper methysticum) and St. John's wort (Hypericum perforatum) have neurotoxic potential, particularly if combined with other herbal or standard pharmaceuticals. Podophyllum peltatum (mayapplc), widely used in Ghinese herbal medicine, is potentially neurotoxic.
Water Hemlock {Cicuta maculata) Water hemlock is a highly toxic plant found primarily in wet, swampy areas and sometimes mistakenly ingested as wild parsnips or artichokes. Although related to poison hemlock, its clinical toxidrome is quite different. The principal toxin, the long-chained aliphatic alcohol cicutoxin, is a highly potent, noncompetitive GABA receptor antagonist (Uwai et al. 2000). Symptoms consist of initial gastrointestinal effects (abdominal pain, salivation, and diarrhea) followed by generalized convulsions, obtundation, and coma. Mortality is secondary to refractory status epileptieus; seizures are treated with standard protocols.
Peyote
(Lapbapbora
williamsii)
Peyote is a small cactus native to the southwestern United States and Mexico, but it can be cultivated anywhere. The principal agent is mescaline, which has actions similat to those of the hallucinogenic indoles. A peyote button, the top portion of the cactus, contains about 45 mg of mescaline; 6 to 9 buttons (5 mg/kg) are sufficient to be hallucinogenic. Dizziness, drowsiness, ataxia, paresthesias, sympathomimetic symptoms, nausea, and vomiting are frequent accompanying clinical features. Ingestions are rarely life-threatening.
Morning Glory (Ipomoea tricolor) The active agents in morning glory seeds are various amides of lysergic acid. The seeds are consumed for purposes of abuse. The neuropsychological effects are similar to those of lysergic acid diethylamide (LSD) and consist of hallucinations, anxiety, mood changes, depersonalization, and drowsiness. Acute clinical effects may also include mydriasis, nausea, vomiting, and diarrhea.
Excitatory Amino Acids Various Latbyrus species, including L. sativus (chickling pea), L. clymenum (Spanish vetch), and L. cicera (flatpodded pea) are responsible for lathyrism (Spencer 1995). These hardy plants are an important part of the diet of people in the India subcontinent, Africa, China, and some parts of Europe. Epidemics of lathyrism often coincide with periods of famine or war, probably a result of excessive dietary dependency on these legumes. The disease, knowrn since antiquity, is still endemic in many underdeveloped countries; astounding prevalence rates as high as 6 6 % have been reported during famines. The putative toxin is beta-Noxalylamino-L-alanine (L-BOAA), an amino acid with potent agonist activity at the (R.S)-a-amino-3-hydroxy-5methyl-isoxazole-4-propionic acid (AMPA) subclass of glutamate receptors. L-BOAA is capable of inducing ncurolathyrism in several animal models. Clinically, the affected patients present with subacute or insidious onset of spastic paraparesis, upper motoneuron signs, and gait instability. Muscle aching and paresthesias may be present, but the sensory examination is largely normal. Cognition ami tv:vbella: lumtioiis are \(\nvd. Partial recovery after discontinuation of i.athyrus intake is possible, but interestingly, there are reports of deterioration without further exposure many years later. Historically the Chamorro people of Guam have had a high incidence of parkinsonism, amyotrophic lateral sclerosis, and dementia; however, the occurrence has now markedly decreased in the younger population. The etiology of this complex is uncertain; many have speculated that it is due to unique aspects of their diet, especially the consumption of flour made from the seeds of the cycad (Cycas rumpbii). Among other compounds, cycads contain
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NEUROLOGICAL DISEASES
a toxic a m i n o acid, ^-N-methylamino-L-alanine. (BMAA) t h a t has heen s h o w n to d a m a g e m o t o n e u r o n s in p r i m a t e s and cause parkinsonian and behavioral changes. [Neurodegenerative diseases in other p o p u l a t i o n s have also suggested a possible link to plant-detived n e u r o t o x i n s . Causal relationships are often difficult to prove in these instances.
M u s h r o o m Poisoning Of the m o r e t h a n 5 0 0 0 varieties of m u s h r o o m s , a p p r o x i mately 100 a r e k n o w n to be toxic to h u m a n s . Ingestion by children comprises the majority of cases t e p o r t e d to poison centers. These exposures arc generally n o t serious, because usually only small a m o u n t s a r e ingested a n d m o s t " l a w n " m u s h r o o m s are harmless. Adults m o t e frequently c o n s u m e m u s h r o o m s in larger quantities and m o r e likely d e v e l o p toxic s y m p t o m s . Aside from accidental ingestion, m u s h r o o m s such as Psihcybe sp,, Panaeolus s p . , Amanita mu scar la, a n d Amanita panthcrma a r e p o p u l a r a m o n g drug users for their psychoactive effects. M a n y a t e used also in tribal ceremonies as an intoxicant. T h e classification system most c o m m o n l y a d o p t e d by clinicians divides p o i s o n o u s m u s h r o o m s into g r o u p s
Table 64C.3;
a c c o r d i n g to clinical symptomatology. The gtoups associated with significant neurological m o r b i d i t y are listed in T a b l e 6 4 C . 3 . T h e most lethal m u s h r o o m s belong to the Amanita g e n u s a n d c o n t a i n v a r i o u s cyclic polypeptides, including the a m a t o x i n s , p h a l l o t o x i n s , and virotoxins. A m a t o x i n s h a v e p o t e n t h e p a to toxicity a n d n e p h r o t o x i c i t y . In significant intoxications, severe gastrointestinal s y m p t o m s a p p e a t initially, after a characteristic latency period of 6 - 2 4 h o u r s , followed by fulminant hepatic a n d renal failute 3-5 days later. Seizures, e n c e p h a l o p a t h y , and c o m a often a c c o m p a n y systemic o r g a n failure. W i t h the exception of p o i s o n i n g by some m o n o m e t h y l h y d r a z i n e - c o n t a i n i n g genera (gyromitrin), toxicities a t e rarely life t h r e a t e n i n g . In 2 0 0 1 , nearly 8 5 0 0 m u s h r o o m ingestions w e t e reported in emergency r o o m s in rhe United States; t h c t e were no fatalities, b u t 38 w e r e classified as h a v i n g significant medical o u t c o m e s (Litovitz 2 0 0 2 ) , P o i s o n o u s m u s h r o o m s often closely resemble edible varieties. A specimen m a y be distorted d u r i n g t r a n s p o r t or after c o o k i n g . T h e task of t a x o n o m y is best left to a mycologist. Even in the absence of a positive identification, the n a t u r e of t h e s y m p t o m s and t h e time of their onset after ingestion are v a l u a b l e guides to diagnosis a n d m a n a g e m e n t . Supportive care a n d d e c o n t a m i n a t i o n a r e the m a i n s t a y s
Poisonous Mushrooms
Principal toxins Cyclic polypeptides (especially amatoxins)
Monomethylhydrazines (Gyromitrin)
Coprine
Mll.i.!
Isoxazoles (Muscimol, ibotenic acid)
Indoles (psilocybin, psilocin)
Mushrooms {representative
examples)
Amanita pballoides ("death cap"), Amanita mrosa, Amanita bisporigera, Amanita verria, and others Gyromitra sp, ("false morels")
Coprinus atrame.ntarms ("inky cap") and other Coprinaceae C.lilotybc and btocybe genera Amanita muscatia ("fly agaric"), Amanita gemmata, Amanita pantbenna ("the panther"), Amanita cotburnata Psilocybe caerullpes, Psliocybe cubensis, Panaeolus foenisecii, Gymnopbilus speclabilis, Psathyrella foenisecii
Mode of action
Time of onset/main clinical features
Inhibition of mRNA synthesis; lie pa to toxicity and nephrotoxicity
6-24 hr: GI symptoms; 3-5 days: hepatotoxicity and renal failure
Functional pyridoxine deficiency; GABA deficiency (through decreased GAD activity) Inhibition of aldehyde dehydrogenase (disulfiramIike) Cholinergic agonist
6-10 hr: GI symptoms, hemolysis; seizures respond to pyridoxine 20-120 min: flushing, palpitations, and headache after alcohol ingestion 15-120 min: cholinergic hyperactii it; 30-90 min: ethanol-like intoxication; euphoria, hallucinations, dysarthria, ataxia, myoclonic jerks, seizures, and coma 30-60 min: euphoria, hallucinations, mydriasis, tachycardia, seizures (in children)
GABA receptor agonist; glutamate receptor agonist; anticholinergic
Structural analogue of serotonin (5-HT); actions resemble LSD
GABA = y-aminobutyric acid; GAD = glutamic acid decarboxylase; GI = gastrointestinal; 5-HT lysergic acid diethylamide.
5-hydroxytrypta mine; LSD
NEUROTOXINS OF ANIMALS AND PLANTS of t r e a t m e n t . This can be further s u p p l e m e n t e d by specific treatments, such as infusion of p y r i d o x i n e (gyromitrin poisoning), a t r o p i n e (muscarine poisoning), or physostigmine (ibotenic acid a n d muscimol poisoning), as needed.
REFERENCES Bond, G. R. 1999, "Snake, spider, and scorpion cnvcnomation in North America," Vediatr Rev, vol. 20, pp. 147-151 Royer, D., Huebner, K., McNally, J., & Buchanan, P. 2 0 0 1 , "Dearh from Centruroidcs scorpion sting [abstract]," J Toxicol Clin Toxicol, vol. 39, pp. 561-562 Centers for Disease Control. 1995, "Jimson weed poisoning— Texas, New York, and California, 1994," MMWR Morb Mortal Wkly Re/;, vol. 44, pp. 41-44 Gold, B. S., Dart, R. C, & Barish, R. A. 2002, "Bites of venomous snakes," N Engl J Med, vol. 347, pp. 347-356
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Lawrence R. A. 1998, "Poison centers and plants: More poUyanna data?" J Toxicol Clin Toxicol, vol. 36, pp. 225-226 Litovitz, T. L., Klein-Schwartz, W., Rodgers, G. C, Jr., et a I. 2001, "Annua] report of the American Association of Poison Control Centers Toxic Exposure Surveillance System," Am ] Emerg Med, vol. 20, pp. 391-452 Markland, F. S., Jr. 1997, "Snake venoms," Drugs, vol. 54, pp. 1-10 Sehiavo, C, Matteoli, M., 6c Montecucco, C. 2000, "Neurotoxins affecting neuroexocytosis," Physiol Rev, vol. 80, pp. 717-766 Spencer, P. S. 1995, "Lathyrism," in Handbook of Clinical Neurology: Intoxications of the Nervous System, ed. F. A. de Wolff, Elsevier, Amsterdam Woestman, R., Perkin, R., & Van Stralen, D. 1996, "The black widow: Is she deadly to children?" Rediatr F.merg Care, vol. 12, pp. 360-364 Uwai, K., Ohashi, K., Takaya, Y., et al. 2000, "Exploring the structural basis ol neurotoxicity of Ciypolyacetylenes isolated from water hemlock," j Med Chem, vol. 4 3 , pp. 4508-4515
Chapter 64 Effects of Toxins and Physical Agents on the Nervous System D. MARINE TOXINS Neil E. Schwartz and Yuen T. So Ciguatera Fish Poisoning Clinical Features Diagnosis Treatment Pufferfish Poisoning Scombroid Fish Poisoning
17.16 1737 1737 1737 1737 1738
Seafood is a vital component of the human diet worldwide and is essential fot the economic stability of many regions. Various toxic syndromes have occurred from the consumption of contaminated fish and shellfish, some of which have neurological consequences. Descriptions of marine food poisoning date back to ancient times. A carving on the tomb of the Egyptian Pharaoh Ti (circa 2700 KC) depicts the dangers of the toxic puffcrfish, and the Old Testament warning that forbids the eating of fish that "hath not fins and scales" may have carried the same truth. Galen claimed that moray eels, possible vectors of various marine toxins, were dangerous to eat. Ciguatera intoxication was known in China during the T'ang Dynasty (618-907 AD); it was later described by early Spanish explorers and in the journals of Captain Cook's expedition in 1774. George Vancouver recognized paralytic shellfish poisoning in the Pacific Northwest toward the end of the eighteenth century. Periodic outbreaks of marine intoxications affecting humans or wildlife continue to make news headlines. In addition to their obvious clinical concern, many of these toxins have been essential in our quest to understand cellular neurophysiology, in particular, ionic fluxes through excitable membranes. Some toxins have been exploited for other human purposes, such as tetrodotoxin-tipped darts and arrows used in the Americas for hunting purposes. Most marine toxins originate from micro-organisms, typically unicellular flagellated algae (dinoflagellates). During periods of intense algal proliferation (blooms), high concentrations of toxins accumulate in fish or shellfish, which then act as transvectors for human disease. Typically, the toxins do not adversely affect the transvector; in fact, there is often bio-concentration of the toxin as it is consumed by larger animals further up the food chain.
Shellfish Poisoning Paralytic Shellfish Poisoning Neurotoxic Shellfish Poisoning Amnestic Shellfish PoiMniini; Diarrhetic Shellfish Poisoning Others
L738 1739 1739 1739 1740 1740
This chapter highlights some of the more common intoxications that occur from ingestion of contaminated seafood (Table 64D. 1), Other marine-associated intoxications, such as those that occur from venomous fish, cchinoderms, sponges, red whelks, cyanobactcria, and coelenterate stings are not covered here. Likewise, envenomation with conotoxins (predatory mollusks from the superfamily Conidac), although of tremendous interest to the research neuroscientist, is less relevant for the clinical neurologist. The proliferation of toxin-producing microalgae depends on poorly understood interactions of a number of environmental and seasonal factors. Outbreaks of shellfish poisoning are associated with so-called "red tides," which refer to algal blooms and tile subsequent reddish-brown discoloration of the water. Red tides have great economic effects on coastal communities dependent on both tourism and fisheries; blooms can cause massive fish kills, wiping out entire fish farms within hours. Not all red tides are toxic, and shellfish contaminations do not necessarily follow red tides (Whittle and Ga Mac her 2000). Moreover, ciguatera poisoning {see Ciguatera Fish Poisoning in next section) is not associated with blooms or any other reliable forewarning. The marine toxins arc generally colorless, tasteless, and odorless. Normal food screening and preparation procedures do not typically prevent intoxication. This heat and acid stability renders marine toxins particularly dangerous to unsuspecting consumers of contaminated seafood and poses difficulty in formulating public health strategies for prevention. Globalization of the food industry, with its efficient methods of transportation, raises the possibility of intoxication with imported fish and shellfish not typically found in the United States. The American Association of 1735
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NFUROLOCICAL DISEASES
Tabic 64D.1:
Fish and shellfish poisoning
Syndrome
'Principal toxins
Toxin source
Transvector
Path op hysio logy
Ciguatera fish poisoning
Ciguatoxins; ma i to toxin; others Tetrodotoxins
Dinoflagdlates (Gambwrdiscus toxicus and others) Presumed bactetial [}Vibrios spp., IPseudomonas spp.) Presumed bacterial [}Vibrios spp,)
Fish (multiple species of reef fish)
N a + and C a + + channel activation N a T channel blockade
J'uil. Irtish poisoning Scombroid fish poisoning
I listamme
Paralytic shellfish poisoning (PSP)
S.iximxin and derivatives
Neurotoxic shellfish poisoning (NSP)
Brcveioxms
Amnestic shellfish poisoning (ASP)
Domoic acid and its cogencrs
Diari hetit shellfish poisoning (DSP)
Okadaic acid and derivatives; dinophysistoxins
[dinoflagdlates {Alexandrium spp., Gymnodium catena turn, Pyrodinium bahamense) Dinoflageltates [Gymnodinuim breve) Diatoms {Pseudo-nitzscbia spp., Nitzscbia actydrapbila, Amphora coffeifornus) I (uniflagellates {Dinophysis sp., Prorocentrum spp., Proceratium reticulatttm, Coolia sp.)
Poison C o n t r o l Centers (AAPCC) logged over 6 7 , 0 0 0 incidents of food poisoning in the United States in 2 0 0 1 ; exposure data for m a r i n e intoxications, however, are n o t reported separately (Litovjtz et al. 2 0 0 2 ) . Physicians w h o treat any suspected cases should r e p o r t t h e m to public health agencies, as any index case m a y be the beginning of a wider o u t b r e a k . Whenever possible, the c o n t a m m a n d food should be retrieved and tested, and m a n y t o x i n assays a r e currently available. Diagnosis is d e p e n d e n t on the history of ingestion and t h e recognition of the a p p r o p r i a t e clinical features. T r e a t m e n t , unfortunately, is mostly s y m p t o m a t i c . Although m a r i n e toxins can cause significant m o r b i d i t y , most illnesses are short-lived and mortality is rare.
C I G U A T E R A FISH P O I S O N I N G Ciguatera is a m a r i n e food poisoning endemic to t h e tropics, but it is also the m o s t c o m m o n nonbacterial fish borne poisoning in the United States. T h e ciguatera toxins are produced by algae t h a t thrive in the tropical or subtropical coral reef ecosystem, extending between iS' N o r t h a n d 3 5 " South. The epiphytic dinoflagellate Gambierdiscus toxicm has been implicated in ciguatera, but o t h e r organisms m a y also play a role. T h e algae a r e consumed by small h e r b i v o r o u s fish t h a t in t u r n a r c eaten
Various {puffcrfish, salamanders, newt, and others) Scombroid fish (tuna, mackerel, skipjack, ere.) and non-scombroid fish (mahi-mahi, sardines, etc.) Shellfish
Shellfish
Shellfish; fish (?)
Shellfish
H i stain in ergic i-l'n i •
Na + channel blockade
Transforms fast Na_t channels into slower ones Glutamate receptor activation
Serine/threonine protein phosphatase nhibirion
by c a r n i v o r o u s ones. As such, larger a n d older fish such as b a r r a c u d a , eel, sea bass, g r o u p e r , red s n a p p e r , a n d a m b e r jack a r e m o r e toxic. Practically any reef fish eaten in significant q u a n t i t y , h o w e v e r , m a y cause ciguatera; m o r e t h a n 4 0 0 species have been implicated. O u t b r e a k s can also occur in residents of t e m p e r a t e areas after travel or c o n s u m p t i o n of i m p o r t e d fish. Accurate disease incidence is n o t available because of unavoidable undcr-rceognition and under-reporting. O n e estimate p u t s the a n n u a l n u m b e r of cases between 2 0 , 0 0 0 and S0,000 a m o n g people in e n d e m i c areas, p r e d o m i n a n t l y Australia, the C a r i b b e a n , a n d the islands of the South Pacific. A telephone survey estimated t h a t 7% of P u e r t o Rico's residents might h a v e suffered at least o n e episode of ciguatera in their lifetime. In the United States, most cases a r e e n c o u n t e r e d in H a w a i i , R h o d e Island, a n d Florida. Even in C a n a d a , there a r c an estimated 1 0 0 0 cases per year from t o u r i s m a n d i m p o r t e d fish. Mortality has been reported a t less t h a n 0 , 5 % . N o d e a t h s from ciguatera have been d o c u m e n t e d in the United States. A n u m b e r of toxins a r e responsible for ciguatera, including c i g u a t o x i n s and m a i t o t o x i n . C i g u a t o x i n s are a g r o u p of lipid-solublc, highly o x y g e n a t e d cyclic polyethyl molecules similar in structure to the brevetoxins (see N e u r o t o x i c Shellfish Poisoning, later in this c h a p t e r ) . C i g u a t o x i n s act o n t e t r o d o toxin-sensitive voltage-gated
MARINE TOXINS
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sodium channels in nerves and muscles, leading to increased sodium permeability at rest and membrane depolarization. This results in spontaneous neuronal firing that presumably underlies the neurological symptoms. Maitotoxin is a watersoluble bisulfated compound that increases calcium ion influx through voltage independent calcium channels; it is the most potent nonproteinaceous toxin known (LD50 = 50 ng/kg, i.p.; Yasumoto 2001). Gambierol and palytoxin, lipid- and water-soluble toxins, respectively, have also been implicated in ciguatera (Daranas, Norte, and Fernandez 2001).
largely based on the characteristic gastrointestinal, neurological, and cardiovascular disturbances. Clustering of cases in people who consumed the same fish helps confirm the diagnosis. However, there is significant variation in individual susceptibility, even when two persons eat a similar quantity. Nerve-conduction studies may show slowing of both sensory and motor nerve-conduction velocities, with prolongation of the absolute refractory, relative refractory, and supernormal periods. These findings are consistent with prolonged opening of sodium channels in the axonal cell membranes.
Clinical Features
Treatment
Symptoms of abdoiiiin.il pain, nausea, vomiting, and diarrhea are usually the first to appear and may last 1-2 days. Neurological symptoms are almost invariably present in ciguatera and arc the dominant feature in poisoning that occurs from Pacific Ocean fish (Lewis 2001). Patients develop centrifugal spread of paresthesias involving the oral cavity, pharynx, limbs, trunk, and, most disagreeably, genitalia and perineum. Particularly characteristic is a paradoxic temperature reversal; patients perceive cold as burning, tingling, or unbearable heat. A smaller proportion may sense warm objects as cold. 1 leadache, weakness, fatigue, arthralgia, myalgia, metallic taste, and pruritus are common. Bizarre symptoms such as a sensation of loose teeth are occasionally described; referrals to psychiatrists have been made by clinicians unacquainted with the disease. Curiously, symptoms are worsened by alcohol consumption, exercise, sexual intercourse, or dietary factors. The severity of symptoms is typically dosedependent, with more severe poisonings tending to occur after consumption of the toxin-rich head, liver, and viscera of contaminated fish. Paralysis and death have occurred. Rare cases of polymyositis and peripheral neuropathy have also been reported. Irritability may be the only neurological symptoms in children, but life-threatening cases occur more frequently in this age group. Acute transient cardiovascular abnormalities are sometimes seen, and there tends to be an increase in parasympathetic tone. Most neurological symptoms remit in approximately one week, although somedegree of paresthesias, asthenia, weakness, and headache may persist for months to years. The long-lasting symptoms, which are often accompanied by depression, may ultimately resemble chronic fatigue syndrome. Lipid storage and slow release of toxin may underlie the prolonged nature of some symptoms (Pearn 2001).
Decontamination of the gastrointestinal tract with charcoal may be beneficial if the patient presents soon after ingestion. Intravenous mannitol (20%; 1.0 g/kg at 500 mlVhour) is a specific treatment for acute ciguatera. The mechanism of action may be related to the reduction of edema in Schwann cells, but this is a matter of debate. Neurological improvement can be dramatic in over 6 0 % of patients, especially if mannitol is given soon after symptom onset; gastrointestinal symptoms, however, are resistant to this therapy. Repeat dosages may be helpful. Fluid and electrolyte status should be assessed and corrected if necessary, because mannitol may induce severe dehydration and electrolyte derangements. Supportive care during acute disease may include fluid supplementation, control of bradycardia, and symptomatic treatment of anxiety, headache, and pain. Calcium gluconate, anticonvulsants, and corticosteroids have been tried wir'i varying results. The chronic symptoms of ciguatera arc difficult to treat. Amitriptyline or other tricyclic antidepressants may provide partial relief.
Diagnosis Although a commercially available immunoassay exists for ciguatoxiu detection in fresh fish, it is often impossible to find what remains of the offending species. Diagnosis is
PUFFERFISH POISONING Tetrodotoxin (TTX) is the causative agent in pufferfish poisoning. Pufferfish (family Tetraodontidae) have a worldwide distribution in both freshwater and saltwater but are most commonly found in the waters around Japan and China. Over 100 species are identified, known variously as pufferfish, tarn bores, porcupine fish, jugfish, and blowfish. Other sources of TTX include the ocean sun fish, toad fish, parrotfish, Australian blue-ringed octopus, gastropod mollusk, horseshoe crab (eggs), Atelopid frogs (skin), newts (genus Taricba), and some salamanders. The source of pufferfish TTX is debatable. It is thought to be marine bacteria, possibly Vibrio, thai colonize the fish and allow the TTX to be sequestered. Concentrations are especially IneJ'- m the skin, liver, roe, and gonads and relatively low in the muscles, hugu refers to a preparation of pufferfish in Japan that is considered a delicacy. Specially trained fugu chefs certified by the government fillet the fish
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NEUROLOGICAL DISEASES
in a way that avoids contamination by the deadly viscera. A handful of these chefs prepare pufferfish in the United States. Despite these precautions, fugu poisoning accounts for approximately half the fatal food poisonings in Japan, with up to 50 deaths each year. Toxicity is seasonal, and pufferfish is served only from Octobet to March. TTX is a heat-stable, water-soluble heterocyclic small organic molecule that selectively blocks voltage-gated sodium channels in excitable membranes. It interferes with the inward (excitatory) flow of sodium current that occurs during an acrion potential, 'lerrtnloroxin blocks in pulse conduction in somatic and autonomic nerve fibers, reduces the excitability of skeletal and cardiac muscles, and has profound effects on vasomotor tone and central mechanisms involved in respiration. A dose of 1-2 mg of purified TTX can be lethal. Toxicity has been documented with the consumption of as little as 1.4 ounces of fugu. The clinical symptoms of TTX poisoning are similar to those of saxitoxin (STX)-induced paralytic shellfish poisoning (sec Paralytic Shellfish Poisoning, later in this chapter). Lip and tongue paresthesias appear within minutes of ingestion. Gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain are common. Progressive ascending weakness is apparent in moderately severe cases. Reflexes may be preserved early in the course of paralysis. Dysphoria, dysphagia, hypoventilation, and profound hypotension develop in more severe intoxications. Coma and seizures may be seen. Fatality rates are high, with estimates at 5 0 - 8 0 % , mostly due to respiratory insufficiency, cardiac dysfunction, and hypotension. Treatment is supportive. Gastric lavage and charcoal are indicated if presentation is early. Anticholinesterases have variable success. Patients who survive the acute period of intoxication (approximately the first 24 hours) tend to recover without neurological sequelae, while those who succumb tend to do so within the first several hours. Fluorescent spectrometry can detect TTX, and the mouse bioassay for STX detection is also positive for TTX.
SCOMBROID FISH POISONING Scombroid fish poisoning—also known as histamine fish poisoning, p s e u d o a l l e l e fish poisoning, or "mahi-mahi flush"—is among the most common causes of fish toxicity worldwide. The AAPCC does not maintain specific data on scombroid fish poisoning, but it represents 5% of foodborne disease outbreaks reported to the Centers for Disease Control and Prevention. Poisoning can occur after eating improperly stored fatty, dark-fleshed scombroid fish (family Scombri da e; e.g., tuna, mackerel, skipjack) or non-scombroid fish (e.g., mahi-mahi, marlin, sardines, .iiu hi ivies . Alleued fish typical [\ have a peppery, inei.il lie, or bitter flavor. The pathophysiology is incompletely inhk IMIIOJ, lull poisoning is believed to be caused lij bacterial decarboxylation of histidme to biogenic amines
such as histamine. This occurs at temperatures above 15°G Histamine is heat-stable, so once it is formed by improper storage it cannot be inactivated by proper cooking. It is typically present at levels below 0.1 mg/100 g in normal fish but can be higher than 20-50 mg/100 g in toxic fish. Oral consumption of similar quantities of histamine does not cause symptoms to the same degree, raising the possibility that another mechanism is at play in scombroid toxicity. The syndrome is distinctive; it closely resembles an acute allergic reaction and is often misdiagnosed as such. Clinical features include pruritus, throbbing headache, skin flushing, urticaria, oral burning or paresthesias, palpitations, and gastrointestinal disturbances. Symptoms occur within minutes after fish ingestion and are self-limited to 3-6 hours. Patients at the extremes of age and those with asthma are most vulnerable. Persons taking isoniazid or monoamine oxidase inhibitors may have more severe symptoms because of blockade of histaminasc. Diagnosis is made by a careful history and examination. Histamine levels can be measured in fish, and urinary levels of histamine and N-methylhistidine may be elevated in affected patients, but these studies are not typically used clinically. Intravenous histamine receptor types 1 and 2 (Hj and H 2 ) blockers should be given promptly, as their administration often provides rapid symptomatic relief. Treatment is otherwise supportive. Epinephrine is sometimes given under the assumption that an allergic reaction is taking place; it should typically be reserved for cases with symptomatic bronchospasm.
SHELLFISH POISONING Food poisoning caused by shellfish is more likely to be from infectious agents than toxins. Hepatitis A, Norwalk virus, and various Vibrio species can be transmitted through the ingestion of shellfish. Classically, four syndromes may result from consumption of shellfish contaminated bytoxins: patalytic shellfish poisoning, neurotoxic shellfish poisoning, amnestic shellfish poisoning, and diarrhetic shellfish poisoning. All arc primarily associated with bivalve mollusks (clams, mussels, scallops, oysters), filter feeders that can accumulate toxic microalgae at high levels. Outbreaks are common during the summer months, especially during periods of red tides. The World Wide Web is a good source for up-to-date information on harmful algal blooms. Although the teaching in North America and Britain is that shellfish arc safe in mouths that contain the letter "r." toxic contamination may occur in any month and in the absence of red tides. The incidence of shellfish poisoning has been on the decline in the United States, even as the incidence of harmful algal blooms is on the rise. This is probably due to greater public awareness and governmental safety measures such as forced beach closures and shellfish analysis.
MARINE TOXINS
Paralytic Shellfish Poisoning Paralytic shellfish poisoning (PSP) occurs in the United States along the coast of New England, in the Pacific Northwest, and in Alaska. It is the most severe of the shellfish intoxications, with mortality rates of 1-12%>, with higher rates being in areas without advanced life support capabilities. Children appear to be more sensitive than adults. Dinoflagellates of the species Alexandrmm are the primary source of the saxitoxins, the agents responsible for the neurological symptoms of PSP. Blooms occur between April and October, with shellfish remaining toxic for several weeks after the bloom subsides. Saxitoxin (STX) is a heat-stable toxin that acts primarily on the peripheral nervous system, where it binds reversibly to voltage-gated sodium channels in nerve and muscle membrane. Its action is similar to TTX (see Pufferfish Poisoning, earlier in this chapter). In comparison with TTX, STX has a greater potency to cause skeletal muscle weakness but has a lesser propensity to induce severe hypotension. It also has a shorter duration of action. Symptoms typically appear within 5-30 minutes of ingestion of contaminated shellfish. Paresthesias develop in almost all patients and initially involve the perioral areas, oral cavity, face, and neck. These symptoms spread to the limbs and trunk in severe cases. Some patients complain of an unusual floating sensation. Brainstem symptoms and signs are sometimes present; these include dysarthtia, dysphagia, dysphonia, ophthalmoplegia, nystagmus, and dilated pupils. Other neurological symptoms include headache, gait ataxia, and limb incoordination. Gastrointestinal symptoms are less common. Despite the name of this syndrome, muscle paralysis does not develop in every patient. If present, weakness may involve muscles of the face, jaw, swallowing, respiration, and upper and lower limbs. In severe cases, respiratory paralysis appears within 2-12 hours of ingestion; the incidence of required respiratory support is 3-6%. Untreated respiratory paralysis is responsible for the deaths seen in PSP. Spontaneous recovery begins to appear after 12 hours and is usually complete within a few days. Weakness, however, may persist for weeks. There is no antidote, and treatment is supportive. Initial diagnosis is largely dependent on recognition of the history and clinical features. An enzyme-linked immunosorbent assay (El.ISA) is available for STX, but its utility is limited by the variability of toxin constituents in each outbreak. If the contaminated shellfish is available, a useful test is the mouse bioassay. A mouse unit is defined as the minimum amount necessary to induce death of a mouse in 15 minutes. The lethal dose for humans is approximately 5000-20,000 mouse units. The mouse assay is employed to monitor commercial shellfish production in many parts of the world. Nerve-conduction studies may show reduced amplitude of the sensory and motor responses and prolonged latencies with slowed nerve-conduction
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velocities. Unlike acute demyelinating neuropathies, in which electrophysiological abnormalities lag behind clinical findings, the electrophysiological abnormalities in PSP are most prominent at symptom onset and improve over a few days as clinical symptoms resolve.
Neurotoxic Shellfish Poisoning Neurotoxic shellfish poisoning (NSP) is caused by the di no flagellate Gymnodinium breve, which is found primarily in the Gulf of Mexico, the Caribbean Sea, and the waters around New Zealand. These microalgae are known for causing the infamous Florida red tides. They elaborate a group of lipophilic polyether toxins called brevetoxins, which cause depolarization of excitable membranes, persistent activation, and repetitive firing of nerves and muscles by transforming fast voltage-gated sodium channels into slower ones. Brevetoxins are probably more toxic to wildlife than humans, and red tides from blooms of G. breve are typically associated with massive fish, invertebrate, and seabird kills. Clinical presentation is characterized by the simultaneous onset of gastrointestinal and neurological symptoms within minutes to hours after ingestion. Nausea, diarrhea, rectal burning, myalgia, circumoral paresthesias, dizziness, and ataxia are common. Less common signs and symptoms include tremor, dysphagia, mydriasis, and hyporeflexia. In general, the neurological symptoms are milder than those of PSP. Temperature reversal similar to that seen in ciguatera may be reported. A separate respiratory syndrome has been attributed to inhalation of brevetoxin aerosolized by the surf. A response consisting of conjunctival irritation, rhinorrhea, cough, and bronchoconstriction can be seen in sensitive individuals. No human deaths have been associated with NSP. There is a mouse bioassay for the detection of brevetoxin; radioimmunoassay (RIA) and ELISA are also available.
Amnestic Shellfish Poisoning In November iyS7, 107 Canadians were stricken by a novel illness after eating mussels harvested off the Prince Edward Island coast. Gastrointestinal symptoms were followed by cognitive dysfunction and headache. The syndrome, referred to as amnestic shellfish poisoning (ASP), was found to be microalgae toxin-mediated. The toxin was later identified as domoic acid, an analogue of kainic acid. It functions as a potent agonist at excitatory ionotropic glutamate receptors. A pennare diatom, Psetidonitzschia pungens, was the probable source of the domoic acid. Very high concentrations of the excitotoxin were found in the digestive glands of uneaten mussels and those sampled from three river estuaries in Prince Edward Island. Since the initial epidemic, domoic acid has been found in
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anchovies in Monterey Bay, California; in razor clams and Dungeness crabs in the Pacific Northwest; and in the marine food web along the Texas coast (Morris 1999). Massive killing of seabirds and mammals in the waters around Baja, California, have been attributed to domoic acid (Sierra-Beltran et al. 1998). Domoic acid acts as an excitatory neurotransmitter in animal models; it is approximately three times more potent than kainic acid and over 30 times more potent than glutamic acid. Neurological disease results from its excitotoxic actions, especially on the limbic system. Symptoms usually appear within a few hours of ingestion. Almost all patients have diarrhea, vomiting, or abdominal cramps, although the severity varies. Roughly one-half of patients have headache, and approximately 2 5 % present with anterograde memory . loss. In those with neurological dysfunction, the findings are quite varied. They include disorientation, mutism, seizures, myoclonus, and altered state of consciousness (ranging from somnolence to coma). Reflexes may be depressed or hyperactive, and some patients may have Babinski's signs. Two patients were reported to have a unique alternating hemiparesis and complete external ophthalmoplegia. After ASP, gradual improvement occurs over a threemonth period. Those with residual deficits often have anterograde amnesia with relative preservation of intellect and other higher cortical functions. Some patients develop temporal lohe epilepsy. There also may be coexisting distal limb weakness and atrophy, and electrophysiological testing suggests a picture of either a pure motor neuronopathy or a sensorimotor axonopathy. In a few patients who have died, autopsy revealed astrocytosis and selective neuronal loss in the amygdala and hippocampus (Cendes et al. 1995). These lesions are reminiscent of those seen in the rat model of kainate-induced seizures. In the one reported outbreak, the mortality rate was 3 % , all of which occurred in elderly patients. Treatment is primarily symptomatic. Previous experience suggests that diazepam and phenobarbital, but not phenytoin, are the drugs of choice in the control of seizures. Diagnosis may be established with high-per forma nee liquid chromatography (HPLC); the mouse bioassay was deemed too insensitive. A surveillance program now exists in Canada to monitor commercial shellfish operations, with mussels and clams being analyzed regularly for domoic acid.
Diarrhctic Shellfish Poisoning Diarrhetic shellfish poisoning (DSP) is a self-limiting gastrointestinal illness without clinical evidence of neurotoxicity. It is most common in Japan but has also been desctibed in Europe, South America, Canada, and
New Zealand; there have been no confirmed cases in the United States. Okadaic acid, a polycthcr toxin that is a highly selective inhibitor of protein phosphatase type 1 (PP1) and 2A (PP2A), is responsible for the pathophysiological features. Diarrhea, nausea, and vomiting are almost universal symptoms. A mouse bioassay is available for analysis of shellfish. Complete recovery is expected within 3 days. No deaths have been reported from DSP.
OTHERS New marine intoxications with neurological consequences continue to be described. Neurocognitive deficits have been reported in the so-called P/sesteria-associated syndrome, a recently described constellation of symptoms linked to the dinoflagellate Pfiesteria piscicida {the "fish killer"). Deficiencies in learning and memory, headaches, and acute confusional state have been seen. Exposure is probably mediated by aerosoli/ation or skin contact with an undetermined toxin and not shellfish consumption (Morris 1999). An outbreak of an illness reminiscent of DSP in several people who ate mussels cultivated in Ireland led to the identification of azaspiracid. When injected into mice, the toxin causes paralysis and convulsions prior to death. The source is thought to be a dinoflagellate. Many other marine microalgae toxins found in shellfish have been characterized; the dangers and utilities of these compounds are still under investigation (Daranas, Norte, and Fernandez 2001).
REFERENCES Cendes, F., Andcrmann, F,, Carpenter, S., et al. 1995, "Temporal lobe epilepsy caused by domoic acid intoxication: Evidence for glutamare receptor-media ted excitotoxkity in humans," Ann Neurol, vol. 37, pp. 123-126 Daranas, A. H., Norte, M,, Fernandez, J, J. 2001, "Toxic marine microalgae," Toxicon, vol. 39, pp. 1101-1132 Lewis, R. J. 2001, "The changing face of ciguatera," Toxicon, vol. 39, pp. 97-106 Litovitz, T. I.., Klein-Schwartz., W., Rodgers, G. C, Jr., eta). 2001, "Animal report of the American Association of Poison Control Centers Toxic Exposure Surveillance System," Am j Emerg Med, vol. 20, pp. 391-452 Morris, J. G., jr. 1999, "Pfiesteria, 'the cell from hell,' and other toxic algal nighrmares," Clin Infect Dis, vol. 28, pp. 1191-1198 Pearn, J. 2001, "Neurology of ciguatera," j Neurol Neurosurg Psychiatry, 2001, vol. 70, pp. 4-8 Sierra-Ikltniii, A. P., Oni/., A., Nunc/, K„ et al. 1998, "An overview of the marine food poisoning in Mexico," Toxicon, vol. 36, pp. 1493-1502 Whittle, K. & Gallacher, S. 2000, "Marine toxins," Br Med Bull, 2000, vol. 56, pp. 236-253 Yasumoto, T. 2001, "The chemical and biological function of natural marine toxins," Chem Rec, vol. 1, pp. 228-242
Chapter 64 Effects of Toxins and Physical Agents on the Nervous System E. EFFECT OF PHYSICAL AGENTS ON THE NERVOUS SYSTEM Michael J. Aminoff [nni/itii> l(.u:i.uniii b.ncephaloparhy Myelopathy Plexopathy Nonionizing Radiation
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The nervous system may be damaged by physical agents such as kmi/.iiu; .siul nonionizing "ulialinn, r';rl nary, extreme heat or cold, and vibration. The extent of damage depends on the intensit) aiul duration ol exposure.
IONIZING RADIATION Electromagnetic and particulate radiation may lead to cell damage and death. Radiation therapy affects the nervous system by causing damage to cells (particularly their nuclei) in the exposed regions; these cells include neurons, glia, and the blood vessels supplying neural structures. As a late carcinogenic effect, radiation therapy may also produce tumors, particularly sarcomas, that lead to neurological deficits. Neurological injury is proportional to both the total dose and the daily fraction of radiation received.
Electrical Current and Lightning Vibration Hyperthermia I I;.. pothemua Burns
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neurological deficits. Symptoms resolve after several weeks without specific treatment. A brainstem encephalopathy, manifest by ataxia, nystagmus, diplopia, and dysarthria, also may develop if the brainstem was included in the irradiated field. Spontaneous recovery over a few weeks is usual, hut the disorder sometimes progresses to obtundation, coma, or death. Delayed radiation encephalopathy occurs several months or longer after cranial irradiation. It may be characterized by diffuse cerebral injury (atrophy) or focal neurological deficits with signs of increased intracranial pressure. The disorder may result from focal cerebral necrosis caused bydirect radiation damage or by vascular changes. Immunological mechanisms also may be involved. Occasionally patients develop a progressive disabling disorder, with cognitive and affective disturbances and a disorder of gait, approximately 6-18 months after whole-brain irradiation. Pathological examination in some instances has shown demyelinating lesions.
Encephalopathy Radiation encephalopathy is best considered according to its time of onset after exposure (De Angelis et al. 2001). Acute radiation encephalopathy occurs within a few days of exposure and is characterized by headache, nausea, and a change in mental status. It may be related to increased intracranial pressure from breakdown of the blood-brain barrier due to the immediate effects of the energy dispersal in the nervous tissue. Treatment with high-dose corticosteroids usually provides relief. Early delayed radiation encephalopathy is probably caused by dcmyelination and occurs between 2 weeks and 3 or 4 months after irradiation. Headache and drowsiness are features, as is an enhancement of previous focal
Myelopathy A myelopathy may result from irradiation involving the spinal cord. Transient radiation myelopathy usually occurs within the first year or so after incidental spinal cord irradiation in patients treated for lymphoma and neck and thoracic neoplasms. Paresthesias and Lhermitte's phenomenon characterize the syndrome, which is self-limiting and probably relates to demyelination of the posterior columns. A delayed severe radiation myelopathy may occur approximately one year after completion of radiotherapy. Patients present with a focal spinal cord deficit that progresses over weeks or months to paraplegia or quadriplegia. This may 1741
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NEUROLOGICAL DISEASES
simulate a compressive myelopathy or paraneoplastic subacute necrotizing myelopathy, but the changes on magnetic resonance imaging (MRI) are usually those of a focal increased T2-weighted myelomalacia with cord atrophy. The cerebrospinal fluid is usually normal, although the protein concentration is sometimes elevated. Corticosteroids may lead to temporary improvement, but no specific treatment exists. The disorder is caused by necrosis and atrophy of the cord, with an associated vasculopathy (Okada and Okeda 2001). Occasional patients develop sudden back pain and leg weakness several years after irradiation, with MRI revealing hematomyelia; symptoms usually improve with time. In some instances, inadvertent spinal cord involvement, usually by irradiation directed at the para-aortic nodes in cases of seminoma, leads to a focal lower-limb lower motor neuron syndrome. The neurological deficit may progress over several months or years hut eventually stabilizes, leaving a flaccid, asymmetrical paraparesis. Recovery does nor occur.
Plexopathy A radiation-induced plexopathy may rarely occur soon after radiation treatment for neoplasms, particularly of the breast and pelvis, and must be distinguished from direct neoplastic involvement of the plexus. Paresthesias, weakness, and atrophy typify the disorder, which tends to plateau after progressing for several months. The plexopathy may develop 1-3 years or longer after irradiation that involves the brachial or lumbosacral plexus. In this regard, doses of radiation exceeding 6000 cGy, use of large daily fractions, involvement of tbc upper part of the brachial plexus, lymphedema, induration of the supraclavicular fossa, and the presence of myokymic discharges on electromyography all favor a radiation-induced plexopathy. Although radiation plexopathy is often painless, a point favoring this diagnosis rather than direct infiltration by neoplasm, pain is conspicuous in some patients. Symptoms progress at a variable rate (Fathers et al. 2002). The plexopathy is associated with small-vessel damage (endarteritis obliterans) and fibrosis around the nerve trunks (Johansson et al. 2001).
NONIONIZING RADIATION Nonionizing radiation that strikes matter is transformed to heat, which may lead to tissue damage. Ultraviolet radiation is produced by the sun, incandescent and fluorescent light sources, welding torches, electrical arc furnaces, and germicidal lamps. Ultraviolet radiation is absorbed primarily by proteins and nucleic acids. Susceptibility to it is increased by certain drugs, such as chlorpromazine and tolbutamide, and by certain plants,
such as figs, lemon and lime rinds, celery, and parsnips, which contain furocoumanns and psoralens. Short-term exposure to ultraviolet light can damage the rerina and optic nerve fibers. A severe central scotoma may result from macular injury. Prevention requires the use of goggles and face masks in work environments where exposure to highintensity ultraviolet radiation is likely to occur. Exposures to laser radiation can induce ocular damage. This is particularly a problem when the wavelength of the laser beam is not in the visible portion of the electromagnetic spectrum, because the patient may not be aware of the exposure. Concern has been raised that occupational or environmental exposure to high-voltage electrical power lines may lead to neurological damage from exposure to high-intensity electromagnetic fields. However, the effects of such exposure are uncertain and require further study. Nonionizing radiation at the radio frequency used by cellular telephones has been reported to cause sleep disturbances, headache, and other nonspecific neurological symptoms. Several studies have raised concerns that such radiation may cause brain tumors or accelerate their growth, although any heating of cerebral tissue by cellular telephones is minimal, and a clear theoretical basis for such an association with brain tumors is lacking. In any event, a recent case-control study failed to identify any major increased risk associated with the use of cellular telephones, at least in the short term (Inskip et al. 2001). The neurological implications of longterm use of cellular telephones or changes in telephone technology are unknown. High-intensin
noise m the acme senmg IK.LV 1CL:.J lo
tinnitus, vertigo, pain in the ear, and hearing impairment. Chronic exposure to high-intensity noise of any frequency leads to focal cochlear damage and impaired hearing.
ELECTRICAL CURRENT AND LIGHTNING Electrical injuries (whether from manufactured or naturally occurring sources) are common. Their severity depends on the strength and duration of the current and the path in which it flows. Electricity travels along the shortest path to ground. Its passage through humans can often be determined by identifying entry and exit bum wounds. When its path involves the nervous system, direct neurological damage is likely among survivors. With the passage of current through tissues, heat is produced that is responsible, at least in part, for any damage, but nonthermal mechanisms may contribute also (Winkelman 2001). In addition, neurological damage may result from circulatory arrest and from trauma related to falling or a shock pressure wave. A large current that passes through the head leads to immediate unconsciousness, sometimes associated with ventricular fibrillation and respiratory arrest. Confusion, disorientation, seizures, and transient focal deficits are common in survivors (Duff and McCaffrey 2001), but
EFFECT OF PHYSICAL AGENTS ON THE NERVOUS SYSTEM
recovery generally occurs within a few days. Some survivors develop a cerebral infarct after several days or weeks, attributed to thrombotic occlusion of cerebral blood vessels. Residual memory and other cognitive disturbances are also common. Weaker current leads only to headache or other mild symptoms for a brief period. When the path of the current involves the spinal cord, a transverse myelopathy may occur immediately or within 7 days or so and may progress for several days. The disorder eventually stabilizes, after which partial or full recovery occurs in many instances. Upper and lower motor neuron Jetu iti .nul ii'iiMin J-.Muriuuuvs are a minion. Inn ilic sphincters are often spared. Unlike traumatic myelopathy, pain is not a feature. Autopsy studies show di-myclination of long tracts, loss of anterior horn cells, and areas of necrosis in the spinal cord. Segmental muscle atrophy may occur also within a few days or weeks of electrical injury of the spinal cord. Whether this relates to focal neuronal damage or has an ischemic basis is uncertain. The current pathway is typically across the cervical cord from one arm to the other, and the resulting muscle atrophy in the arms may be accompanied by an upper motor neuron deficit in the legs. Sensory disturbances (in upper or lower limbs) and sphincter dysfunction also occur. Occasional reports have suggested the occurrence of a progressive disorder simulating amyotrophic lateral sclerosis after electrical injury. Peripheral or cranial nerve injury in the region of an electrical burn is often reversible, except when high-tension current is responsible, in which case thermal coagulation necrosis is likely. Care must be taken to distinguish such neuropathies from compartment or entrapment neuropathies, which are suggested by severe pain and a delay between injury and development of the neuropathy. Compartment syndromes develop because of muscle swelling and necrosis, and entrapment syndromes because of swelling of tissues in confined anatomical spaces. Immediate decompression of the compartment is indicated in these cases. Occasional patients have developed hemorrhagic or thrombotic stroke after electrical injuries, for uncertain reasons. Venous sinus thrombosis has also been described. Suggested mechanisms include coagulation necrosis of part of the vascular wall with aneurysmal distention and rupture ot intramural thrombosis. Intense vasospasm, acute hypertension, intramural dissections, or transient circulatory arrest may also contribute.
VI Li RATION Exposure to vibrating tools such as pneumatic drills has been associated with both focal peripheral nerve injuries, such as carpal tunnel syndrome (Herbert et al. 2001), and vascular abnormalities, such as Raynaud's phenomenon (Byhind et al. 2001). The mechanism of production is uncertain but presumably reflects focal damage to nerve fibers.
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HYPERTHERMIA Exposure to high external temperatures may lead to heat stress disorders. Heat stroke, the most severe, sometimes has an exertional basis, and disturbances of thermoregulatory sweating may be contributory. Classic heat stroke occurs especially in older persons with chronic disorders such as diabetes or obesity and in hypermetabolic states such as thyrotoxicosis. Anticholinergic or diuretic drugs and dehydration predispose to heat stroke because they impair sweating and thereby limit heat dissipation. Hyperthermia leads to thirst, fatigue, nausea, weakness, and muscle cramps and eventually to confusion, delirium, obtundation, or coma, bur coma can develop without any prodrome. Seizures are frequent, focal neurological deficits are sometimes present, and papilledema may occur. With recovery, symptoms and signs generally clear completely, but cognitive changes or focal neurological deficits may persist. Cataracts have been attributed to dehydration. Cardiac output is reduced, pulmonary edema may occur, and adult respiratory distress syndrome is sometimes conspicuous. Other systemic manifestations include a respiratory alkalosis and often a metabolic acidosis, hypokalemia or hyperkalemia, hypoglycemia, other electrolyte disturbances, and various coagulopathies. Rhabdomyolysis is common, and acute renal failure may occur in exertional heat stroke. The prognosis depends on the severity of hyperthermia and its duration before initiation of treatment. With proper management, the mortality rate is probably about 5 % , Treatment involve control of the body temperature by cooling, rehydration of the patient, correction of the underlying cause of the hyperthermia, and prevention of complications. When excessive muscle activity is responsible, neuromuscular blockade may be necessary. In the malignant hyperthermia syndrome, the responsible anesthetic agent is discontinued, the patient is vigorously cooled, oxygenation is ensured, and intravenous dantrolene is administered. Thyrotoxic crisis is treated with thyroidblocking drugs. Patients with pheocbromocytoma are treated with a-adrenergic antagonists. Cooling is achieved by evaporation or by direct external cooling, as by immersion of the patient in cold water. The skin should be massaged vigorously to counteract the cutaneous vasoconstriction that results from external cooling and that impedes heat removal from the cure. Antipyretic agents are unhelpful. Hypotension is treated by fluid administration rather than vasoconstrictor agents, which should be avoided if possible. High doses of mannitol and use of diuretics may be required to promote urinary output. Electrolyte and glucose abnormalities also require treatment. Hyperthermic limb perfusion with doxorubicin or mcphalan, two widely used chemotherapeutic agents in patients with melanomas or sarcomas, may lead to a variety
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of neuromuscular abnormalities related to the perfusion temperature, but this is also influenced by any pre-existing changes and awaits further clarification (Bonifati et al. 2000).
HYPOTHERMIA A core temperature below 35 = C may occur in very young or elderly persons with environmental exposure, coma, hypothyroidism, malnutrition, severe dermatological disorders (because of excessive heat loss and inability to regulate cutaneous vasoconstriction), and alcoholism. Alcohol promotes heat loss by vasodilation and may lead to coma directly or from trauma with resultant environmental exposure to cold. Hypothermia also occurs in persons exposed to low temperatures in the working environment, such as divers, skiers, and cold-room workers. The usual compensatory mechanism for cooling is shivering, but this fails at body temperatures below approximately . W C . As the temperature declines, respiratory requirements diminish, cardiac ourput falls, and significant hypotension and cardiac arrhythmias ultimately develop. Neurologically there is increasing confusion, psychomotor retardation, and obtundation until consciousness is eventually lost. The tendon reflexes are reduced and muscle tone increases, bill extensor plantai responses are not usually found. The electroencephalogram (EEG) slows and ultimately shows a burst-suppression pattern or becomes isoelectric with increasing hypothermia. At core temperatures below 32"C, the appearance of brain death ma) be simulated clinical!) and electroencephalograph] cally, but complete recovery may follow appropriate treatment. Management involves slow rewarming of patients and the prevention of complications such as aspiration pneumonia ar.d iiKtabolie. acidosis. 1 1) potecsmn may occur from dehydration but can usually be managed by fluid replacement. Plasma electrolyte concentrations must be monitored closely, especially because of the risk of developing cardiac arrhythmias, With recover)-, -.here AW usually no long-term sequelae. Nerve damage may occur as a consequence of the tissues becoming frozen by the cold (frostbite). This involves the extremities and is usually irreversible.
BURNS Following common usage, rhe term thermal burn refers to a burn caused by direct contact with heat or flames. Patients with severe burns may have associated disorders such as anoxic encephalopathy from carbon monoxide poisoning, head injury, or respiratory dysfunction from smoke inhalation. Central neurological disorders may occur later during hospitalization and are secondary to various
systemic complications. Thus metabolic encephalopathies may relate ro anoxia, liver or kidney failure, and hyponatremia, and central pontine myelinolysis may occur also. Infections (meningitis or cerebral microabscesses) are common, especially in the second or third week after the burn. Vascular complications, including multiple strokes, may result from septic infarction, disseminated intravascular coagulation, venous thrombosis, hypotension, or intracranial hemorrhage. Imaging studies are therefore important in clan tying die underlying disorder. Peripheral complications of burns are also important. Nerves may be damaged directly by hear, leading to coagulation necrosis from which recovery is unlikely. A compartment syndrome may arise from massive swelling of tissues and mandates urgent decompressive surgery. In other instances, neuropathies result from compression, angulation, or stretching as a result of incorrectly applied dressings or improper positioning of the patient. A critical illness polyneuropathy and myopathy is now well recognized in patients with multiorgan failure and sepsis, including patients with burns, and is discussed in
Chapter 82.
REFERENCES Bonifati, D. M., Ori, C, Rossi, C. R., et al. 2000, "Neuromuscular damage after hyperthermic isolated limh perfusion in patients with melanoma or sarcoma treated with chemotlierapcutic agents," Cancer Chemother Pharmacol, vol. 46, pp. 517-522 Bylund, S. H., Burstrom, L., & Knutsson, A. 2002, "A descriptive study of women injured by hand-arm vibration," Ann Occuji Hyg, vol. 46, pp. 299-307 De Angelis, L. M., Delattre. J-Y., Sc Posner, J. B. 2001, "Neurological complications of chemotherapy and radiation therapy," in Neurology and General Medicine (3rd ed), ed. M. J. Aminoff, Churchill Livingstone, New York Duff, K. & McCaffrey, R. J. 2001, "Electrical injury and lightning injury; a review of their mechanisms and neuropsychological, psychiatric, and neurological sequelae," Neuropsychol Rev, vol. 11, pp. 101-116 Fathers, E., Thrush, D., Huson, S. M., Sc Norman, A. 2002, "Radiation-induced brachial plexopathy in women treated for carcinoma of the breast," Clin Rehahil, vol. 16, pp. 160-165 Herbert, R., Gerr, F., & Dropkin, J. ''Clinical evaluation and iii.iiias'.i'iiiiiii ol work related earpal runnel syndrome," \»t j Ind Med, vol. 37, pp. 62-74 Inskip, P. D., Tarone, R. E., Hatch, E. E., et al. 2001, "Cellulartelephone use and brain tumors," N Engl J Med, vol. 344, pp. 79-86 Johansson, S., Svensson, H,, l.arsson, L. G., & Denekamp, J, 2000, "Brachial plexopathy after postoperative radiotherapy of breast cancer patients—A long-term follow-up," Acta Oncol, vol. 39, pp. 373-382 Okada, S. & Okcda, R. 2001, "Pathology of radiation myelopathy," Neuropathology, vol. 21, pp. 247-265 Wfiikilnuin. M, I). .?.l)01, "Nellie: logical crime leatiois ;>t lhernial and electrical burns," in Neurology and General Medicine (3rd ed), Churchill Livingstone, New York
Chapter 65 Brain Edema and Disorders of Cerebrospinal Fluid Circulation Gary A. Rosenberg Blood-6rain Interfaces Cerebral Blood Vessels Choroid Plexuses and Capillaries Produce Cerebrospinal Fluid and Interstitial Fluid Ependymal and Pial Surfaces Arachnoid Granulations and Absorption of Cerebrospinal Fluid Cerebrospinal Fluid Pressure Brain Edema Molecular Cascade in Injury Vasogenic Edema and the Neuroinflammatory Response
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Infection, Ischemia, and Inflammation Cytotoxic Brain Edema Treatment of Brain Edema Idiopathic Intracranial Hypertension Clinical Features Treatment Hydrocephalus Hydrocephalus in Children Adult-Onset Hydrocephalus Normal-Pressure Hydrocephalus
1752 1752 1755 1757 1757 1758 1758 \~>H
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Brain cells depend on the constant delivery of oxygen and glucose by the cerebral circulation. Cerebral endothelial cells are metabolically active, selectively permeable, epithelial-like, secreting structures that are critical in maintaining a constant fluid and electrolyte environment. Adhesions between endothelial cells are tight, and only substances that are lipid soluble are able to easily cross them. These tight junctions separate brain cells from substances circulating in the blood. Brain cells are surrounded by interstitial fluid (TSF), which is contiguous with the cerebrospinal fluid (CSF). Enzymatic and osmotic processes continuously form CSF and ISF, the choroid plexuses being the main source for the CSF and cerebral capillaries and cellular metabolism the source of the ISF. Together the CSF-ISF serve the same function for brain cells that lymph provides for other cells in the body. Loss of either oxygen or glucose for even short periods causes cellular damage and may lead to cell death. Cell swelling is poorly tolerated because of the constraints imposed by the bony skull and the tough dural membranes. The brain and spinal cord arc subject to different physical processes than other otgans in the body because they lie within the rigid bony compartments of the skull and spinal canal. The character of the CSF, with its constituents, pressure, and flow, are of great importance to the function of the central nervous system (CNS). Increased intracranial pressure results from increased tissue within the rigid bony box of the skull (space-occupying lesions, such as tumor, abscess, and hematoma}, increased fluid (cerebral edema of several types}, and impaired flow of CSF (hydrocephalus).
Brain edema is a life-threatening complication of many neurological conditions. Damaged cells swell, injured blood vessels leak, and blocked absorption pathways force fluid co enter brain tissues. F.ach of these mechanisms results in a potential increase in intracranial volume. Compensation for the potential increase occurs by displacement of CSF and venous blood from the skull. Further volume increases cause brain tissue to shift. Herniation of brain leads to a life-threatening situation, requiring rapid assessment of the cause and utgent treatment. Because [he CSF and [SI .u/i ;>•. mic 'Hid, : lumbar puncture to withdraw CSF provides insight into brain cell function that is critical in diagnosis and management of patients. The analysis of CSF gives important information on bleeding, inflammation, and infection in the brain that is not available by other methods. Proper use of the information obtained by lumbar puncture, which is central to neurological diagnosis and requires an understanding of normal CSF and ISF physiology. Cerebrospinal fluid studies show increased pressure, the presence of cells, indicating infection and inflammation, and elevated levels of protein, showing a breakdown of the normal barriers between the brain and the blood or the production of those proteins by the brain cells. Diagnosis depends on the findings of the CSF examinations in certain conditions, such as idiopathic increased intracranial hypertension, in which an elevated pressure is essential for the diagnosis. Other conditions in which the examination of the CSF is the major diagnostic test include meningitis, subarachnoid hemorrhage with a negative computed tomography (CT), and carcinomatous 1745
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NEUROLOGICAL DISEASES Tabic 65.1:
Causes of increased intracranial pressure (ICP)
Site of increased ICP
t)j6
NEUROLOGICAL DISEASES
FIGURE 65.10 A patient with sagittal sinus occlusion that developed after pregnancy. The images shown were obtained several months after the event and demonstrate the ability ro recover. At onset of the illness, there was papilledema and increased intracranial pressure. ; A I he •-..i:-.iii.-il •• mis is in< n.i in this coronal view from an MR venogram. (B) A lateral view from the venogram, showing flow in the sagirtal sinus [arrow) and straight sinus (arrowhead), (C) The region of prior venous infarction is shown on the axial Tj-weighted MR image, (D) The same region as in C on the coronal T^-weighted image. (Courtesy Blaine Hart, MD.)
For many years osmotic therapy has been the treatment of choice to temporarily lower intracranial pressure. Initially, urea was used, but the small molecule entered the brain, causing rebound edema. Current osmotic treatment is done primarily with mannitol, which reduces brain volume, lowers CSF production, and improves cerebral blood flow. Osmotherapy with low doses of mannitol infused ovet several days lowers intracranial pressure. Earlier studies employed 3 g/kg of mannitol, which had a dtastic effect on the serum electrolytes and permitted only one or two doses to be given. More recently, it was found that low doses of mannitol (0.25-1.0 g/kg) are as effective as the higher doses without affecting the electrolytes. The lower doses taised the serum osmolality slightly, suggesting that the agent had several mechanisms of action. The effect of the small change in the osmolality is to reduce the brain tissue volume; the effect is more prominent in the noninfarcted than in the infarcted hemisphere (Videcn ct al. 2001). Other effects are that mannitol reduces CSF and ISF secretion by 5 0 % , which may contribute to its action. Some investigators have proposed that mannitol hyperosmolality alters the
theological properties of blood, whereas others have noted an antioxidant effect. Prolonged administration of mannitol results in an electrolyte imbalance that may override its benefit and that must be carefully monitored. Although mannitol is often used in acute stroke, its efficacy has not been proven. Corticosteroids lower intracranial pressure primarily in vasogenic edema because of their beneficial effect on blood vessel permeability. They have been less effective in cytotoxic edema, howevet, and are not recommended in the treatment of edema secondary ro stroke or hemorrhage, hi fact, systemic complications of corticosteroids can worsen the patient's condition in the treatment of patients with intracerebral hemorrhage. Edema surrounding brain tumors, particularly metastatic brain tumors, responds dramatically to treatment with high doses of dexamethasonc. The corticosteroid closes the BBB rapidly. Hence, it is important to obtain contrast-enhanced MRl or CT scans before treatment with cotticosteroids; otherwise, enhancement of the lesion may be missed. High doses of corticosteroids have been shown to be effective in brain edema secondary to inflammation in multiple sclerosis.
IJRAIN EDEMA AND DISORDERS OP CEREBROSPINAL FLUID CIRCULATION
Opening of the BBB is frequently seen on MRI with gadolinium contrast in patients with multiple sclerosis (Noseworthy ct al. 2000). The opening of the BBB is associated with elevated levels of the proinflammatory cytokine, TNF-or. Inflammatory lesions, such as those that occur in acute attacks of multiple sclerosis, respond well to high-dose methylprednisolone. Treatment with 1 gram per day of methylprednisolone for 3-5 days reduces the inflammatory changes in the blood vessels during an acute exacerbation. Dramatic reduction in enhancement on MRI may he seen after treatment. However, the effect is lost after several months.
IDIOPATHIC INTRACRANIAL HYPERTENSION Before the advent of CT scanners, the complaint of headache and the finding of papilledema raised the suspicion of hydrocephalus or tumor. When tests were negative for either of these conditions, the condition was called otitic hydrocephalus or pseudotumor cerebri. The latter term has remained in use along with benign intracranial hypertension. None of these terms is satisfactory, and the descriptive term, idiopathic intracranial hypertension (OH) is preferred,
Clinical features Patients with IIH have headaches that are diffuse, worse at night, and often wake them from sleep in the early hours of the morning. Sudden movements, such as coughing, aggravate headache. Headaches may be present for several months before a diagnosis is made. Some patients complain of dizziness. Transient loss of vision (transient obscuration) may occur with change of position. Visual fields may show an enlarged blind spot due to the encroachment of the swollen nerve head into the region of the macula. Prolonged papilledema may lead to sector scotomas and, rarely, vision loss. Damage to one or both sixth cranial nerves may occur as an effect of shifts of cerebral tissue; because the sixth cranial nerve is remote from the site of the process producing intracranial hypertension, the cranial neuropathy is a false localizing sign. Diagnosis requires ruling out other causes of increased intracranial pressure. All patients require a CT or MRI scan to look for hydrocephalus and mass lesions. After a mass lesion is ruled out, lumbar puncture is needed with careful attention to accurately measuring the CSF pressure, which must be elevated by definition. Characteristic findings in the CSF include normal or low protein, normal glucose, no cells, and elevated CSE pressure. The upper limit for normal CSF pressure is above 180 mm H 2 0 , and most IIH patients will have readings well above 200 mm H 2 0 . Measurement of CSF pressure should be done with legs extended and neck straight. Movements of the fluid column with
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respiration should be seen to confirm proper placement of the needle. It is important to obtain an accurate pressure reading at the time of the initial lumbar puncture because die diagnosis is made by the presence of increased CSF pressure. Measurements of pressure in subsequent lumbar punctures may be influenced by the loss of fluid during the first puncture. IIH occurs more frequently in women than in men. Obesity and menstrual irregularities, with excessive premenstrual weight gain, are often present. Headache, often worse in the morning, is the main complaint. Because many illnesses are associated with IIH, a search for an underlying cause is essential before the diagnosis is made by exclusion. MR] has rekindled interest in conditions that cause occlusions of the venous sinuses. When the sinuses draining blood Irniv. the brain are obstructed, absorption oi CS1 is reduced, causing the pressure of the CSF to increase. MR venography is better for showing the thrombosis of the sinuses than conventional MRI. The role of venous sinus obstruction in III I, although important to rule out, may be limited. Hypercoagulable states should be looked for in patients with venous sinus obstruction. Obesity is often found in women with IIH. Endocrine abnormalities have been extensively investigated in both obese and nonobese subjects, but none has been identified. Drugs associated with the syndrome include tctracyclinetype antibiotics, nalidixic acid, nitrofurantoin, sulfonamides, and trimethoprim-sulfamethoxazole (Table 65.4). Paradoxically, the withdrawal of corticosteroids, which are used to treat increased intracranial pressure, can cause an increase in intracranial pressure. Large doses of vitamin A, which are used in the treatment of various skin conditions, may cause the syndrome. Hypcrcapnia leads to retention of carbon dioxide and increase in blood volume. Sleep apnea and lung diseases may cause headaches and papilledema due to this mechanism. Less frequent causes include Guillain-Barrc syndrome, in which IIH may be due to an increase in CSF protein or an inflammatory response. Uremic patients have an increased incidence of papilledema with IIH. Patients with renal failure have increased levels
Tabic 65.4: Drugs frequency associated with idiopathic intracranial hypertension Minocycline Isotretinoin Nalidixic acid Tetracycline Trimethoprim-sulfamethoxazole Cimetidinc Prednisolone Methylprednisolone Tamoxifen tSeclomctfiasone Source: Schutta, H. S. 8c Corbett, J. J. 1997, "Intracranial hypertension syndromes,"in Clinical Neurology, 12th ed,eds R. J. Joynt & R. C. Griggs, Lippincon, Philadelphia.
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of vitamin A, use corticosteroids, and take cyclosporine, which have all been linked to 11H. Cerebral edema was seen in one patient with early I1H, who had a brain biopsy at the time of subtemporal decompression, .1 treatment that is no longer used. However, two IIH patients who came to postmortem examination had no histological evidence of cerebral edema. Blood volume is increased and cerebral blood flow decreased. CSF circulation is impaired. Diseases that chronically raise cerebral venous pressure often produce increased intracranial pressure without increased ventricular size. The primary sites of obstruction may be the superior vena cava, jugular veins, or large cerebral veins. Increased superior sagittal sinus or transverse sinus pressure has been reported in IIH. Many investigators favor an elevation of dural venous sums pressure as a reasonable mechanism.
Treatment Treatment involves reducing intracranial pressure. Acetazolamide is an inhibitor of carbonic anhydrase that lowers CSF production and pressure. It is given in a dose of 250 mg twice daily, which may be increased to 1 g per day. Occasionally, higher doses may be needed. Electrolytes must be monitored to look for metabolic acidosis. Distal paresthesias are reported to occur in up to 2 5 % of patients. The hyperosmolar agent, glycerol (0.25-1.00 g/kg two or three times daily), and the diuretic, furosemide (20-60 mg daily), have also been used to lower intracranial pressure. Corticosteroids reduce increased intracranial pressure, but the pressure may increase when they are tapered. Drug effects are often transient, and when the syndrome does not resolve spontaneously, other treatments are needed. Although the relationship of obesity to IIH is uncertain, loss of weight can lead to resolution of the syndrome, and some patients have undergone surgical stomach size reduction to control the obesity. Visual fields should be measured and the size of the blind spot plotted. When the papilledema spreads into the region of the macula, visual acuity falls, and in extreme cases, blindness may occur. Although most patients with IIH retain normal vision, a small percentage of patients develop impairment of vision. When vision is threatened, and drugs and lumbar punctures do not lower the CSF pressure, surgical intervention is necessary. Lumboperitoneal shunting has a reportedly high success rate. However, shunt malfunction
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Fenestration of the optic nerve sheath to drain CSF into the orbital region reduces the intracranial pressure, and some consider it the treatment method of choice in medically refractory patients. In the obese patients with IIH, weight loss is an important adjunct treatment, and some authors argue that it is as important as acctazolamide.
HYDROCEPHALUS Obstruction of drainage of the CSF causes hydrocephalus, which is defined as enlargement of the ventricles. Although detection of enlarged ventricles has been greatly aided by CT and MRI, the separation of ventricular enlargement due to hydrocephalus from that due to loss of brain tissue remains .1 challenge. In carls life, obstruction oi the ventricular outflow most commonly occurs in the aqueduct, leading to noncommunieating hydrocephalus, while in the elderly, resistance to drainage of the CSF after the exit into the subarachnoid space results in a communicating hydrocephalus. Enlargement of the cerebral ventricles in children younger than 2 years produces enlargement of the head circumference because the skull sutures are still open. Children with bead growth that is more rapid than expected for age are suspected of having hydrocephalus and are imaged. In the elderly, the onset of symptoms may be gradual, beginning with problems of gait and intellect, which can suggest many different diagnoses. Obstruction prior to the outflow of CSF at the foramina of Luschka and Magendie results in a noncommunieating type of hydrocephalus, whereas in the communicating type of hydrocephalus, enlargement of the ventricles takes place with preserved flow of CSF between the ventricles and the subarachnoid space. Obstruction of CSF circulation may result in increased CSF pressure as the cerebral ventricles enlarge. Acute, noncommunieating hydrocephalus develops rapidly, reaching 8 0 % of maximal ventricular enlargement within 6 hours. A slower phase of enlargement follows the initial rapid expansion, and ventricular enlargement plus continual production of CSF causes fluid accumulation in the petiventricular white matter interstitial space. When the hydrocephalus stabilizes and enters a chronic phase, the CSF pressure may decrease, resulting in normal pressure recordings on random measurements. Atrophy may occur in the chronically hydrocephalic white matter. When the rate of ventricular enlargement stabilizes in patients with incomplete ventricular obstruction, CSF production is balanced by absorption at alternate sites. This time course is unpredictable, and occasionally, patients assumed to have arrested hydrocephalus can undergo acute decompensation after many years of apparent stability.
Hydrocephalus in Children Hydrocephalus in children is often due to a structural abnormality, such as Chiari I or II malformation, congenital aqueducts I stenosis, aqueductal stenosis due to intrauterine infection or other congenital causes, such as anoxic injury, intraventricular hemorrhage, and obstruction of the CSF pathways after bacterial meningitis. Bulging of the anterior fontancllc may be seen, along with thinning of the skull and separation of the sutures. If the diagnosis is
BRAIN EDEMA AND DISORDERS OE CEREBROSPINAL FLUID CIRCULATION
delayed, abnormal eye movements and optic atrophy may develop. Spasticity7 of the lower limbs may be observed at any stage. Acute enlargement of the ventricles is associated with nausea and vomiting. During the neonatal and early childhood period, irritability is the most common symptom of hydrocephalus. The child feeds poorly, appears fretful, and may be lethargic. In the older child, headache may be a complaint. Vomiting due to increased intracranial pressure may be present in the morning. Remote effects of the increased pressure may affect the sixth cranial nerves on one or both sides, leading to the complaint of diplopia. The enlarged ventricles affect gait. A wide-based ataxic gait may be present due to the stretching of the white matter tracts from the frontal leg regions around the ventricles. Premature infants weighing less than 1500 g at birth have a high risk of intraventricular hemorrhage, and approximately 2.5% of these infants develop progressive ventricular enlargement, as shown by CT or ultrasound scans. Ventricular size in the neonate may be followed at the bedside with B-mode ultrasound through the open fontanellc. Long-term follow-up studies of children with intraventricular hemorrhage due to prematurity show that 5% require shunting for hydrocephalus. The survivors of a large germinal plate hemorrhage often have multiple disabilities. Before the widespread availability of antibiotics and vaccinations, meningitis was a frequent cause of hydrocephalus in children. Often, there was concurrent cerebral infarction, resulting in brain atrophy with ventricular enlargement. Separation of the atrophy from the obstructive hydrocephalus may be difficult. Once the sutures are closed, which generally occurs by the age of 3, hydrocephalus causes signs of increased intracranial pressure rather than head enlargement. Meningitis, aqueductal stenosis, Chiari malformations, and mass lesions may be the cause of hydrocephalus in these young children. Tumors originating from the cerebellum and from the brainstem produce acute symptomatology, including headaches with vomiting, diplopia, visual blurring, and ataxia. Symptoms are due to the acute hydrocephalus secondary to obstruction of the aqueduct of Sylvius and to pressure on brainstem structures. Examination shows papilledema, possible sixth cranial nerve palsy, and spasticity of the lower limbs. When the hydrocephalus is more long-standing, endocrine dysfunction may occur, involving short stature, menstrual irregularities, and diabetes insipidus. Excessively rapid growth of the head is the hallmark of hydrocephalus in the child before closure of the sutures. Charts are available to plot head growth and to compare it with the standardized curves for normal children. Bulging of the anterior fontanellc is found even with the child relaxed and upright. After 1 year, the firmness of the fontanellc cannot be used because the sutures have closed. Other findings include the "cracked-pot" sound on percussion of the skull (McEwen
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sign), engorged scalp veins, and abnormalities of eye movements. As spasticity develops, the deep tendon reflexes are increased. Treatment involves shunting CSE from the ventricles to drain fluid into another body cavity. In very young children, the shunt is often placed in the peritoneal cavity. hi the older child, i ventriculoperitoneal shunt is generallyused. Complications of shunt placement include malfunction and shunt infection.
Adult-Onset Hydrocephalus In the adult, symptoms of hydrocephalus include headaches, papilledema, diplopia, and mental status changes. Sudden death may occur with severe increases in pressure. Rarely, hydrocephalus causes an akinetic mutism due to pressure on the structures around the third ventricle. Other symptoms include temporal lobe seizures, CSF rhinorrhea, endocrine dysfunction {e.g., amenorrhea, polydipsia, and polyuria), and obesity, which suggest third ventricle dysfunction. Gait disturbances are reported in patients with aqueductal stenosis, but hyper-reflexia with Babinski's sign is infrequent. Adult-onset hydrocephalus has similar causes to those in children, but the frequencies differ. As in children, acute obstruction of the ventricles results in rapidly progressive hydrocephalus with symptoms of raised intracranial pressure. Adults are more likely than children to present with an acute blockage of CSF flow by intraventricular masses, such as a colloid cyst of the third ventricle or an ependymoma of the fourth ventricle. These tumors cause sudden headaches, ataxia, and loss of consciousness with symptoms that may be intermittent due to the ball-valve effect of the masses. CT or MRI, which reveals the structural lesion in the ventricular system, can make the diagnosis. Cerebellar hemorrhage and cerebellar infarction with edema cause an acute hydrocephalus by compression of the brainstem, occluding the aqueduct of Sylvius and fourth ventricle outflow pathways and causing noncommunicating hydrocephalus, which can be seen on CT and results in acute elevation in intraventricular pressure. Patients with cerebellar hemorrhage usually have a history of hypertension. Increasing drowsiness and difficult)' walking often follow the acute onset of headache. Hemiparesis and brainstem findings evolve after the ataxia, providing a clue that the origin of the problem is in the posterior fossa. The expanding hemorrhagic mass in the posterior fossa, if it is encroaching on the brainstem, requires urgent neurosurgical attention, with placement of a ventricular catheter to decompress the lateral and third ventricles, followed by posterior fossa craniectomy to remove the mass effect and pressure on the brainstem. In patients with cerebellar infarction, the progression is generally slower because the maximum swelling takes place in 24-48 hours, but the consequences of the enlarging posterior fossa mass are
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the same as with hemorrhage, and surgery may he necessary to remove the necrotic tissues and restore the normal flow of CSF. CT is needed in the acute setting, particularly when MRI is not readily available, but visualization of the cerebellar infarction, which may be missed on the CT, is clearly seen on the diffusion-weighted scan (Figure 65.1 1). Treatment of hydrocephalus involves an operation to insert a tube to shunt CSF from the ventricles to another body cavity, such as peritoneum (ventriculoperitoneal shunt). These devices have one-way valves that respond to pressure. In an emergency, hydrocephalic ventricles can be assessed readily due to the increase in their size. Shunt malfunction may cause abrupt decompensation. Symptoms of acute increased intracranial pressure from a shunt malfunction resemble those seen with onset of the hydrocephalic process. Adult-onset hydrocephalus that is communicating may be due to a tumor in the basal cisterns, subarachnoid bleeding, or infection or inflammation of the meninges, but only a small percentage of these patients require insertion of a shunt. In the preantibiotic era, syphilis, tuberculosis, and
fungal infections more commonly caused chronic obstruction of the subarachnoid pathways and hydrocephalus. Cultures of the CSF are indicated in the elderly patient with enlarged ventricles, and searching for other sources of infection in lungs and other organs may be helpful in establishing the type of infection.
Normal-Pressure Hydrocephalus Chronic hydrocephalus in the adult can produce symptoms of gait disturbance, incontinence, and memory loss, with or without symptoms and signs of raised intracranial pressure, including headache, papilledema, and false localizing signs. Causes of chronic hydrocephalus include subarachnoid hemorrhage, chronic meningeal infections, and slowgrowing tumors blocking the CSF pathways. Normal-pressure hydrocephalus (NPH) is a term commonly used to describe chronic, communicating adult-onset hydrocephalus. Typically, patients with NPH have the triad of mental impairment, gait disturbance, and incontinence.
FIGURE 65.11 Cerebellar infarct with secondary hydrocephalus. (A) Initial diffusion-weighted image with cerebellar infarct in the territory of the left posterior inferior cerebellar artery. (B) Initial axial T^-weighted MR image shows n nil VL'iitrii ii'..ii si/.c. C.) ] >\\ 1 3 days larer, showing swelling of the infarction in the cerebellum. ;D l.diu planar ] _> .ixi.il imagu shows enlargement of the ventricles prior to surgery for hydrocephalus. (Courtesy Blaine Hart, MD.)
D
UHAIN i;niAlA AND DISORDERS OF CF.Rl-.KUOSl'INAI. FH(1I> CIRCULATION
NPH can develop secondary to trauma, infection, or subarachnoid hemorrhage, but in about one third, no etiology is found. Enlarged ventricles ore seen on CT or MRI. By definition, lumbar puncture generally reveals a normal CSF pressure. Normal pressure is an unfortunate term because patients who have undergone long-term monitoring with this syndrome have intermittently elevated pressures, often during the night. The presenting symptoms may be related to gait or to mental function. When gait is the presenting factor, the prognosis for treatment is better. NPH causes an apraxic gait, which is an inability to lift the legs as if they wete stuck to the floor. The motor strength is intact, reflexes are usually normal, and liabinski's sign is absent. Patients may be misdiagnosed as having Parkinson's disease because the gait disorder is similar in the two syndromes, suggesting that the etiology of the problem in the hydrocephalic patient lies in the basal ganglia. Because many of these patients also have hypertension, and some have small or large strokes, such patients may have other neurological findings, including spasticity and hyper-reflexia with Bahinski's signs. The combination of cerebrovascular disease and hydrocephalus is a poor prognostic sign for treatment with shunts. NPH leads to a reduction in intellect, which at times may he subtle. The dementia is of the subcortical type, and involves slowing of vetbal and motot responses with preservation of cottical functions, such as language and spatial resolution. Neuropsychological testing quantitates the decline in intellect and the degree of dementia. Patients are apathetic and may appear depressed. Incontinence of urine may occur early in the coutse, particularly in patients with prominent gait disturbance. In the early stages of the illness, presumably as the ventricles are undergoing enlargement, patients can experience drop attacks ot btief loss of consciousness. Headache and papilledema are not a part of the syndrome. Diagnosis of adult-onset NPH and selection of patients for placement of a ventriculoperitoneal shunt has been difficult (Boon ct al. 2000). Many of these patients have hypertensive vascular disease with lacunar infarcts. Featutcs of Parkinson's disease were noted in earlier reports of the syndrome, and it is now recommended that all patients with Parkinson's disease have scans to rule out hydrocephalus. CT and MRI have aided in separating Parkinson's disease, lacunar state, and NPH, although NPH may occasionally coexist with these diseases. Patients diagnosed with vascular diseases, such as lacunar state or subcortical arteriosclerotic encephalopathy (Binswanger's disease), along with the hydrocephalus respond poorly to shunting, and if there is a positive response, it may be transient as the underlying disease progresses. Selection of patients for shunting requires a combination of clinical findings and diagnostic test results, because no test can totally predict whether a patient will likely benefit from an operation.
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There may be a correlation between improvement in gait after removal of CSF and improvement after shunting. Cisternography is a useful procedure that involves the injection of a radiolabeled tracer into the CSF with monitoring of its absorption for 3 days. Normally, the radiolabeled material fails to enter the ventricles, moving over the convexity of the brain and leaving the CSF space within 12-24 hours. In patients with large ventricles due to atrophy, there may be a delay in circulation time, with some isotope being seen in the ventricles during the first 24 hours. Communicating hydrocephalus with abnormal CSF circulation shows pctsistent ventricular filling for more than 48 hours. In patients with NPH, there is reflux of the tracer into the cetebral ventricles by 24 hours and retention in the ventticles for 48-72 hours. This suggests that transependymal absorption is occurring and that pcriventricular white matter has become an alternate route of CSF absorption. A positive cisteruogram is seen in some patients with hypertensive cerebrovascular disease and Binswanger's encephalopathy because of the overlap in the three syndromes. CI and MRI in Nll'l I -hov. thai the temporal horns i>i' the lateral ventricles are enlarged and that cortical atrophyis less than anticipated fot age. This is in contrast to patients with hydrocephalus ex vacuo due to a degenerative disease, such as Alzheimer's disease, in which there is atrophy of the cerebral gyri and enlargement of the ventricles. Another useful finding on proton density MRI is the presence of presumed transependymal fluid in the frontal and occipital periventricular regions. Quantitative cisternography using single-photon emission CT has been successfully used to predict the results of a shunt. Other proposed diagnostic methods, including measuring rate of absorption of CSF by infusion of saline or artificial CSF into the thecal sac, clinical improvement after CSF removal, or the prolonged monitoring of intracranial pressure, have been used with some success to select patients for surgery. Decreased cerebral blood flow has been reported in NPH; regional cerebral blood flow is reduced in both cortical and subcortical regions. Patients who show clinical improvement with shunting have a concomitant increase in cerebral blood flow. Removal of CSF may result in an increase in cerebral blood flow in patients in whom NPH is likely to respond to shunt therapy. The number of patients undergoing shunt operations at most centers has fallen as the initial enthusiasm, which resulted in many shunts and a low success fate, has waned. None of the currently available tests by themselves identifies the patients that will benefit from shunting. Most helpful is a combination of clinical signs and judiciously chosen laboratory tests. Success rates vary between investigators, with some reports describing improvement in approximately 80% of treated patients and others reporting lower rates. Shunts for presumed NPH fail about one third of the time, and as
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m a n y as o n e fourth of the patients may have major c o m plications, including a high rate of infection a n d s u b d u r a l h e m a t o m a s after s h u n t placement. Clearly, m o r e information is needed to aid in the m a n a g e m e n t of patients with this u n c o m m o n , but treatable, s y n d r o m e .
REFERENCES Rohn, D. & Dauemau, D. 2002, "Diabetic ketoacidosis and cerebral edema," Curr Of?in Pediatr, vol. 14, pp. 287-291 Boon, A. J., Tans, J. T., Delwd, E. J., et si. 2000, "The Dutch normal-pressure hydrocephalus study, i low to select patients for shunting? An analysis of four diagnostic criteria," Surg Near, vol. 5 3 , pp. 201-207 Carhuapoma, J. R., Wang, P. Y., Beauchamp, N. J., et al. 2000, "Diffusion-weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal injury after intracerebral hemorrhage," Stroke, vol. .51, pp. 726-732 Covarrubias, D. J,, Luetmer, P. H., & Campeau, N. G. 2002, "Posterior reversible encephalopathy syndrome: Prognostic utility of quantitative diffusion-weighted MR images," AJ NR Am J Neuroradiol, vol. 23, pp. 1038-1048 Cuzncr, M. L. & Opdcnakker, G. 1999, "Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system,"/ Neuroimmunol, vol. 94, pp. 1-14 Edge, J. A., Hawkins, M. M., Winter, D. L., 8c Dunger, IX B. 2001, "The risk and outcome of cerebral oedema developing during diabetic ketoacidosis," Arch Dis Child, vol. 85, pp. 16-22 Fischer, S., Wobben, M., Marti, H. H., et al. 2002, "Hypoxiainduccd hyperpermeability in brain microvessel endothelial cells involves VEGF-mediated changes in the expression of zonula ivi linJi-r:-- I ." \\icrt>t\n-t lies, \ ol. 6 3 , pp. 70-80
Gaschc, Y., Copin, J. C, Sugawara, T, et al. 2001, "Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia," j Cereb Blood Flow Mettib, vol. 2 1 , pp. 1393-1400 Gu, 2 . , Kaul, M., Yan, B., et al. 2002, "S-nitrosylation of matrix meralloproteinases: Signaling pathway to neuronal cell death," Science, vol. 297, pp. 1186-1190 Hacker.!, P. H. &c Roach, R. C. 2001, "High-altitude illness," N Engl J Med, vol. 345, pp. 107-114 Leib, S. L., Clements, J. M., Lindberg, R. [.., et al. 2001, "Inhibition of matrix metal I ©proteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis," Brain, vol. 124, pp. 1734-1742 Noseworthv, J. If., I.iicchinetti, C., Rodriguez, M., Sc Weinshenker, B. G. 2000, "Multiple sclerosis," N Engl j Med, vol. 343, pp. 938-952 Rao, K. V. & Notenberg, M. D. 2001, "Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia," Metab Brain Dis, vol. 16, pp. 67-78 Rosenberg, G. A. 1990, Brain Fluids and Metabolism, Oxford University Press, New York Rosenberg, G. A., Estrada, E. Y., 8c Dencoff, j. E. 1998, "Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain," Stroke, vol. 29, pp. 2189-2195 Videen, T. O., Zazulia, A. R., Manno, K. M„ et al. 2001, "Manmtol bolus preferentially shrinks non-infatcted brain in patients with ischemic stroke," Neurology, vol. 57, pp. 2120-2122 Xi, G., Hua, Y., Bhasin, R. R., et al. 2001, "Mechanisms of edema formation after intracerebral hemorrhage: Effects of extravasated red blood cells on blood flow and blood-brain barrier integrity," Stroke, vol. 32, pp. 2932-2938 Yong, V, W., Power, C„ Forsyth, P., 6c Edwards, D. R. 2001, "Metalloproteinases in biology and pathology of the nervous system," Nat Rev Neurosci, vol. 2, pp. 502-51 1
Chapter 66 Developmental Disorders of the Nervous System Harvey B. Sarnat and Laura Flores-Sarnat Embryological and Fetal Development of the Nervous System Neural Maturation Mitotic Proliferation of Neuroblasts (Ncuronogenesis) Disorders of Neurotiogenesis Programmed Cell Death (Apoptosis) Disorders of Programmed Cell Death Neuroblast Migration I'he Major Mechanism of Neuroblast Migration: Radial Glial Fiber Guides Disorders of Neuroblast Migration Growth of Axons and Dendrites Disorders of Neuritc Growth Electrical Polarity- of the Cell Membrane Disorders of Membrane Polarity Synaptogenesis Disorders of Synaptogenesis Biosynthesis of Neurotransmitters Disorders of Neurotransmitter Synthesis
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EMBRYOLOGICAL AND FETAL DEVELOPMENT OF THE NERVOUS SYSTEM Congenital malformations of the nervous system are best understood in the context of embryology. The scope of modern embryology now encompasses not only classical descriptive morphogenesis, but also the molecular genetic programming of development. Maturation refers both to growth, a measurement of physical characteristics over time, and development, the acquisition of metabolic functions, reflexes, sensory awareness, motor skills, language, and intellect. Molecular development is the maturation of cellular function. In the case of neurons, it includes the development of an energy production system to actively maintain a resting membrane potential, the synthesis of secretory molecules as neurotransmitters, and the formation of membrane receptors. Membrane receptors respond to various transmitters at synapses, to a variety of trophic and adhesion molecules, and during development, to substances that attract or repel growing axons in their intermediate and final trajectories. The role of homeobox genes in the differentiation of neural structures is an aspect of development recognized relatively recently. Molecular genetic data are rapidly becoming available because of intense interest in this key to understanding neuroembryology in general and neural induction in particular (Sarnat and Menkes 2000). Other aspects of current investigative interest include the
Myclination Disorders of Myclination Cajal-Rctzius Neurons of the Fetal Brain Supra tegmenta I Influences on Muscle Maturation Etiologies of CNS Malformations Ischemic Encephalopathy in the Ferus Molecular Genetic Classification of Malformations of the Nervous System Clinical Expression of Malformations of the Nervous System Disorders of Neu tula tion (1-4 Weeks' Gestation) Midline Malformations of the Forebrain (4-8 Weeks' Gestation) Disorders of Early Neuroblast Migration {8-20 Weeks' Gestation) Disturbances of Late Neuroblast Migration (after 20 Weeks' Gestation) Disorders of Cerebellar Development (32 Days' Gestation to I Year Postnatally)
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roles of neurotrophic factors, hormones, ion channels, and neurotransmitter systems in fetal brain development. Many genetic models of human cerebral malformations have been created by genetic manipulation in animals, and these contribute greatly to our understanding of human dysgeneses and provide insights also into the pathogenesis of epilepsy and other functional results of dysgeneses (Chcvassus-au-Louis et al. 1999). Maturation progresses in a predictable sequence with precise timing. Insults that adversely affect maturation influence events occurring at a particular time. Some insults are brief (e.g., a single exposure to a toxin), whereas others act over many weeks or throughout gestation, such as some congenital infections, diabetes mellitus, and genetic or chromosomal defects. Even brief insults may have profound influences on later development, by interfering with processes essential to initiate the next stage of development, so that the timing of an adverse event often is difficult. The anatomical and physiological correlates of neurological maturation reflect the growth and development of the individual neuron and its synaptic relations with other neurons. The mature neuron is a secretory cell with an electrically polarized membrane. Though endocrine and exocrine cells are secretory, and muscle cells possess excitable membranes, only neurons embrace both functions. The precursors of neurons arc neither secretory nor excitable. The cytological maturation of neurons is an 1763
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aspect of ontogenesis that is as important as their spatial relations with other cells for future function and also for the pathogenesis of some functional neurological disorders of infancy, such as neonatal seizures. Neuroblasts are defined as postmitotic neuroepithelial tells committed to neuronal lineage. These cells have not yet achieved all functions of mature neurons such as membrane polarity, secretion, and synaptic relations with other neurons, and often they are still migratory. The term blast thus is used differently for neural development than for hematopoieses, in which blast cells are still in the mitotic cycle. The events of neural maturation after initial induction and formation of the neural tube are each predictive of specific types of malformation of the brain and of later abnormal neurological function. These are (1) mitotic proliferation of neuroblasts, (2) programmed death of excess neuroblasts, (3) neuroblast migration, {4) growth of axons and dendtites, (5) electrical polarity of the cell membrane, (6) synaptogencsis, (7) biosynthesis of neurotransmitters, and (8) myelinstion of axons. Malformations of the nervous system are unique. No two individual cases are identical, even if they can both be categorized as similar, such as alobar holoprosencephaly, agenesis of the corpus callosum, or type 2 lissencephaly. Functional expression of anatomically similar cases also may vary widely. For example, two cases of holoprosencephaly with nearly identical imaging findings and similar histological patterns of cortical architecture and subcortical heterotopia at autopsy may differ in that one infant may have epilepsy refractory to pharmacological control, whereas the other may have no clinical seizures at all. The difference may be at the level of synaptic organization and the relative maturation of afferent input and neuronal maturation (Sarnat and Born 1999).
NEURAL MATURATION Mitotic Proliferation of Neuroblasts (Neuronogenesis) After formation of the neural tube, neurons and glial cells are generated by proliferation of neuroepithelial cells in the ventricular zone with mitoses at the ventricular surface. The rate of division is greatest during the early first trimester in the spinal cord and brainstem and during the late first and early second trimester in the forebrain. "Within the ventricular zone of the human fetal telencephalon, 33 mitotic cycles provide the total number of neurons required for the mature cetebral cortex. Most mitotic activity in the ncuroepithelium occurs at the ventricular surface, and the orientation of the mitotic spindle determines the subsequent immediate fate of the daughter cells. If the cleavage plane is perpendicular to the ventricular surface, the two daughter cells become equal neuroepithelial cells preparing for further mitosis. If, however, the cleavage is parallel to the ventricular surface, the two daughter cells are unequal
(asymmetrical cleavage). In that case, the one at the ventricular surface becomes another neuroepithelial cell, whereas the one away from the ventricular surface separates from its ventricular attachment and becomes a postmitotic neuroblast ready to migrate to the cortical plate. Furthermore, the products of two genes that determine cell fate, called numb and notch, are on different sides of the neuroepithelial cell. Therefore, with symmetrical cleavages, both daughter cells receive the same amount of each, but with asymmetrical cleavage, the cells receive unequal ratios of each, which also influences their subsequent development (Mione et al. 1997). The orientation of the mitotic spindle requires centractin. Active mitoses cease well before the time of birth in most parts of the human nervous system, but a few sites retain a potential for postnatal mitoses of neuroblasts. One recognized site is the periventricular region of the cerebral hemispheres (Kendler and Golden 1996). The best-documented site is the external granular layer of the cerebellar cortex, where occasional mitoses persist until I year of age. Postnatal regeneration of these neurons after most are destroyed by irradiation or cytotoxic drugs is demonstrated in animals and may occur in humans as well. Primary olfactory receptor neurons also retain a potential for regeneration. In fact, if a constant turnover of these neurons did not occur throughout life, the individual would become anosmic after a few upper respiratory infections, which transiently denude the intranasal epithelium. Recently, a population of "stem cells'1 with mitotic potential has been demonstrated in the suliventncular /.one anil hippocampa! dentate gyrus (Johansson etal. 1999). These have generated a great deal of interest because of a potential for regeneration of the damaged adult brain and because they may be induced to mature as neurons (Schuldiner et al. 2001).
Disorders of Neuronogenesis Destructive processes may destroy so many neuroblasts that regeneration of the full complement of cells is impossible. This happens when the insult petsists for a long time or is repetitive, destroying each subsequent generation of dividing cells. Inadequate mitotic proliferation of neuroblasts results in hypoplasia of the brain (Figure 66.1). Such brains are small and grossly malformed because neuroblast migration is affected directly or by destruction of the glial cells with radial processes that guide migrating nerve cells. The entire brain may be affected, or portions may be selectively involved. Cerebellar hypoplasia is often a selective interference with proliferation of the external granular layer. In some cases, cerebral hypoplasia and microcephaly are the result of precocious development of the ependyma before all mitotic cycles of the neuroepirhelium are complete because ependymal differentiation arrests mitotic activity at the ventricular surface (Sarnat 1992). The mutation of a gene that programs neuronogenesis may
DEVELOPMENTAL DISORDERS OF THE NERVOUS SYSTEM
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FIGURE 66.1 Severe cerebral hypnphsi;!. The brain of this term neonate weighed only 12.6 g (normal mean is 350 g), although the cranium was closed and mainly filled with fluid, The dysplasia architecture of the telencephalon. incluJ-iu', dysplasia cerebellar tissue, extended into a frontal encephalocele (e) and was not that of a neural tube defect or fetal infarction. The spinal cord (sp) is well formed except for the absence of descending tracts. The cerebellum (e) is small but normally laminated. This brain probably represents lack of neuronal proliferation. Note the wellformed fossae at rhe base of the skull, despite the absence of cerebri I development. (Reproduced with permission from Sarnat, H. B., de Mello, D. E., Blair, J. D., ct al. J 9S2, "Heterotopic growth of dysplastic cerebellum in frontal encephalocele in an infant of a diabetic mother," Can j Neurol So, vol. 9, pp. 31-35.) he another explanation for generating insufficient neuroepithelial cells, although this pathogenesis remains hypothetical in humans.
Programmed Cell Death (Apoptosis) Excessive neuroblasts are formed in every part of the nervous system by normal mitotic proliferation. This abundance is reduced by a programmed process of cell death until the definitive number of immature neurons is achieved. The factors that arrest the process of programmed cell death in the fetus are multiple and are in part genetically determined. Cells that do not match with targets are more vulnerable to degeneration than are those that achieve synaptic contact with other cells. Kndocrine hormones and neuropeptides modulate apoptosis. Some homeotic genes, such as c-fos arc important in the regulation of programmed cell death in the nervous system, and other suppressor genes stop the expression of apoptotic genes.
stopping at the proper time. In this disorder, continued loss of spinal motor neurons (SMN) after all surplus embryonic neuroblasts are deleted is expressed as a progressive denervating process. Genetic factors are crucial in determining the arrest of cell death, which accounts for the hereditary character of spinal muscular atrophy. The SMN defective gene at the chromosome 5ql3.1 locus has now been isolated and is normally responsible for arresting apoptosis in motor neuroblasts (Roy et al. 1995),
Disorders of Programmed Cell Death
Other neurodegenerative diseases of fetal life and infancy arc more widespread within the central nervous system (CNS) rather than limited to one type of neuron, such as the motor neuron. They also are characterized by progressive neuronal loss that is apoptotic rather than necrotic in character: There is no inflammatory or glial reaction, and the features of the DNA degradation differ from ischemic necrosis. An example is pontocerebellar hypoplasia, a group of progressive degenerative diseases that begin prenatally and continue postnatally. Despite the name, they involve much more than the cerebellar system. These diseases are associated with extensive cerebral cortical and basal ganglionic abnormalities, even in motor neurons, which cause a clinical presentation at birth resembling spinal muscular atrophy. This autosomal recessive group of diseases, all genetically distinct from olivopontocerebellar atrophy, exemplifies a semantic difficulty: If an atrophic process begins before development is complete, it results in both hypoplasia and superimposed atrophy.
Spinal muscular atrophy (see Chapter 79) is an example of a human disease caused by programmed cell death not
In the CNS, glial cells also undergo programmed cell death. Glial necrosis is intimately linked to the interhemispheric passage of commissural fibers in the corpus
Two phases of apoptosis are distinguished. One involves yet undifferentiated neuroepithelial cells or neuroblasts with incomplete differentiation; another phase involves fully differentiated neurons of the fetal brain.
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callosum. In a murine model of callosal agenesis, glial cells that do not degenerate act as a barrier to crossing axons and prevent the corpus callosum from forming.
Neuroblast Migration No neurons of the mature human brain occupy the site in which they were generated from the neuroepithelium. They migrate to their mature site to establish the proper synaptic connections with appropriate neighboring neurons and to send their axons in short or long trajectories to targets. The subependymal germinal matrix (Figure 66.2) is the subventricular zone of the embryonic concentric layers and consists of postmitotic, premigratory neuroblasts and glioblasts. In general, the movement of maturing nerve cells is centrifugal, radiating toward the surface of the brain. The cerebellar cortex is exceptional in that external granule eel Is first spread over the surface of the cerebellum and then migrate into the folia. Migration of neuroblasts begins at about 6 weeks' gestation in the human cerebrum and is not completed until at least 34 weeks of fetal life, although the majority of germinal matrix cells after midgestation are glioblasts. Glioblasts continue to migrate until early in the postnatal period. Within the brainstem, neuroblast migration is complete by 2 months' gestation. Cerebellar external granule cells continue migrating throughout the first year of life. Neuroblast migration permits a three-dimensional spatial relation to develop between neurons, which facilitates the formation of complex synaptic circuits. The timing and sequence of successive waves of migrating neuroblasts are precise. In the cerebral cortex, immature nerve cells reach the pial surface and then form deeper layers as more recent arrivals replace their position at the surface. Neurons forming the most superficial layers of neocortex are thus
the last to have migrated, although in the three-layered hippocampus, the most superficial neurons represent the earliest migratory wave. The laminated arrangement of the mammalian cerebral cortex requires a large cortical surface area to accommodate increasing numbers of migrating neuroblasts and glioblasts, Convolutions provide this large surface area without incurring a concomitant increase in cerebral volume. The formation of gyri and sulci is thus a direct result of migration (Figure 66.3). Most gyri form in the second half of gestation, which is a period of predominant gliogenesis and glial cell migration. Therefore, the proliferation of glia in the cortex and subcortical white matter may be more important than neuroblast migrations in the formation of convolutions, but the growth of dendrites and synaptogenesis also may influence gyration by contributing mass to the neuropil. The timing and sequence of gyral formation in the human brain arc as predictable as other aspects of cerebral maturation. The gestational age of a premature infant may be determined to within a 2-week period or less from the convolutional pattern of the brain at autopsy.
THE MAJOR MECHANISM OF NEUROBLAST MIGRATION: RADIAL GLIAL FIBER GUIDES The majority of neuroblasts arriving at the cortical plate do so by means of radial glial guides from the subventricular zone. A second route, that of tangential migration, uses axons as the guides for the migratory neuroblasts. The genetically determined programming of neuroblast migration begins when cells are still undifferentiated neuroepithelial cells and even before all their mitotic cycles are complete. Neuroepithelial cells express the gene products of the lissencephaly gene (LIS1), as do ependymal cells and FIGURE 66.2 Coronal section of forebrain of 16-week normal fetus, showing extensive subependymal germinal matrix (g) of neuroblasts and glial precursors that have not yet migrated. The surface of the brain is just beginning to develop sulci (arrowheads). Migrating neuroblasts (m) are seen in the subcortical white matter. The corpus callosum (ce) is artifaetually ruptured and the two hemispheres should be closely approximated. (en = caudate nucleus; ic = anterior limb of internal capsule.) (Hematoxylin-eosin stain.)
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B FIGURE 66.3 Lateral (A) and ventral (B) views of a normal brain of a 16-week ferus. The primary sulci, such as the sylvian fissure, calcarine fissure, and central sulcus, are forming, hut secondary and Tertiary sulci and gyri are not yet developed, and the Surface of the brain is smooth. Cajat-Retzius cells of the molecular layer of cerebral cortex, This gene is defective in type 1 tissencephaly (Miller-Dieker syndrome), a severe disorder of neuroblast migration (Clark et al. 1997). How it functions in migration is not fully understood. Most neurons of the forcbrain are guided to their predetermined site from the germinal matrix (embryonic subventricular /one) by long, radiating fibers of specialized fetal astrocytes (Figure 66.4). The entire wall of the fetal cerebral hemisphere is spanned by the elongated processes of these glial cells, whose cell bodies are in the
periventricular region and terminate as end-feet on the limiting pial membrane at the surface of the brain (see Figure 66.4), Radial glial cells are the first astroglial cells of the human nervous system converted into a mature fibrillary astrocyte of the subcortical white matter; some are still present at birth. Mature astrocytes are present throughout the CNS by 15 weeks' gestation, and gliogenesis continues throughout fetal and postnatal life. Several types of glial cells are recognized between 20 and 36 weeks' gestation. FIGURE 66.4
Radial glial fibers
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The mechanical process of neuroblasts gliding along a radial glial fiber is facilitated by a number of specialized proteins at the radial glial fiber surface membrane or extracellular space. An example is astrotactin, which is secreted by the neuroblast itself (Zheng et al. 1996). The glial cell (e.g., LI neural cell adhesion molecules [Jouet and Kenwrick 1995| and orhc" adhesion molecules also facilitate gliding. Fetal ependymal cells have radiating processes that resemble those of the radial glial cell but do not extend beyond the germinal matrix and secrete molecules in the extracellular matrix. Some adhesion molecules are present in the extracellular matrix (Thomas et al. 1996). These molecules serve as lubricants, as adhesion molecules between the membranes of the neuroblast and the radial glial fiber, and as nutritive and growth factors. They stimulate cell movement by a mechanism still poorly understood. Deficient molecules lead to defective migration, For example, the abnormality of the LI adhesion molecule is the defective genetic program in X-linked hydrocephalus accompanied by poly microgyria and pachygyria. The process of transformation of radial glial cells into astrocytes and ependymal cells begins during the first half of gestation and is completed postnatal ly. During midgestation, when neuronal migration is at a peak, many radial glial cells remain attached to the ventricular and pial surfaces, increasing in length and curving with the expansion and convolution of the cerebral wall. From 28 weeks' gestation to 6 years of age, astrocytes of the frontal lobe shift from the periventricular to the subcortical region. The centrifugal movement of this band of normal gliosis marks the end of neuronal migration in the cetebral mantle. Ependyma does not completely line the lateral ventricles until 22 weeks' gestation (Sarnat 1992}. In addition to the radial migration to the cerebral cortex, tangential migration also occurs, but the number of neuroblasts is far smaller (Rakic 1995). These migrations perpendicular ro the radial fibers probably use axons rather than glial processes as guides for migratory neuroblasts, which explains why all cells in a given region of cortex are not from the same clone or vertical column. Most of the tangentially migrating neuroblasts in the cerebral cortical plate are generated in the fetal gangltonic eminence, a deep relecephalic structure that later becomes the basel ganglia. Tangential migrations occur in the brainstem and olfactory bulb as well as in the cerebrum. The subpial region is another site of neuroblast migration that docs not use radial glial cells.
Disorders of Neuroblast Migration Nearly all malformations of the brain are a direct result of fauln- neuroblast migration or at least involve a secondary impairment of migration. Imperfect cortical lamination, abnormal gyral development, subcortical heterotopia, and other focal dysplasias are related to some factor that
interferes with neuronal migration, whether vascular, traumatic, metabolic, or infectious. The most severe migrational defects occur in early gestation, often associated with events in the gross formation of the neural tube and cerebral vesicles. Heterotopia of brainstem nuclei also occurs. Later defects of migration are expressed as disorders of cortical lamination or gyration, such as lissencephaly, pachygyria, and cerebellar dysplasias. These insults of the third trimester of gestation cause more subtle or focal abnormalities of cerebral architecture. Most disturbances of neuroblast migration involve arrested migration before the journey is complete. These disorders may be divided into three anatomical phases, depending on where the migratory arrest occurred. An example of neuroblasts never having begun to migrate from the periventricular region is periventricular nodular heterotopia an X-linked genetic disorder due to defective expression of the gene Filamin-A. If neuroblasts began migrating, but became arrested in the subcortical white matter and did not reach the cortical plate, subcortical laminar heterotopia may result, another X-linked recessive trait, but due to a different gene called Dnublecortin (DCX). If the neuroblasts reached the cortical plate but did not arrange themselves with correct lamination, this abnormal architecture of the cortical plate often is accompanied by abnormalities of gyration, such as lissencephaly or pachygyria. Several different genes, including LIS! and Reelin (RTN), are important in cortical plate organization (Curran and D'Arcangelo 1998) and are mutated in malformations of the terminal phase of neuroblast migration. Lissencephaly is a condition of a smooth cerebral cortex without convolutions. At midgestation, the brain is essentially smooth; only the interhemispheric, sylvian, and calcarine fissures are formed. Gyri and sulci develop between 20 and 36 weeks' gestation, and the mature pattern of gyration is evident at term, although some parts of the cerebral cortex, such as the frontal lobes, are still relatively small. In lissencephaly type 1 (Miller-Dieker syndrome), the cerebral cortex remains smooth. The histopathological pattern is that of a four-layer cortex in which the outermost layer (1) is the molecular layer, as in normal six-layered neocortex. La yet 2 corresponds ro layers 2 through 6 of normal neocortex, layer J3 is cellsparse as a persistent fetal subplate zone, and layer 4 consists of incompletely migrated neurons in the subcortical intermediate zone. In lissencephaly type 2 (WalkerWarburg syndrome), poorly laminated cortex with disorganized and disoriented neurons is seen histologically, and the gross appearance of the cerebrum is one of a smooth brain or a few poorly formed sulci (Figure 66.5), The cerebral mantle may be thin, suggesting a disturbance of cell proliferation as well as of neuroblast migration, Malformations of the brainstem and cerebellum often are present as well (see Figure 66.5). Lissencephaly of type 1 and type 2 (Walker-Warburg syndrome, Fukuyama muscular dystrophy, muscle-eye-bra in disease of Santavuori)
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provide a clue to pathogenesis. Schizencephaly occurs both as a genetic trait (the defective gene is EMX2) and sporadically; in some cases, it is a form of porencephaly due to fetal cerebral infarction. In the cerebral hemisphere, most germinal matrix cells become neurons during the first half of gestation, and most form glia during the second half of gestation. Nonetheless, j small ium::KT o: gerir.sual matrix cells arc neuronal precursors, migrating into the cerebral cortex in late gestation. Because the migration of the external granular layer in the cerebellar cortex is not completed until 1 year of age, a potential for acquired insults to interfere with late migrations persists throughout the perinatal period. Anatomical lesions, such as periventricular leukomalacia, intracerebral hemorrhages and abscesses, hydrocephalus, and traumatic injuries, may disrupt the delicate radial glial guide fibers and prevent normal migration, even though the migrating cell itself may escape tin- focal destructive lesion.
FIGURE 66.5 Sagittal Tl-weighted magnetic resonance image of a 10-month-old girl with lissencephaly type 2 and Dandy-Walker malformation. The cerebral mantle is thin, and the latetal ventricle is greatly enlarged. A few abnormal shallow fissures at the cerebral surface may indicate abortive gyration or pachygyria. The cerebellum is severely hypoplastic {arrow indicates anterior vermis), and the posterior fossa contains a large, fluid-filled cyst. The brainstem also is hypoplastic, and the basis pontis is nearly absent. A differential diagnosis of this image is pontocerebellar hypoplasia, but the high position of the toreula indicates a DandyWalker malformation. are genetic diseases, but lissencephaly also may occur secondary to nongeneric disturbances of neuroepithelial proliferation or neuroblast migration, including destructive encephaloclastic processes, such as congenital infections during fetal life. Other abnormal patterns of gross gyration of the cerebral cortex also occur secondary to neuroblast migratory disorders. Pachygyria signifies abnormally large, poorly formed gyri and may be present in some regions of cerebral cortex with lissencephaly in other regions. Poly microgyria refers to excessively mi men HIS and abnormally small gyri that similarly may coexist with pachygyria; it docs not necessarily denote a primary migratory disorder of genetic origin. Small, poorly formed gyri may occur in zones of fetal ischemia, and they regularly surround porencephalic cysts due to middle cerebral artery occlusion in fetal life. Schizencephaly is a unilateral or bilateral deep cleft usually in the general position of the sylvian fissure but is not a sylvian fissure: This cleft is the full thickness of the hemispheric wall, and no cerebral tissue remains between the meninges and the lateral ventricle (the pial-ependymal seam). If the cerebral cortical walls on either side of the deep cleft are in contact, the condition is called closed lips, and if a wide subarachnoid space separates the two walls, it is known as open lips, but these two variants do not
Damaged radial glial cells tend to retract their processes from the pial surface. The migrating neuron travels only as far as its retracted glial fibers carry it. If this fiber is retracted into the subcortical white matter, the neuroblast stops there and matures, becoming an isolated hetcroropic nodule composed of several nerve cells that were migrating at the same time in the same place. In these nodules, neurons of various cortical types differentiate without laminar organization and with haphazard orientations of their processes, but a few extrinsic axons may prevent total synaptic isolation of the nodule. Interference with the glial guide fibers in the cerebral cortex itself results in neurons cithet not reaching the pial surface or not being able to reverse direction and then descending to a deeper layer. The consequence is imperfect cortical lamination, which interferes with the development of synaptic circuits. These distutbances of late neuroblast migration do not ptoducc the gross malformations of early gestation and may not be detected by imaging techniques. They may account for many neurological sequelae after the perinatal period, including seizures, perceptual disorders, impaired coordination of gross or fine motor function, learning disabilities, and mental retardation. In sum, disorders of neuroblast migration may be due either to defective genetic programming or may be acquired secondary to lesions in the fetal brain that destroy or interrupt radial glial fibers. Cells may not migrate at all and become manire neurons in the periventricular region, as occurs in X-linked periventricular nodular heterotopia (Eksioglu et al. 1996) and in some cases of congenital cytomegalovirus infection. Cells may become arrested along their course as heterotopic neurons in deep subcortical white matter, as occurs in many genetic syndromes of Iissencephaly-pachygyria and in many metabolic diseases, including cerebrohepatorcnal Zellweger syndrome and in many aminoacidurias and organic acidurias. The same aberration may occur in acquired insults to the radial glial cell during ontogenesis. Cells may overmigrate beyond
B
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the limits of the pial membrane into the meninges as ectopic neurons, either singly or in clusters known as marginal glkmeurnnal heterotopia or brain warts. Rarely, herniation of the germinal matrix into the lateral ventricle may occur through gaps in the ependyma; those cells mature as neurons, forming a nonneoplastic intraventricular mass that may or may not obstruct cerebrospinal fluid (CSF) flow. Whether disoriented radial glial fibers actually guide neuroblasts to an intraventricular site or are physically pushed into a direction of less resistance is uncertain.
of the most useful methods for demonstrating dendritic arborizations. Among the many contributions of this technique to the study of the nervous system, beginning with the elegant pioneering work of Ramon y Cajal, none has surpassed its demonstration of the sequence of normal dendritic branching in the human fetus. Newer immunocytochemieal techniques for demonstrating dendrites also are now available, such as microtubule-associated protein 2. These techniques may be applied to human tissue resected surgically, as in rhc surgical treatment of epilepsy, and to the tissue secured at autopsy.
Growth of Axons and Dendrites Disorders of Neurile Growth During the course of neuroblast migration, neurons remain largely undifferentiated cells, and the embryonic cerebral cortex at midgestation consists of vertical columns of tightly packed cells between radial blood vessels and extensive extracellular spaces. Cytodifferentiation begins with a proliferation of organelles, mainly endoplasmic reticulum and mitochondria in the cytoplasm, and clumping of condensed nuclear chromatin at the inner margin of the nuclear membrane. Rough endoplasmic reticulum becomes swollen, and ribosomes proliferate, The outgrowth of the axon always precedes the development of dendrites, and the axon forms connections before the differentiation of dendrites begins. The projection of the axon toward its destination was first recognized by Ramon y Cajal, who named this growing process the cone d'accroissetnent (growth cone). The tropic factors that guide the growth cone to its specific terminal synapse, whether chemical, endocrine, or electrotaxic, have been a focus of controversy for many years. However, it is now well demonstrated that growth cones are guided during their long trajectories by diffusible molecules secreted along their pathway by the processes of fetal ependyma! cells and perhaps some glial cells. Some molecules, such as braindenved neurotrophic growth factor, netrin and $-100$ protein, attract growing axons, whereas others, such as the glycosaminoglycan keratan sulfate (not to be confused with the protein keratin), strongly repel them and thus prevent aberrant decussations and other deviations. Matrix proteins, such as laminin and fibronectin, also provide a substrate for axona! guidance. Cell-to-cell attractions operate as the axon approaches its final target. Despite the long delay between the migration of an immature nerve cell and the beginning of dendritic growth, the branching of dendrites eventually accounrs for more than 9 0 % of the synaptic surface of the mature neuron. The pattern of dendritic ramification is specific for' each type oi neuron. Spines form on the dendrites as short protrusions with expanded tips, providing sites of synaptic membrane Jitii-i-nliation. The Golgi method of impregnation of neurons and their processes with heavy metals, such as silver or mercury, has been used for more than a century and continues to be one
If a neuron becomes disoriented during migration and faces the wrong direction in its final site, its axon is capable of reorienting itself as much as 180 degrees after emerging from the neuronal cell body. Dendrites, by contrast, conform strictly to the orientation of the cell body and do not change their axis. The dendritic tree becomes stunted if axodendritic synapses are not established. Because so much dendritic differentiation and growth occurs during the last third of gestation and the first months of the postnatal period, the preterm infant is particularly vulnerable to noxious influences that interfere wirh maturation of dendrites. Extraordinarily long dendrites of dentate granule cells and prominent basal dendrites of pyramidal cells have been described in term infants on life-support systems. Retardation of neuronal maturation in terms of dendrite development and spine morphology has been described in premature infants, compared with term infants of the same conceptional age, possibly as a result of asphyxia. Infants with fetal alcohol syndrome also have a reduced number and abnormal geometry of dcmlnric opines oi conical neurons. Traditional histological examination of the brains of mentally retarded children often shows remarkably few alterations to account for a profound intellectual deficit. The study of dendritic morphology by the Golgi technique has revealed striking abnormalities in some of these cases. The alterations are best documented in chromosomal diseases, such as trisomy 13 and Down syndrome. Long, thin, tortuous dendritic spines and the absence of small, stubby spines are a common finding. Children with unclassified mental retardation but normal chromosomal numbers and morphology also show defects in the number, length, and spatial arrangement of dendrites and synapses. Abnormalities of cerebellar Purkinje's cell dendrites occur in cerebellar dysplasias and hypoplasias. They consist of cactus-like thickenings and loss of brauchlet spines. Abnormal development of the dendritic tree is also a common finding in many metabolic encephalopathies, including Krabbe's disease and other leukodystrophies, Menkes' kinky hair disease, gangliosidoses, ceroid lipofuscinosis, and Sanfilippo's syndrome. Among genetically
DEVELOPMENTAL DISORDERS OF THE NERVOUS SYSTEM
determined cerebral dysgeneses, aberrations in the structure and number of dendrites and spines are reported in cerebrohepatorenal (Zellweger) syndrome and in tuberous sclerosis.
Electrical I'olariu of llic Cell Membrane The development of membrane excitability is one of the important markers of neuronal maturation, but little is known about the exact timing and duration of this development. Membrane polarity is established before synaptogenesis and before the synthesis of neurotransmitters begins. Because the maintenance of a resting membrane pfiriT.ri.il rviiuin"-. considerable energ\ expenditure to fuel the sodium-potassium pump, the undifferentiated neuroblast would be incapable of maintaining such a dynamic condition as a resting membrane potential. The development of ion channels within the neural membrane is another important factor in the maturation of excitable membranes and the maintenance of resting membrane potentials.
Disorders of Membrane Polarity Epileptic phenomena are largely due to inappropriate membrane depolarizations. They represent a complex interaction of excitatory and inhibitory synapses that modulate the resting membrane potential, metabolic alterations, and many unknown factors that also contribute to the discharge threshold of neural membranes. Cerebral malformations ate often associated with seizures because of abnormal synaptic circuitry, and the role of abnormal resting membrane potentials in development is largely speculative at this time. Electrolyte imbalances in the serum certainly influence the depolarization threshold, and hypothalamic disturbances may alter endocrine function and electrolyte balance.
Synaptogenesis Synapse formation follows the development of dendritic spines and the polarization of the cell membrane. The relation of synaptogenesis to neuroblast migration differs in different parts of the nervous system. In the cerebral cortex, synaptogenesis always follows neuroblast migration. In the cerebellar cortex, however, the external granule cells develop axonal processes that become the long parallel fibers of the molecular layer and make synaptic contact with Purkinje cell dendrites before migrating through the molecular and Purkinje cell layer to their mature internal position within the folium. Afferent nerve fibers reach the neocortex early, before lamination occurs in the cortical plate. The first synapses are axodendritic and occur both external to and beneath
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the cortical plare in the future layers I and VI, w:hich contain the first neurons that have migrated. An excessive number of synapses form on each neuron, with subsequent elimination of those that are not required. Outside the CNS, muscle fibers also begin their relation with the nefvous system by receiving multiple sources of innervation from multiple motor neurons, later retaining only one. Transitory synapses also form at sites on neurons where they are not found in the matute condition. The spinal motor neurons of newborn kittens display prominent synapses on theit initial axonal segment, where they are never found in adult cats. Somatic spines are an important synaptic site on the embryonic Purkinje cell, bur these spines and their synapses disappear as the dendritic tree develops. A structure-function correlation may be made in the developing visual cottex. In preterm infants of 24-25 weeks' gestation, the visual evoked potentials (VEPs) recorded at the occiput exhibit an initial long-latency negativity, but by 28 weeks' gestation, a small positive wave precedes this negativity. The change in this initial component of the VEP corresponds to dendritic arborization and the formation of dendritic spines that occurs at that time. The electroencephalogram (KEG) of the premature infant follows a predictable and time-linked progression in maturation that has been extensively studied. The EEC reflects synaptogenesis more closely than any other feature of cerebral maturation and thereby provides a noninvasive and clinically useful measure of neurological maturation in the preterm infant. Fetal EEC may even detect neurological disease and seizures in utero.
Disorders of Synaptogenesis Because the formation of dendritic spines and the formation of synapses are so closely related, the same spectrum of diseases already discussed is equally appropriate for consideration in this section. The rate of maturation of the EECi is often slow in preterm infants, who are generally unwell, even if they do not have specific neurological disease, which may reflect an impairment of synapse formation. Chronic hypoxemia particularly delays neurological maturation.
Biosynthesis of Neurotransmitters The synthesis of neurotransmitters and ncuromodulating chemicals is based on the secretory character of the neuron, without which synaptic transmission is impossible. Several types of substances serve as transmitters: (1) acetylcholine (ACh); (2) monoamines, including dopamine, norepinephrine, epinephrine, and serotonin; (.•>) neuropeptides, including substance P, somatostatin, and opioid-conraining
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NHUR01.0CICAL DISEASES
peptide chains, such as the enkephalins; and (4) simple amino acids, including glutamic acid, aspartic acid, yaminobutyric acid (GABA), and glycine. Some transmitters are characteristically inhibitory (such as glycine, GABA, and ACh in the CNS). Each neuronal type produces a characteristic transmitter (motor neurons produce ACh, cerebellar Purkinje cells produce GABA, and granule cells produce glutamic acid in the adult). Neuropeptides may coexist with other types of transmitters in some neurons. In some parts of the brain, transitory fetal transmitters may appear during development and then disappear. Substance 1' and somatostatin are present in the fetal cerebellum at midgestation, but these neuropeptides are never found in the mature cerebellum. In the cerebral cortex of the frontal lobe, there is laminar distribution of cholinergic muscarinic receptors of the mature brain that is the inverse of the pattern in the fetus. The functions of these transitory transmitter systems are unknown. Some serve as trophic molecules rather than transmitters in early development. Even amino acid transmitters, such as GABA, may serve mainly a trophic function at an early stage in development. In situ hybridization and new immunocytochemical Technique cki nor. M:\IIY r.eiirorransir-trci^ in neurons of the developing brain of experimental animals and may be applied to human tissue under some circumstances (Dupuy and Houser 1997). The ontogeny of neurotransmitter systems depends not only on the mechanisms of synthesis of chemical transmitters, but also on the development of highly specific receptors of these chemical signals and the ability of these receptors to modify excitability of neuronal membranes and to trigger action potentials after the recognition of specific molecules (Rho and Storey 2001; Simeone et al. 2003).
Disorders of Neurotransmitter Synthesis Ischemic and hypoxic insults impair RNA transcription and result in arrest of the synthesis of secretory products. Many of the clinical neurological deficits observed in neonates who underwent birth asphyxia are probably the result of neurotransmitter depletion and functional synaptic block. Some amino acid neurotransmitters, by contrast, arc neurotoxic when released in large quantities. The excitatory amino acids glutamic acid and aspartic acid induce transsynaptic degeneration when released in this way, as might occur with hypoxic stresses, and may be a major source of irreversible brain damage in asphyxiated neonates, Developmental disorders due to inborn errors of metabolism that block the chemical pathway of transmitter synthesis may hypothetically occur bur are probably incompatible with survival if they interfere with the synthesis of a major transmitter, such as ACh, monoamines, or an essential peptide. Defects in the metabolic pathways of particular amino acids are known, and many
of these are associated with mental retardation, epilepsy, spastic diplegia, and other chronic neurological handicaps. Phenylketonuria (a disorder of phenylalanine metabolism) and maple syrup urine disease (a disorder of the metabolism of the branched-chain amino acids leucine, isoleucine, and valine) are we 11-documented examples. However, it is not cettain whether absence of the product of the deficient enzyme or toxicity of high levels of precursors upstream from the enzyme deficiency is the principal insult to the nervous system,
Myelination Myelin insulates individual axons and provides greatly increased speed ot conduction. It is not essential in all nerves, and many autonomic fibers of the peripheral nervous system remain unmyelinated throughout life. Conduction velocity in central pathways is important in coordinating time-related impulses from different centers that converge on a distant target and in ensuring that action potentials arc not lost by synaptic block. The nervous system functions on the basis of temporal summation of impulses to relay messages across synapses. Myelination of pathways in the CNS occurs in a predictable spatial and temporal sequence. Some tracts myelinate as early as 14 weeks' gestation and complete their myelination cycle in a few weeks. Examples include the spinal roots, medial longitudinal fasciculus, dorsal columns of the spinal cord, and most cranial nerves. Between 22 and 24 weeks' gestation, myelination progresses in the olivary and cerebellar connections, the ansa lenticularis of the globus pallidus, the sensory trigeminal nerve, the auditory pathways, and the acoustic nerve as well as the trapezoid body, lateral lemniscus, and brachium of rhe inferior collicuius. By contrast, the optic nerve and the geniculocalcarine tract (i.e., optic radiations) do not begin to acquire myelin until near term. Some pathways are late in myelinating and have myelination cycles measured in years. The corpus callosum begins myelinating at 4 months postnatally and is not complete until midadolescence. Some ipsilateral association fibers connecting the frontal with the temporal and parietal lobes do not achieve full myelination until about 32 years ol age. Myelination can now be accurately measured in specific central pathways of the living patient by using T2-weigh ted magnetic resonance imaging sequences, but the time at which myelination can be detected is somewhat later than with traditional myelin stains of brain tissue sections, such as Luxol fast blue. Newer neuropathologies! methods, using gallocyanin and immunoreactiviry to myelin basic protein, may detect myelination even earlier than the traditional strains. Electron microscopy remains the most sensitive method of demonstrating the earliest myelination in tissue sections.
DEVELOPMENTAL DISORDERS OF THF NERVOUS SYSTEM
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Disorders of Myclination Many metabolic diseases impede the rate of myelination. Hypothyroidism is a classic example. Menkes kinky hair disease, a disorder of copper absorption and metabolism, is another example. Many aminoacidurias, including phenylketonuria, are also associated with delayed myelination. Cerebrohepatorcnal (Zellweger) syndrome is well documented with neuropathological findings that include disorders of neuroblast migration and of myelination. Some leukodystrophies, such as Krabbc disease and perinatal sudanophilic leukodystrophy, are already expressed in fetal life with defective myelination. Chronic hypoxia in premature infants is probably the most common cause of delayed myelination and contributes to the delay found in clinical neurological maturation, Myelination depends on fatty acids that must be supplied by the maternal and infant diet; nutritional deficiencies during gestation or in postnatal life may result in delayed myelination and are clinically expressed as developmental delay. Unlike disorders of neuronal migration, delay in myelination is not necessarily irreversible if the insult is removed; myelination may catch up to reach the appropriate level of maturity.
Cajal-Retzius Neurons of the Fetal Brain Cajal-Retzius cells arc large, mature, stellate neurons in the marginal (outermost) zone of the fetal cerebral cortex. They are the first cells to appear at the surface of the embryonic cerebrum, preceding the first wave of radial migration from the subventricular zone and forming a plexus in the marginal (later the molecular) zone. They migrate to the surface either lrom the ganglionic cmiiiciKV or from the midbrain neuromere (Sarnat and Flores-Sarnat 2002). The first afferent processes to enter the marginal layer are dendrites of pyramidal cells of layer VI; synapses between Cajal-Retzius and pyramidal neurons of layer VI form the first intrinsic cortical circuits (Marin-Padilla 1998). They eventually have synaptic contacts with cortical neurons in all layers. Cajal-Retzius cells contain acetylcholinesterase and oxidative enzymes and secrete GABA and probably also ACh as neurotransmitters. Their long axons extend parallel to the surface of the brain, plunging short branches into layer II (Figure 66.6). Cajal-Retzius neurons are sparse by term but persist even in the adult, though their function after maturity is uncertain. Cajal-Retzius neurons strongly express the transcription product of the I .IS I gene, which is defective in X-linkcd hydrocephalus associated with polymicrogyria and defective neuroblast migration, and they also strongly express Reelin (RLN), another gene essential for radial neuroblast migration {Clark et al. 1997; Sarnat and Flores-Sarnat 2002). No other specific diseases involving Cajal-Retzius neurons are yet described.
FIGURE 66.6 Silver stain of molecular layer of motor cortex in a 20-wcek fetus. The long fibers [arrowheads] extending parallel to the surface of the brain are axons of Cajal-Retzius neurons. They disappear with further cerebral maturation. (Bielschowsky stain. Bar= 10 urn.)
The fetal cerebral cortex has a subpial or external granular layer that histologically resembles that of the cerebellum but is of quite a different character. Cells of the cerebral cortex rise in columns from the germinal matrix of the hippocampus to form a thin layer on the surface of the archicortex at 12 weeks' gestation. They rapidly spread over the neocortex in a predictable sequence to cover the entire convexity by the sixteenth to eighteenth week, with the layer reaching the greatest thickness by 22 weeks' gestation. Subsequent involution of the external granular layer results from migration of these cells into the cerebral cortex, where they can no longer be distinguished. Only remnants of this once-prominent layer persist at term, confined to the inferior temporal and orbital surfaces. These surfaces are the last sites from which they finally disappear from the neocortex, although a few may persist over the paleocortex even into adult life. Their fate within the cerebral cortex is unknown, but it is speculated that they mature into glial cells because they lack ultra structural features of neurons, and they stain immunocytochemically for glial fibrillary acidic protein but not for vimentin.
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NEUROLOGICAL DISEASES
The subpial granular layer of the cerebral hemispheres is partially or totally absent in most cases of holoproscnccphaly, even at the gestational period when it is expected to be most prominent; this absence may contribute to the marginal glioncural heterotopia found in the meningeal spaces and superficial cortical layers. The layer of the subpial granule cells may serve as a barrier to reverse the direction of migration in neuroblasts reaching the surface. In the Fukuyama type of congenital muscular dystrophy associated with cerebral cortical dysplasia, a heterotopic layer of stellate glial cells forms at the surface of the cerebral cortex, into which migrating neurons accumulate as they reach the surface rather than reversing direction and entering deeper layers of the cortex.
preservation of the normal ratios of fiber types, similar to the changes that follow disuse or immobili/ation of muscle. It is speculated that many of the small bulbospinal "subcorticospinal" tracts (i.e., vestibulospinal, reticulospinal, olivospinal, tectospinal, and rubrospinal) are more important than is the larger corticospinal tract during the stage of histochemical differentiation of muscle between 20 and 28 weeks' gestation. These small descending pathways are generally well myelinated and functional at that time, whereas the corticospinal tract does not even begin its inyelination cycle or proliferation of axonal terminals until after muscle development is complete.
Etiologies of CNS Malformations Suprasegmental Influences on Muscle Maturation The motor unit is capable of developing normally in the absence of suprasegmental modification, as in infants with severe hypoplasias of the brain (see Figure 66.1). Malformations of the brainstem and cerebellar hypoplasia in particular are associated with a variety of aberrations in histochemical differentiation. These aberrations include (1) delayed maturation; (2) more than 8 0 % predominance of type 1 or type 2 myofibers, with or without uniform hypoplasia of one or the other type {Figure 66.7); and (3) classic congenital muscle fiber-type disproportion. Malformations limited to the cerebral cortex do not cause fiber-type predominance. Muscle biopsy of children with cerebral palsy from birth asphyxia or other perinatal insults shows only nonspecific type 2 muscle fibct atrophy, with
The causes of cerebral malformations generally fall into one of two categories. The first category is genetic and chromosomal disease in which there is defective programming of cerebral development. This genetic category also includes many inborn metabolic diseases, in which cerebral dysgenesis may be due to biochemical insults during development rather than, or in addition to, primary errors in molecular genetic codes for neural programming. The second category includes all induced malformations in which a teratogenic influence acts at a particular time in ontogenesis; the malformation depends on the timing of the insult in relation to brain development at that moment. The timing may be brief, as with a single exposure to a toxic drug, a dose of radiation, or a traumatic injury of the fetal lira in. It may be repeated two or more times or may
FIGURE 66.7 Histochemical type 2 myofiber numerical predominance and relative smallness of type 2 fibers. Type I fibers are stained lightly; type 2 fibers are dark. The small type 2 fibers do not show the angular contour characteristic of denervated muscle fibers in the adult or of those atrophic secondary to disuse. This muscle biopsy was taken from a 3-year-old boy with generalized hypotonia and cerebellar hypoplasia. (Myosin ATPase stain preincubated at pH 10.4. Bar=15 urn.)
DEVELOPMENTAL DISORDERS OF THE NERVOUS SYSTEM be prolonged and involve the fetus at several stages of development. Examples of die latter include certain congenital infections, such as toxoplasmosis and cytomegalovirus disease, which may be active throughout most of gestation, even into the postnatal period. Genetic factors are the most frequent causes of malformations during the first half of gestation; environmental factors are more important in late gestation and may cause disturbances of late neuroblast migrations, particularly in premature infants. In some cases, no definite inductive factor is identified despite intensive clinical investigations during life and meticulous postmortem studies.
Ischemic Encephalopathy in the Fetus Among the environmental factors that may interfere with the developmental process in utero or postnatally, cither briefly or more chronically, none is more important as a cause of morbidity than ischemic or hypoxic encephalopathy, Circulatory insufficiency or hypoxemia may interfere with migrations by causing infarction, which interrupts glial guide fibers. Ischemia also affects the fetal cerebrum by producing watershed infarcts between zones of artetial supply because of poorer collateral circulation compared with the mature brain. Thin-walled vessels radiate perpendicular to the surface of the brain. The precursors of these radial vessels originate from leptomeningeal arteries and are evident at 15 weeks' gestation in the human embryo; horizontal branches appear in deep cortical layers at 20 weeks' gestation and increase to supply the superficial cortex by 27 weeks' gestation. The capillary network of the cortex proliferates mainly in the postnatal period, as radial arterioles dectease in number. Severe ischemia of the immature brain may result in cuffs of surviving nerve cells surrounding the radial arterioles, with vertical columns of necrotic tissue between these zones related to immaturity of the vascular bed, Alternating radial zones of viable cerebral tissue and infarctcd tissue thus occur in the cerebral cortex. Infarcts not only destroy maturing nerve cells that have already completed their migration hut also interfere with continuing and future migrations into those regions. The zones of infarction eventually become gliotic, and the geometric architecture of the cortex is disrupted. The existence of fetal watershed zones of the cortical vascular bed is important in the pathogenesis of ulcgyria an atrophy of gyri that grossly resembles polymicrogyria. Focal areas of cortical atrophy and gliotic scarring after perinatal ischemic or hypoxic encephalopathy have been known for many years. The four-layered cortex of polymicrogyria is traditionally consideted quite a different lesion than ulegyria, resulting from a primary disturbance of neuroblast migration. Some authors question this interpretation, however, and provide evidence of postmigratory laminar necrosis of the cortex. Polymicrogyria is
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frequently distributed in vascular territories of fetal brain and often forms a rim surrounding a porencephalic cyst in the territoty of the middle cerebral artery. Multicystic encephalomalacia and hydranencephaly arc end-stage sequelae of massive cerebral infarction in the developing brain. Watershed zones also exist in the brainstem, between the territories supplied by paramedian penetrating, short circumferential, and long circumferential arteries, which all originate from the basilar artery. Transient hypoperfusion in the basilar artery in fetal life may produce watershed infarcts in the tegmentum of the pons and medullar oblongata. This is a probable pathogenesis of Mobius' syndrome and probably also of "failure of central respiratory drive" in neonates with hypoventilation not due to pulmonary or neuromuscular disorders. The cause is involvement of the tractus solitarius, which receives afferents from chemoreceptors, such as the carotid body, and provides efferent axons to motor neurons that innervate the diaphragm and intercostal muscles.
MOLECULAR GENETIC CLASSIFICATION Of MALFORMATIONS OF THE NERVOUS SYSTEM Classification is a fundamental human thought process, allowing us to organize data in a systematic manner and understand relations. The classification of the malformations of the CNS traditionally is based on descriptive morphogenesis, but the new insight into the molecular genetic programming of neural development in the last decade (Simeonc 2002) requires that rhese new data be integrated with anatomical criteria to be etiological!)' relevant and clinically useful. For example, lissencephaly and holoprosencephaly are two important malformations, each formerly thought to be distinctive dysgeneses, but we now recognize many different genetic defects that cause each; hence they are end stages of ontogenetic errors with diverse etiologies (see following). A pure genetic classification to replace anatomical criteria, by contrast, would not be useful to clinicians, radiologists, ot pathologists and would be incomplete because many genetic mutations remain imkr.owr. A ;), including prenatal ultrasound. The imaging features of each anatomical variant are distinctive (Halm and Pinter 2002) and correspond well ro the gross neuropathological findings (Golden 1998). The anterior cerebral artery is usually a single azygous vessel coursing just beneath the inner table of the skull, a pathognomonic finding. The sagittal sinuses are deformed or replaced by a network of large abnormal veins that resembles the early embryonic pattern of venous drainage. The EEG in holoprosencephaly shows multifocal spikes that often evolve into hypsarrhythmia. In the neonatal period, the waking EEG is characterized by almost continuous high-voltage alpha-thcta monorhythmic activity, becoming discontinuous in sleep. VEPs also arc abnormal or altogether absent, The clinical cotttse of holoprosencephaly is characterized by severe developmental delay and mental retardation and by a mixed pattern of seizures that often are refractory ro anticonvulsant medications. The presence or absence of seizures docs not correlate with the anatomical severity or variant of the defective forebrain and also correlates poorly with the genetic mutation (Hahn and Pinter 2002). A better correlation may be with the degree of mediolateral extension of genetic expression in disrupting the histological architecture of the cortex, or may relate to an abnormal sequence of maturation of axosomattc (inhibitory) and axodendritic (excitatory: synapses in relation to the maturation of the neuron innervated by these axonal terminations (Sarnat and Elores-Sarnat 2001a). Some patients develop hydrocephalus and require shunting, and this condition is paradoxically more common in
DEVELOPMENTAL DISORDERS OF THE NERVOUS SYSTEM
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the less severe anatomical forms of the malformation. In the severe, alobar form, a "dorsal cyst" occupies the entire posterior half to two thirds of the intracranial space and occasionally even protrudes through the anterior fontanelle as a unique encephaloeele that may be larger than the rest of the head. No other type of encephalocele is found at the anterior fontanelle. The dorsal cyst seems to originate from a dilated suprapineal recess of the third ventricle and later is a dorsal membrane that includes the roof of the forebrain, extending from the hippocampi (Sarnat and Flores-Sarnat 2001a). Hndocrine dysfunction may be present, associated with hypothalamic or pituitary involvement, and vasopressinsensitive diabetes insipidus occurs in about K6% of cases, other hypothalamic-pituitary dysfunction being much less frequent (Plawner et al. 20021. The basis of this specific involvement of the paraventricular and supraoptic hypothalamic nuclei may be hypoplasia in some cases in which the midline hypoplasia involves the diencephalon as well as the forebrain (most patients), hut also occurs in some children without hypothalamic noncleavage. One hypothesis is that the expression of the gene Orthopcdia (OTP) is secondarily suppressed by the primary genetic defect; OTP and downstream genes, such as SIM1 and BRN2, are essential for terminal differentiation of neuroendocrine cells of these hypothalamic nuclei (Sarnat and Flores-Sarnat 2001a). The treatment of HPF is directed toward the complications, such as seizures, hydrocephalus, and endocrine disturbances. Educational potential and needs depend on the degree of mental retardation, speech, and visual impairment. Isolated Arhinencepkaly
and
Kallmann's
Syndrome
Absence of olfactory bulbs, tracts, and tubercles commonly accompanies more extensive malformations, such as holoprosencephaly and septo-optic dysplasia, but may occur with callosal agenesis or as an isolated cerebral anomaly. Kallmann's syndrome is an X-linkcd or autosomal dominant condition limited to males, in which anosmia secondary to arhinencephaly without other forebrain malformations is associated with lack of secretion of gonadotropic hormones. The genetic defect is KALI at the chromosome Xp22..'? locus, but the FMX2 gene also is implicated, though schizencephaly does not occur with Kallmann's syndrome (Taylor et al. 1999). Olfactory reflexes may he elicited in the neonate consistently after 32 weeks' gestation and provide a useful supplement to the neurological examination of newborns suspected of cerebral dysgenesis. FIGURE 66.9 Unenlianced computed tomographic scan of a 6-year-old boy with semilobar holoprosencephaly. The lateral ventricles are fused, particularly frontally, but show some division into two occipital horns. A deep abnormal sulcus is seen across the fused frontal lobes (arrowheads). This is one of several radiological variants of holoprosencephaly.
Septo-Optic-Pituitary
Dysplasia
The association of a rudimentary or absent septum pellucidum with hypoplasia of the optic nerves and
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NEUROLOGICAL DISEASES
chiasm was first recognized hy De Mosier in 1956. Underdevelopment of the corpus callosum and anterior commissure and detachment of the fornix from the ventral surface of the corpus callosum are additional features. Patients with this combination of anomalies overlap others with semilobar holoprosencephaly, and some children with septo-optic dysplasia also have arhinencephaly. Disturbances of the hypothalamic-pituitary axis often occur in septo-optic dysplasia, ranging from isolated growth hormone deficiency to panhypopituitarism and deficient secretion of antidiuretic hormone. Hypothalamic hamartomas, gliosis, and the absence of some hypothalamic nuclei may he associated with a histologically normal pituitary. Absence of the neurohypophysis is demonstrated at autopsy in some cases. Midline cerebellar defects and hydrocephalus occur inconsistently in septo-optic dysplasia. One cerebellar lesion, called rhombencephalosynapsis is aplasia of the vermis and midline fusion of the cerebellar hemispheres and of the dentate nuclei, probably the downrcgulation of a dorsalizing gene at the level of rhombomere 1 (Samat 2000). Clinical manifestations relate mainly to the endocrine deficiencies and vision impairment. Ataxia may be compensated if the cerebellar vermis is mildly involved. Seizures are uncommon. Intellectual development usually is normal. Hypertelorism is nor a constant finding. Chromosomes are invariably normal. The gene HESX1 is defective in at least some cases (Dattani et al. 1998). Familial cases are not reported. There is, however, a high incidence of teenage pregnancy and drug abuse in early gestation in mothers of affected infants. Septo-optic-pituitary dysplasia has been described in an infant of a diabetic mother. Rbmnbmneiic Deletions and Ectopic Genetic
Expression
Rare patients with absence of certain parts of the brain have long been known, but only recently, with the understanding of the families of genes responsible for neural tube segmentation (e.g., HOX, WNT, PAX), have these medical curiosities been understood at the level of molecular embryology. Agenesis of the midbrain and upper pons (metencephalon) with cerebellar hypoplasia is attributed to the FN2 gene, which produces an almost identical malformation in the knockout mouse model (Sarnat ct al. 2002). EN1 and WNT1 genes also are essential for development of the mesencephalic and rhombomere 1, but the annual models of these genetic defects produce rotal agenesis of the cerebellum. Absence of the corpus striatum might be due to mutation of the EMX1 gene, which is essential in the programming of the basal telencephalon but not the cerebral cortex (Sarnat and Flores-Sarnat 2001a). The Chiari malformations, particularly type II, are traditionally but incompletely explained by mechanical theories of pathogenesis, but a molecular genetic hypothesis of ectopic expression provides a more complete and reasonable explanation (see following; Sarnat and
Flores-Sarnat 2001). Whereas many of these genetic malformations are well demonstrated in experimental animal models, none are yet definitively confirmed in humans. Agenesis of the Corpus Callosum A commissural plate differentiates within the lamina terminalis at day 39 of embryonic life. The plate acts as a bridge for axonal passage and provides a preformed glial pathway to guide decussating growth cones of commissural axons. The inter hemispheric projection of the first axons is preceded by microcystis- degeneration m the commissural plate and physiological death of astrocytes. The earliest callosal axons appear at 74 days in the human embryo, the genu and the splenium are recognized at 84 days, and the adult morphology is achieved by 115 days. The pathogenesis of callosal agenesis is related to two aspects of the commissural plate. If this plate is not available to guide axons across, the corpus callosum does not develop. However, failure of physiological degeneration of a portion of the plate results in a glial barrier to axonat passage, and primordial callosal fibers are deflected posteriorly to some other destination within their hemisphere of origin (bundle of Probst) or disappear. Agenesis of rhe corpus callosum is a common malformation, having a 2..'!% prevalence m computed tomographic (CT) scans in North America and 7 - 9 % prevalence in Japan. Most cases are isolated malformations, hut callosal agenesis is an additional feature of many other prosencephala dysplasias; it also occurs with aplasia of the cerebellar vermis and anomalous pyramidal tract. Simple callosal agenesis may involve the entire commissure or may be partial, usually affecting only the posterior fibers. Hypoplasia or partial agenesis of the commissure is much more common than total agenesis. In callosal agenesis, the anterior and hippocampal commissures are always well formed or large. A rare genetic form of callosal agenesis is associated with defective neural crest migration causing aganghonic megacolon (Hirschsprung's disease) is due to a defective human gene, Smad-interacting protein-1 (SMAD1), at the chromosome 2q22-q23 locus (Cachcux ct al. 2001). In the absence of a corpus callosum, the lateral ventricles are displaced laterally and the third ventricle rises between them (Figure 66.10). The ventricles also are often mildly dilated, but intraventricular pressure is normal. The anomaly may be demonstrated by most imaging techniques. The varying degrees of partial callosal agenesis produce several radiographic variants, Clinical symptoms of callosal agenesis may be minimal and unrecognized in children of normal intelligence, although detailed neurological examination discloses deficits in the intcrhemispheric transfer of perceptual information for verbal expression. Mental retardation or learning disabilities arc found in some cases. Epilepsy is common, particularly in patients who are diagnosed early in life.
DEVELOPMENTAL DISORDERS OF THE NERVOUS SYSTEM
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myoclonic epilepsy. This disorder is found almost exclusively in girls and is thought to be X-linked dominant (chromosomal locus is Xp22) and generally lethal in the male fetus. The EEG shows a typical asymmetrical and asynchronous burst-suppression pattern. Neuropathologies! findings in Aicardi's syndrome include a variety of minor dysplasias in addition to agenesis of the corpus callosum and anterior commissure and nonlaminated polymicrogyric cortex with abnormally oriented neurons. I inllosal agenesis is a common compouail m main . limnm somal disorders, particularly trisomies 8, 1 1 , and 13. Lipoma replacing part of the corpus callosum is associated with a high incidence of epilepsy. Colpocephaly Colpocephaly is a selective dilatation of the occipital horns, not due to increased intraventricular pressure but rather due to loss of white matter. Three conditions may cause colpocephaly: (1) it may appear as a primary malformation, histologically associated with poorly laminated striate cortex, subcortical heterotopia, and defective ependymn lining the occipital horns; (2) it is common in many cases of agenesis of the corpus callosum because of absence of the splenium and hypoplasia of white matter; and (3) it may be the acquired result of periventricular leukomalacia, especially in premature infants, because of loss of periventricular white matter in the posterior half of the cerebral hemispheres. FIGURE 66.10 Pneumoencephalogram, from the pre-imaging period, of an lH-month-old boy with agenesis of the corpus callosum associated with an inter hemispheric arachnoidal cyst, a complication of some cases of callosal agenesis. The lateral ventricles are widely separated from the medial side of each hemisphere by the bundle of Probst; the third ventricle rises between them. The brainstem, cerebellum, and cerebral cortical convolutions appear normal. The patient has mental retardation and epilepsy.
Seizures may relate more to minor focal cortical dysplasias than to the callosal agenesis itself. Hypertelorism is present in many but not all cases and often is associated with exotropia and inability to converge. The EEG characteristically shows interhemispheric asynchrony or poor organization, with or without multifocal spikes, but is not specific enough to establish the diagnosis. Asynchronous sleep spindles after 18 mouths of age arc a good clue. Several hereditary forms of callosal agenesis are described besides its occurrence as an additional anomaly in some cases of tuberous sclerosis and various genetic syndromes. An autosomal recessive syndrome of callosal agenesis, mental deficiency, and peripheral neuropathy is known as Andermann's syndrome. Aicardt's syndrome consists of.agenesis of the corpus callosum, chorioretinal lacunae, vertebral anomalies, mental retardation, and
Clinical findings are usually those of mental retardation, spastic diplegia, epilepsy, and vision loss, but it does not always cause complete blindness. Most cases have been demonstrated by CT in the neonatal period or early infancy. Isotope cisternography shows normal CSF dynamics in most cases. Colpocephaly is associated with a number of syndromes and systemic disorders, including cerebrohepato-renal (Zellweger) disease, hemimcgalcnccphaly, and several chromosomal disorders. The EEG in colpocephaly ranges from normal in mild cases to near-hypsarrhythmia in infants who develop myoclonic epilepsy. Bilateral posterior slowing of low voltage with occipital spikes is common. Colpocephaly also develops late in fetal life because of infarction and cystic degeneration of the deep white matter of the posterior third of the cerebral hemispheres, rather than as a developmental disorder of neuroblast migration. It should not be confused with hydrocephalus.
Disorders of Early Neuroblast Migration (8-20 Weeks' Gestation) Lissencephaly
(Agyria)
Lisscncephaly is a failure of development of convolutions in the cerebral cortex because of defective neuroblast
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IMKLKOLOGICAI. DISEASES
migration. The cortex remains smooth, as in the embryonic brain (see Figure 66.8). The migrations of the cerebellum and the brainstem also are usually involved, but the embryonic corpus gangliothalamicus pathway is not distutbed, so the thalamus and basal ganglia are well formed. Structural and metabolic abnormalities of the fetal ependyma may be important factors in disturbing the normal development of radial glial cells. The cytoarchitecture of the neocortex in lissencephaly takes one of two forms. In the first, a four-layered sequence develops. The outermost layer is a widened molecular zone; layer 2 contains neurons corresponding to those of normal laminae III, V, and VI; layer 3 is cell-sparse; and layer 4 contains heterotopic neurons that have migrated incompletely. Decreased brain size leads to microcephaly, with widened ventricles representing a fetal stage rather than pressure hydrocephalus and an uncovered sylvian fossa representing a lack of opcrculation. The second form of
cortical architectural abnormality- in lissencephaly is disorganized clusters of neurons with haphazard orientation, forming no definite layers or predictable pattern. Type 2 lissencephaly is associated with several closely related genetic syndromes: Walker-Warburg syndrome, Fukuyama muscular dystrophy, muscle-eye-brain disease of Santavuori, and Meckcl-Gruber syndrome. Encephalocele may be associated with some cases of lissencephaly (see Figure 66.8}. Miller-Dieker Syndrome (Type 1
Lissencephaly)
Miller-Dieker syndrome is a familial lissencephaly characterized clinically by microcephaly and a peculiar facics that includes micrognathia, high forehead, thin upper lip, short nose with antevcrtcd nares, and low-set ears (Figure 66.11). Neurologically, the children are developmentally delayed in infancy and mentally retarded, lack normal
FIGURE 66.11 (A) This 7-month-old boy has Miller-Dieker syndrome. He has unusual postures of the extremities and opisthotonus, which are not seen in all patients with this genetic disorder. Note the gastrostomy that he required. (B] He has the typical facies of this genetic syndrome, with a high brow, upturned nares, and long phiitrum (upper lip). His gaze is dysconjugate, but there is no paresis of extraocular muscles. (C) Sagittal and (D) parasagittal views of Tl-weightcd magnetic resonance images, showing type I lissencephaly with only mild ventriculomegaly. The cerebellum and brainstem, including the basis pontis, are grossly well formed. The corpus callosum is very thin. Kxtra-fixial (i.e., subarachnoid) spaces are wide over rhe convexities of the cerebral hemispheres and in the cisterns surrounding the brainstem.
DEVELOPMENTAL DISORDERS OF THE NERVOUS SYSTEM responsiveness to stimuli, initially exhibit muscular hypotonia that later evolves into spasticity and opisthotonos, and develop intractable seizures. Death before 1 year of age is common. The EEC often shows focal or multifocal spikewave discharges that later become bisynchronous bursts of diffuse paroxysmal activity and extremely high-voltage diffuse rhythmic theta and beta activity. At autopsy, the original cases showed lack of gyral development in the cerebral cortex, but later patients were found with the typical craniofacial features and clinical course but with gyral development, although the convolution-. were almoin:,il ;.rij pachygyria predominated. I he term Miller-Dieker syndrome was proposed to distinguish this syndrome from other cases of lissenccphaly without the clinical and dysmorphic facial features. A microdcletion at the chromosome 17pl3.3 locus is demonstrated by highrcsolution studies in most patients with Miller-Dieker syndrome, and family members of the original patients also show the defect (Chong et al. 1997). The responsible gene is LIS1. Histological examination of the brain in Miller-Dieker syndrome confirms the presence of a severe disorder of neuroblast migration, as in other cases of lissencephaly. Walker-Warburg and Related (Type 2 Lissencephaly)
Syndromes
Type 2 lissencephaly/pachygyria includes several distinctive disorders of different genetic origin, but all of which involve the terminal organization and architecture of the cortical plate and most of which include a dystrophic myopathy. In Fukuyama muscular dystrophy, a congenital muscular dystrophy is associated with cerebral dysgenesis of this type, due to mutation in the gene Fukutin. Though common in Japan, where it is the second most common muscular dystrophy (after Duchenne type dystrophy), it is rare in othet ethnic populations. The muscle-eyc-brain disease of Santavuori is most common in Finland, but also exists in other northern European ethnic groups. WalkerWarburg is another congenital muscular dystrophy found in diverse ethnic groups. An autosomal recessive type 2 lissencephaly associated with cerebellar hypoplasia is due to defective expression of Reel in, and X-l inked congenital hydrocephalus (usually due to aqueductal atresia) is associated with pachygyria and mutation of the cell adhesion gene L1CAM.
Subcortical Laminar Heterotopia (Band Heterotopia, Double Cortex) and Bilateral Periventricular Nodular Heterotopia Subcortical laminar heterotopia and bilateral periventricular nodular heterotopia both result from X-l inked recessive traits that occur almost exclusively in females. Both disorders present clinically as severe seizure disorders in childhood, although they arc often associated also with
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mental retardation and other neurological deficits. In subcortical laminar heterotopia, a band of gray matter heterotopia within the subcortical white matter lies parallel to the overlying cerebral cortex but separated from it by white matter. Histologically, it is not laminated, as is the normal cortex, and consists of disoriented neurons and glial cells and fibers with poorly organized architecture. The few male fetuses that have not spontaneously aborted have been born with lissencephaly in addition and even more severe neurological deficits. The defective gene and its transcription product in subcortical laminar heterotopia have been identified; the latter is called dotiblecortin ((ileeson et al. 1999). In bilateral periventricular nodular heterotopia, islands of neurons and glial cells occur in the subependymal regions around the lateral ventricles and are neuroepithelial cells that have matured in their site of origin without migrating (Eksioglu et al. 1996). The gene responsible is Filamin-1. Both conditions are best demonstrated by MRI, but also are detected by CT, Scbizencephaly Deep or shallow clefts in the region of the Sylvian fissure, with open or closed lips, is a configuration termed scbizencephaly. Schizencephaly is associated with defective expression of the gene EMX2 (Granata et al. 1997). It may be associated with a variable degree of lissencephaly/ pachygyria and may be bilaterally symmetrical or asymmerrical, more severe on one side or even unilateral. llemtm egalen cephaly This is one of the most enigmatic cerebral malformations because it is a severe dysgenesis limited to one cerebral hemisphere or, less commonly, includes the ipsilatcral cerebellar hemisphere and brainstem ("total hemimegalencephaly"). Though traditionally regarded as another disorder of neuroblast migration, this feature is probably only secondary to involvement of radial glial cells and perhaps the neuroblasts themselves, and the primary process is a disturbance of cellular lineage and also involvement of genes of symmetry expressed as early as gastrulation (Flores-Sarnat 2002a; Elores-Sarnat et al. 2003). Individual neural cells exhibit both glial and neuronal proteins and have abnormal growth and morphology. Some cases of hem lm egalen cephaly are isolated malformations, but others are syndromic, particularly associated with epidermal nevus syndrome, Proteus syndrome and Klippel-Trenaunay-Wcber syndrome. Clinical features and neuropathological findings are virtually identical in isolated and syndromic forms. The principal clinical manifestation is severe partial epilepsy, often refractory to medical treatment and abolished only by hcmisphcrcctomy or other surgical resections. Other less constant features include variable mental retardation and contralateral motor deficit. Mild as well as severe forms
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NEUROLOGICAL DISF.ASF.S
occur. Syndromic forms additionally include the features of the particular syndrome, such as lipoma formation in the ipsilatcral face in epidermal nevus syndrome.
Disturbances of Late Neuroblast Migration (after 20 Weeks' Gestation) Although major neuronal migrations in the developing human brain occur in the first half of gestation, late migrations of immature nerve cells continue. A few neuronal precursors continue to migrate to the cerebral cortex after 20 weeks' gestation. Perinatal disorders of cerebral perfusion, small intraparenchymal hemorrhages in premature infants, intracranial infections, and hydrocephalus are examples of common perinatal complications that may interfere with the late neuronal migrations, either by destroying migrating neuroblasts or by disrupting their radial glial fiber guides. Reactive gliosis is detected as early as 20 weeks' gestation in the fetal brain, and proliferation of astrocytes is already evident 4 days after an insult. Neurons may be blocked from traversing a gliotie plaque.
Disorders of Cerebellar Development (32 Days' Gestation to 1 Year Postnatally) The cerebellum has the longest period of cmbryological development of any major structure of the brain. Neuroblast differentiation in the cerebellar plates (rhombic lips of His) of the dorsolateral future medulla oblongata and lateral recesses of the future fourth ventricle are recognized at 32 days. Neuroblast migration from the external granular layer is nol complete until 1 year postnatally. As a result of this extended ontogenesis, the cerebellum is vulnerable to teratogenic insults longer than arc most parts of the nervous system. Malformations of the cerebellum may be focal, confined to the cerebellum, or associated with other brainstem or cerebral dysplasias. The cerebellar cortex is especially susceptible to toxic effects of many drugs, chemicals, viral infections, and ischemic-hypoxic insults.
Selective
Cerebellar Hemispheric Aplasia
Selective agenesis of the cerebellar hemispheres is much less common than aplasia of the vermis alone. Other components of the cerebellar system, such as the dentate and inferior olivary nuclei, may also be dysplastic. The lateral hemispheres and the inferior olivary and pontine nuclei more commonly arc selectively involved in certain degenerative diseases of genetic origin, such as olivopontocerebellar alropin and nllli-i spirincciYJvllar' degenerations. Dandy-Walker
Malformation
The Dandy-Walker malformation consists of a ballooning of the posterior half of the fourth ventricle, often but not always associated with nonopening of the foramen of Magcndie. In addition, the posterior cerebellar vermis is aplastic, and there may be heterotopia of the inferior olivary nuclei, pachygyria of the cerebral cortex, and other cerebral and sometimes visceral anomalies. Hydrocephalus from obstruction almost always develops, but if it is treated promptly, the prognosis may be good. Neurological handicaps, such as spastic diplegia and mental retardation, probably relate more to the associated malformations of the brain than to the hydrocephalus. Chiari
Malformations
Selective Vermal Aplasia
The Chiari malformation is a displacement of the tonsils and posterior vermis of the cerebellum through the foramen magnum, compressing the spinomedullary junction. This simple form is termed Chiari type I malformation. Type II involves an additional downward displacement of a distorted lower medulla and dysplasia of medullary nuclei and is a constant feature of lumbosacral meningomyelocele. Chiari type III malformation is actually a cervical spina bifida with cerebellar encephalocele. Chiari originally identified a type IV in 1896, but this type is now recognized as cerebellar hypoplasia having no relation to the other types, and the term Chiari malformation type IV should now be used only in its historical context. Hydrocephalus is commonly associated with Chiari malformations.
Selective hypoplasia or aplasia of the vermis, with intact lateral hemispheres, occurs in some genetic disorders, in association with other midline defects involving the forebrain, as in some cases of hoioprosencephaly and of callosal agenesis. A specific autosomal recessive disease, Joubert's syndrome, is characterized clinically by episodic hyperpnea, abnormal eye movements, ataxia, and mental retardation and has a variable but often progressively worsening course, with improvement in some cases. Anomalies of visceral organs and Polydactyly may be associated.
The pathogenesis has been a matter of controversy for many years. Mechanical theories have dominated since the time of Chiari: (1) the traction theory, a result of a tethered spinal cord with traction as the vertebral column grows; (2) the pulsion theory of fetal hydrocephalus pushing the cerebellum and brainstem from above; and (3} the crowding theory in which a small posterior fossa provides insufficient room for the growth of neural structures and causes a "toothpaste tube effect." The torcula is indeed too low and the volume of the posterior fossa small, so that this latter explanation is probably a true contributory factor, but only in late gestation as a superimposed secondary
DEVELOPMENTAL DISORDERS OF THE NERVOUS SYSTEM
1 787
FIGURE 66.12 Cerebellar cortex of infant with cerebellar hypoplasia shows extensive gliosis and loss of ill neuronal elements. This histological appearance resembles that of cerebellar sclerosis secondary to acquired injury, but in the latter condition there arc usually a few neurons still surviving. Some cases of cerebellar hypoplasia show selective loss of granule cells and preservation of l'urkinje's cells. (Hcmatoxylin-eosin stain. liar = 100 urn.)
influence. A molecular generic hypothesis of ectopic expression of a segmentation gene in the rhombomcrcs explains not only the Chiari malformation, but also the brainstem anomalies, the myelodysplasia, and the defective basioccipital and suptaoccipital bone formation that tcsults in a too small posterior fossa (Sarnat 2001a, 2003). Global Cerebellar Hypoplasia Global cerebellar hypoplasia has diverse causes, which include chromosomal and genetically detennincd diseases, Tay-Sachs disease, Menkes' kinky hait disease, some cases
of spinal muscular atrophy, and sporadic cases of unknown cause. Histologically, there may be a selective depiction of granule cells or a loss of Purkinje cells and other neuronal elements in addition to granule cells (Figure 66.12). In selective granule cell depletion, the axons and dendtites of Purkinje cells are deformed. Clinically, the most constant features of cerebellar hypoplasia in infancy are developmental delay and generalized muscular hypotonia. Truncal titubation and ataxia become evident after several months, and nystagmus and intention tremor may appear in severe cases. Tendon stretch reflexes usually are diminished but may be FIGURE 66.13 Focal dysplasia of cerebellar eorrcx. The normal laminar architecture is disrupted, and •IMI'IIK- .liul I'uikinjf cells show .L haphazard orientation and array. Some granule ceils arc spindle shaped, resembling the shape assumed during transit from the external granular layer in normal development. This dysplasia is due to faulty neuronal migration and probably occurred at midgestation. (Hematoxylin-eosin stain. Rar= 15 urn.)
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NEUROLOGICAL DISEASES
hyperactive if corticospinal tract deficit also is present because of cerebral involvement. Focal
Cerebellar
Dysplasias
Focal dysplasias a n d h a m a r t o m a s of t h e cerebellar cortex (Figure 66.13} are often incidental findings at a u t o p s y a n d are often clinically a s y m p t o m a t i c . M o r e extensive lesions present a b n o r m a l cerebellar findings clinically. These small focal m a l f o r m a t i o n s are a disorder of n e u r o n a l migration that m a y be p r o g r a m m e d as genetic defects or, m o r e c o m m o n l y , acquired from brief insults d u r i n g the long period of cerebellar development. Focal ischemic insults and exposure to cytotoxic d r u g s or viruses a r e a m o n g the more c o m m o n causes. T h e granule cells of t h e cerebellar cortex retain a regenerative capacity lost early in gestation by most other n e u r o n s , b u t the regenetative p a t t e r n of lamination in the cerebellar cortex may be imperfect. Craniosynostosis T h e development of the c r a n i u m and sutures is n o w recognized as closely related to neuromeric f o r m a t i o n in the neural tube. M o r e t h a n 100 s y n d r o m e s t h a t include a c o m p o n e n t of craniosynostosis have been identified. Several have a genetic basis, including the s y n d r o m e s of Apert, C r o u z o n , Pfeiffer, a n d Saethre-Chotzen; these a r e related to fibroblast g r o w t h factor receptor defects a n d , in some, specific causative genes such as T W I S T a r e recognized (Flores-Sarnat 2 0 0 2 b ) . T h e genetic basis of t h e mure coniiiuin isolated craniostenoses "1 the coronal and sagittal sutures are not yet k n o w n . O n c e t h o u g h t to be only a cosmetic defect, it is n o w k n o w n that neurological impairment may result in untreated cases. Advances in imaging have e n h a n c e d both p r e n a t a l a n d postnatal diagnosis, and parallel a d v a n c e s in craniofacial surgery makes treatment m o r e effective from both a neurological and cosmetic perspective. T r u e craniosynostosis m u s t be distinguished from positional deformities of the head resulting from a b n o r m a l prenatal compression by the maternal pelvis and postnatal effects of head p o s i t i o n , particularly in p r e m a t u r e infants.
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DEVELOPMENTAL DISORDERS OF THE NERVOUS SYSTEM \1.in:i : .mil, '[.. ov." !'1 .M, S. I . 2001, ''< racking tilt transcriptional code for cell specification in the neural tube," Cell, vol. 106, pp. 1-20 Mione, M. C, Cavanagli, J. F. R., Harris, B., & Parnavelas, J. G. 1997, "Cell fate specification and symmetrical/asymmetrical divisions in the developing cerebral cortex,"/ Neurosci, vol. 17, pp. 2018-2029 Plawner, L. L, Delgado, M. R., Miller, V. S., et al, 2002, "Neuroanatomy of holoprosenccphaly as predictor of function: beyond the face predicting the brain," Neurology, vol, 59, pp. 1058-1066 Rakic, P. 1995, "Radial versus tangential migration of neuronal clones in the developing cerebral cortex," Proc Natl Acad Sci USA, vol. 92, pp. 11323-11327 Rho, J, M„ & Storey, T. W, 2001, "Molecular ontogeny of major neurotransmitter receptor systems in the mammalian central nervous system: N o r e p i n e p h r i n e , dopamine, serotonin. acetylcholine and glycine," / Child Neurol. vol. 1(>, pp. 271-281 Rocsslcr, E., Belloni, E., Gaudenz, K., et al. 1996, "Mutations in the human Sonic hedgehog gene cause hoioprosencephaly," Nat Genet, vol. 14, pp. 357-360 Roy, N., Mahadevan, N., McLean, M., et al., 199.5, "The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy," Cell, vol, 80, pp. 167-178 Sarnat, H. B. 1992, "Regional differentiation of the human fetal ependyma: immunocytochemical m a r k e r s , " / Neuropathol Exp Neurol, vol. 5 1 , pp. 58-75 Samat, H. B. 2000, "Molecular genetic classification of central nervous system malformations," / Child Neurol, vol. 15, pp. 675-687 Sarnat, H. B. 2003, "Regional ependyma) upregulation of vimentin in Chi an 11 malformation, aqueducta! stenosis and hydromyelia," Pediatr Deuel Pathol, vol. 6, in press Sarnat, H. B., Benjamin, D. R., Siebert, J. R., et al. 2002, "Agenesis of the mesencephalon and mettnetphalou wirh cerebellar hypoplasia: Putative mutarion in the t \2 gene. Report of 2 cases in early infancy," Ped Dev Pathol, vol. 5, pp. 54-68
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Sarnat, H. B., Born, D. E. 1999, "Synaptophysin immunocytochemistry with thermal intensification: A marker of terminal axonal maturation in the human fetal nervous system," Brain Dev, vol. 2 1 , pp. 41-50 Samat, H. B., &C Flores-Sarnat, L. 2001a, "Neuropathologies! research strategics in holoprosencephaly," / Child Neurol, vol. 16, pp. 918-931 Sarnat, H. B., & Flores-Sarnat, L. 2001b, "A new classification of malformations of the nervous system: An integration of motphological and molecular genetic criteria as patterns of genetic expression," Eur } Paed Neurol, vol. 5, pp. 57-64 Satnat, H. B., & Flo res-Samat, L. 2002, "Cajal-Retzius and suhplate neurons: Their role in cortical development," Eur J Paed Neurol, vol. 6, pp. 91-97 Sarnat, H, B., & Menkes, J. H. 2000, " H o w to construct a neural tube," / Child Neurol, vol. 15, pp. 110-124 Schuldiner, M., Eiges, R,, Eden, A. et al., 2001, "Induced neuronal differentiation of human embryonic stem cells," Brain Rc$, vol. 913, pp. 201-205 Simeone, A. 2002, "Towards the comprehension of genetic mechanisms controlling brain morphogenesis," Tr Neurosci, vol. 25, pp. 119-121 Simeone, T. A., Donevan, S. D., & Rho, J. M. 2003, "Molecular biology and ontogeny of GABAA and GABAB receptors in the mammalian central nervous system," / Child Neurol, vol. 18, pp. 39-48 Simon, E. M., Hevner, R. F„ Pinter, J. D., et al. 2002, "The middle inierhcmispherie variant of holoprosencephaly," Am J Neuroradsoi, vol. 2 3 , pp. 151-156 Taylor, H. S., Block, K., Bick, D. P., et al. 1999, "Mutation analysis of the EMX2 gene in Kallmann's syndrome," Fertil Steril, vol. 72, pp. 910-914 Thomas, L. B., Gates, M. A., & Steindler, D. A. 1996, "Young neurons from the adult subependymal zone proliferate and migrate along an astrocyte, extracellular matrix-rich pathway," Glia, vol. 17, pp. 1-14 Zheng, C, Heintz, N., & Harten, M. E. 1996, "CNS gene encoding astrotactin, which supports neuronal migration along glial fibers," Science, vol. 272, pp. 417-419
Chapter 67 Developmental Disabilities Ruth Nass Cerebral Palsy Diagnosis Etiology Treatment Mental Retardation Treatment Autistic Spectrum Disorders Diagnosis Specific Clinical Features Evaluation and Etiology Treatment Learning Disabilities Dyslexia Nonverbal Learning Disabilities
1791 1791 1791 1792 [792 1794 1794 1794 1795 1796 1797 1797 1797 1799
CEREBRAL PALSY Diagnosis Cerebral palsy (CP) is a static encephalopathy of prenatal or perinatal origin that affects motor function and tone. Spasticity, hypotonia, ataxia, and/or dyskinesias are the possible motor outcomes. A history of delayed motor milestones and the clinical features are the basis of diagnosis. CP occurs in approximately 2 per 1000 children. Low birth weight/pre term infants currently comprise more than 5 0 % of children with CP. The prevalence is about 60 per 1000 among children weighing less than 1000 grams at birth. In a population-based study of births in the 1990s, the types of CP encountered were hemiplegia (33%), diplegic (44%), quadriplegic (6%), dyskinetic (12%), and ataxic (4%) syndtomes. Diplegic CP is the most common type in the preterm infant. Children with CP may or may not have intellectual problems, and seizures are a concurrent problem in about 4 0 % . The likelihood of each is directly proportional to the severity of the motor impairment and the degree of brain damage.
Etiology The National Perinatal Collaborative Project monitoring more than 50,000 pregnancies documented the following important risk factors among the 200 children with CP; maternal mental retardation (MR), birth weight less than
Developmental Disorders of Motor Function Visuospatial Disabilities Dyscalculia Attention Deficit Hyperactivity Disorder (ADHD) Developmental Language Disorders Subtypes of Developmental Language Disorders Articulation and Kxpressivc Fluency Disorders Disorders of Receptive and Expressive Language Higher Order Language Disorders Ncurobiological liasis t'l I >cvi.lupincir..il Language Disotders Outcome of Developmental Language Disorders Remediation
1800 1801 1801 1802 1803 1804 1804 1805 1806 1806 1807 1808
2000 grams, a malformation of any organ system, and breech presentation or delivery. Commonly used signs of perinatal hypoxic ischemic insults, such as an abnormal fetal heart rate, the presence of meconium, and low Apgar scores, did not predict CP and were relatively common in infants who were ultimately normal. Even when the Apgar score is low, the risk of CP appears to be minimal unless the infant continues to have neurological problems (e.g., lethargy, hypotonia, poor suck, seizures) in the newbotn nursery. Moreover, almost 95% of infants with 5-minute Apgar scores of 3 do not have CP. In a population-based study of births in the early 1990s (Hagberg et al. 2001), the etiology of CP was established in 7 5 % of preterm newborns and in about 8 5 % of term infants. Most were due to perinatal problems. Among term babies with a known etiology of the CP, half were prenatal and half were perinatal. In addition to intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) in premature infants and perinatal hypoxic ischemic encephalopathy (HIE) in term newborns, documented causes of CP include brain malformations, small size for gestational age, congenital infections, maternal infection during pregnancy and labor, and genetic and metabolic disorders. Twin gestation is a risk factor, and a vanishing twin is a proven risk factor for CP in the survivor. Although most metabolic and genetic disorders ultimately cause progressive disability, some may be static for years and have a phenotype that suggests CP. Atypical features of CP and a history of other affected family members should indicate the need for further evaluation. Genetic disorders are the most common
1791
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NEUROLOGICAL DISEASES
cause of "ataxic CP syndromes." Dopamine-responsive
MENTAL RETARDATION
dystonia, .111 r.ir-,:l\ diagnosed arid :i\-;.ik'd disorder, mimics
CP. Other genetic or metabolic disorders that potentially mimic CP include metachromatic leukodystrophy, Krabbe's disease (spastic diplegia CP), Lesch-Nyhan syndrome, glutarie aciduria 1 (dyskinetic CP), ataxia telangiectasia, Leigh disease, and subacute sclerosing panencephalitis (ataxic CP). Brain imaging is extremely useful in determining the etiology and prognosis of cerebral palsy. Brain malformations are relatively common in term infants with CP, whereas PVL is the most common cause of CP in preterm infants (Barkovich 2002). PVL is associated with even more severe disability in term-born children (Krageloh-Mann et al. 1999). HIE is associated with bilateral cerebral infarctions, whereas most unilateral infarctions arc prenatal, not perinatal, in origin (Volpe 2000). Ultrasound abnormalities are different in preterm newborns that develop disabling rather than nondisabling CP (Paneth 2001). Hypothyroidism of prematurity has twice the risk of echolucencies on ultrasound as compared to euthyroid newborns and has an increased risk of cerebral palsy (Leviton et al. 1999). Recent outcome studies of children and adolescents born prematurely suggest a correlation between the presence of magnetic resonance imaging (MRI) abnormalities and greater cognitive difficulties (Rushe et al. 2001). A reduction in cortical and cerebellar volumes among newborns with CP may result from enhanced apoptosis or excitotoxic damage to highly susceptible immature neurons (Bhurta and Anand 2001).
Treatment The prevention of prematurity, respiratory management of preterm infants during the perinatal period, and the development of neuroprotective agents is the focus of CP prevention. Cesarean section and rapid initiation of supportive care may decrease the frequency of CP in the preterm newborn. Most IVH occurs within the first 6 hours after birth and possibly during labor and delivery. Infections during pregnancy as well as chorioamnionitis at delivery appear to be risk factors for CP. Elevated cytokines are the presumed agent toxic to the brain (Gilstrap and Ramin 2000). Rehabilitative therapy influences outcome. The main goals of treatment are to improve motor function and to modify the environment to improve mobility. Orthopedic surgery is sometimes required. Dorsal rhizotomy has been used to decrease spasticity and improve gait or make children who are wheelchair-confined more comfortable. Botulinum toxin has had an important role in the treatment of spasticity. The factors that shorten life expectancy are immobility, profound retardation, and feeding difficulty (Hutton et al. 2000). Children with CP may otherwise live well into adulthood.
Mental retardation (MR) is not an absolute condition, but a construct that assists in educational planning and determining activities of daily living needs. The diagnosis therefore requires both low 1Q (less than 70) and difficulties in at least two areas of adaptive functioning: communication, self-care, home living, social skills, community use, self-direction, health and safety, functional academics, leisure, and work. The definition of mental retardation (American Association of Mental Retardation) links degree of severity to the degree of community support required to achieve optimal independence. In this context, mild retardation means intermittent support, moderate retardation indicates limited support, severe retardation indicates extensive support, and profound retardation indicates pervasive support. When IQ defines mental retardation, 100 is the mean and 15 is the standard deviation. Subdivided by severity, an 10 55-70 is mild, an IQ of 40-55 is moderate, an IQ of 25—40 is severe, and below 25 is profound. A significant variability exists in the level of functioning among children with an IQ around 70; about half require special education and half attend regular school. Those in special schools are more likely to have a personal or family history of language delay. Such differences in functional level of children with the same IQ highlight the need to examine the specific cognitive profile of those with MR (Table 67.1). In industrialized countries, the prevalence of MR is 1-3%. Mild MR represents the majority (75%). In general, individuals with severe retardation are more likely to have a definable biological cause, whereas those with mild retardation tend to come from socially disadvantaged backgrounds and often have a family history of borderline IQ or mild retardation (Opitz 2000; Stromme and Magnus 2000). Recent genetic studies demonstrate submicroscopic deletions in the subtclomcric chromosomal regions in about 3.5% of previously undiagnosed cases of MR (Leonard and Wen 2002). Environmental factors play a role. For example, smoking during pregnancy is associated with more than a 5 0 % increase in the prevalence of MR. The risk of recurrence of severe MR is 3 - 1 0 % and of mild MR is 5-40%. The diagnosis of MR is more common in hoys than in girls (1.4:1). Male excess is present m those with autism, those with undiagnosed nonsyndromic mental retardation, and those with X-linked monogenic disorders. X-linkcd inheritance is responsible for more than 150 known mental retardation syndromes (Partington et al. 2000). Within the last 5 years specific X-linkcd gene abnormalities have been identified in 15 syndromes causing severe MR and in eight causing moderate MR (Leonard and Wen 2002), Fragile X syndrome has been considered the most frequent known X-linked disorder among the moderately handicapped and has been thought to occur with even greater frequency in mild MR. The prevalence of nonspecific (genetic etiology
Table 67.1: Psycho pathology and behavioral problems associated with genetically defined mental retardation syndromes
1Q
I WlglUZt!
Spatial skills
Executive
Social skills
Down trisomy 21
Range 30-70, usually moderate, dementia in adulthood
Commensurate with 1Q
Perseverative impulsive
Relative strengt reported
Williams deletion 7qll
Mild-moderate
Good vocabulary and conversation, weaker grammar, impaired verbal short-term m; trior y Expressive language and conversation a strength, loquacious
Inattentive, distractible,
Social perceptio emotional ex cognition im overly social
Prader-Willi deletion 15qllql3 Fragile X males
Mean 70, range profound MR to average
Oromotor dysfunction
Weak visuospatial 6c global processing, face recognition spared, visuospatial short-term memory deficit Visuospatial strength, jigsaw puzzles a special interest
Moderate to severe, decline after puberty, fully methylated patients more decline
Poor articulation, cluttering, verbal dyspraxia, weak word finding, pragmatics and conversational skills
Fragile X females VCF 22qll haploinsuffkiency (reduced gene dosage)
Normal to mi Id to moderate Borderline to mild
Generally intact Speak in single words despite their ability to converse, but verbal skills stronger than nonverbal
MlilHriMM.lllt
Obsessive
Internalizing an problems ca social functi
Sporadic weakness of visuomotor skills
Weak attention planning, shifting sets
Strength in ada until puberty recognition autistic featu
Nonverbal memory problems Impairments in visuoperceptual ability, NVLD
Relatively weak, ADHD Weak problem solving, planning, abstraction, ADHD
Very shy, anxi Poor social int prevalence o bipolar diso
VCFS = velocardiofacial syndrome; NVI.D = nonverbal learning disability; PWS = Prader-Willi syndrome; ADHD = attention de Modified from Nass and Ross, in press; Burack et al. 1998; Dykens 2000; Tager-Flusberg 1999; Howlin and Udwin 2002.
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NEUROLOGICAL DISEASES
as yet unknown) X-linked MR (XLMR) (2.5/10,000), however, is three times greater. But diagnosis may be difficult because most males with XLMR have no specifiable phcnorypical, neurological, or biochemical features as yet identified. Advances in genetic technology will clearly change this. Several iH'in-f)l(i;n'ail and neuropsyehianic problems M'v associated with MR. Epidemiological studies (Airaksinen et al. 2000) suggest that one fifth of children with MR are epileptic by 10 years of age. The probability of developing epilepsy is fivefold higher in severely MR children (35%) than in children with mild MR (7%). Cerebral palsy is a concurrent disorder in 6 - 8 % of the mildly retarded and in MV'A, of the severely retarded. Blindness or deafness occurs in 2% of the mildly retarded and 1 1 % of the severely retarded. An increased prevalence of psychopathology and maladaptive behavior occurs in children with MR, and almost 4 0 % have a psychiatric disorder (Stromme and Disedi 2000). The most common diagnoses are hyperactivity and autistic spectrum disorders. Overall, autistic features are reported in 9 - 1 5 % of the mildly retarded and 12-20% of the severely retarded. Table 67.1 details specific psychopathology and behavioral problems in several genetically defined MR syndromes.
Treatment Treatment focuses on finding the appropriate educational setting and vocational training for the mildly and moderately retarded and determining home or institutional placement for the severely and profoundly retarded.
AUTISTIC SPECTRUM DISORDERS Diagnosis
FIGURE 67.1 This Venn diagram shows the overlap of all three symptom areas in autism, of two areas in AS, and of disorders involving a single symptom often reported in ASD families. TS = Tourette syndrome; OCD = obsessive-compulsive disorder; AS = Asperger's disorder; SAD = social anxiety disorder; SPD = semantic pragmatic disorder. (Modified from N'ass and Leventhal, in press.)
term is used (Gillberg and Coleman 2000). A hereditary basis is probable in many cases because of (1) a high concordance in monozygotic twins (90%), (2) a 4.5% increased risk for dizygotic twins and siblings, (3) a broader autistic phenotype in families (Piven and Palmer 1999), and (4) an association with several genetic disorders (Spencer 2001). The dramatically diminished risk in relatives who share 5 0 % versus 100% of their DNA is most consistent with an oligogenic inheritance pattern, where more than two and as many as 100 genetic variants may contribute to susceptibility to developing autism. Each gene may make a different contribution to the disorder, with gene A more important for the development of repetitive stereotyped behaviors and gene B mote important for language acquisition (Alarcon et al. 2002; Veenstra-Vanderweele and Cook 2003). Chromosomal abnormalities have been reported on chromosomes 2q37, 7q, and 2 2 q l 3 , 1 3 q among others. Both fragile X and the Rett syndrome mutation can
The triad of impaired sociability, impaired verbal and nonverbal communication skills, and restricted activities and interests, all of early onset, are the diagnostic features of autistic spectrum disorders (ASD) (Rapin 2002) (Figure 67.1). The presence or absence of social disabilities distinguishes developmental language disorders (DLD) from ASD. IQ, language, and social normalcy distinguish nonautistic mental retardation (NAMR) from DLD and ASD (figure 67.2). The range of disabilities seen among children in the spectrum is considerable. Asperger's disorder (Table 67,2) probably represents the high-functioning end of the ASD spectrum. Paralinguistic 1 rather than linguistic problems are characteristic. The iivideiice ol ASD varices from 0.4 to 70.0 per 10,000 children, depending on how the 'Paralinguistic skills include pragmatics—communicarive intent rather than content; prosody - tone of voice to express emotions, for example; understanding humor, sarcasm, and irony.
FIGURE 67.2 The presence or absence of social disabilities distinguishes developmental language disorders (DLD) from ASD. IQ, language, and social normalcy distinguish nonautistic mental retardation (\;AMR) from DLD and ASD.
DEVELOPMENTAL DISABILITIES Tabic 67.2:
Asperger's disorder diagnostic criteria
A. Qualitative impairment in social interaction, manifested by at least two of the following: 1. Impairment in use of nonverbal behaviors to regulate social interaction 2. Failure to develop peer relationships 3. Lack of spontaneous seeking to share enjoyments and interests 4. Lack of social or emotional reciprocity B. Restricted repetitive and stereotyped behavior, interests, and activities, manifested by at least one of the following: 1. Encompassing preoccupation 2. Inflexible adherence to nonfunctional routines 3. Stereotyped and repetitive motor mannerisms 4. Persistent preoccupation with parts of objects C. Disturbance causes significant impairment in functioning D. No clinically significant language delay E. No clinically significant cognitive deficit F. Criteria not met for diagnosis of another pervasive developmental disorder or schizophrenia Source: Modified from Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, D.C.: American Psychiatric Association, 1994.
problems. Approximately two thirds of adults with autism show poor social adjustment (limited independence in social relations), and one half require institutional care. Autistic individuals who are not retarded tend to improve more than those who are. Higher functioning people with autism and Asperger's disorder have the best outcome. Although fair-to-good outcomes are reported in 15-30%, only 5 - 1 5 % become competitively employed, lead independent lives, marry, and raise families. Psychiatric problems are common even in this group. Some adults with Asperger disorder are probably undiagnosed in childhood and adolescence; therefore the percentage of adults with ASD that ultimately functions in the mainstream may be higher than reported. Some adults with ASD are highly productive and original in their work. Bartok, the composer, and Wittgenstein, the philosopher, are believed to have had ASD (Cillberg 2002).
Specific Clinical Features Intelligence and
present with an autistic spectrum phenotype. However, the most common specific cause of autism appears to be maternally inherited duplications of chromosome 1 5 q l l 13, accounting for 1 % to 3% of cases {VcenstraVanderweele and Cook 2003). The symptoms of ASD, like other developmental disorders, often change with age. Approximately one third of autistic children regress between the ages of 1 and 3 years. Conversely, some toddlers and preschoolers, with typical symptoms of autism, may not appear autistic by school age, but may seem a bit odd, have peculiarities of language prosody and pragmatics, and show tenuous social skills. Nonverbal learning disabilities (NVLD) or attentiondeficit hyperactivity disorder (ADHD) is often the schoolage diagnosis. Most retain the typical features of autism, particularly those who are mentally retarded. The natural history of Asperger's disorder is less well documented, and the diagnosis is often delayed until late childhood, adolescence, or even adult life because by definition early language development is normal. Nonverbal learning disabilities (LD) or ADI ID may be the apparent presenting complaint (Klin et a I. 2000). The characteristic overfocus in a particular, or sometimes peculiar, interest area may escalate with time, but may be the key to a special form of adult success. Outcome studies suggest that among children with ASD, ovetall improvement occurs in approximately 4 0 % during adolescence and deterioration occurs in as many as one third (Cillberg and Coleman 2000). The onset of seizures or mood disorders (depression and bipolar disorder) usually underlies the deterioration. Some adolescents may even become catatonic. A minority of children, usually the higher functioning group, improves significantly during adolescence, reaching adulthood with no significant
1795
Cognition
The presence of language and social deficits defines ASD, nor the IQ level (see Figure 67.2). Although 7 0 - 8 5 % of children with ASD are mentally retarded, some have average or even superior intellectual ability. IQ is a keypredictor of long-term outcome in autism, especially when the IQ is less than 50 (Stevens et al. 2000). Those with low IQ generally fare poorly. If Asperger disorder is included as an autism spectrum disorder, the rate of mental retardation in ASD drops considerably. Some consider the core cognitive deficit of ASD to be an inability to grasp other people's thoughts or a failure to develop a theory of mind (Baron Cohen et al. 2001). "Mindblindness" manifests differently at different stages of development (Table 67.3). Language Communication difficulties are a cardinal feature of ASD. The extent of the language deficit generally parallels IQ. In lower functioning ASD children, language if present is echolalic; repetitive and stereotyped phrases are common. Some children fail to process language and despite normal hearing can appear deaf (verbal auditory agnosia). Higher functioning children sometimes talk too much; they talk to talk (semantic and pragmatic deficits). These children are often extremely literal and concrete. Prosody is frequently impaired as evidenced by mechanical, excessively rapid, monotonic, high pitched, or poorly modulated speech. Language skills at age 5 to 6 years are predictive of longterm prognosis. Children with conversational language will do significantly better than children who have little or no language. Abnormalities of play are part of the autistic child's communication disorder. The range of play includes
17%
NEUROLOGICAL DISEASES
Tabic 67.3:
Theory of mind (TOM): Stages of development
14-18 mo
joint attention: adult and child look at a toy together
18-24 mo 2-3 yr
Symbolic play Beginnings of primitive TOM: seeing leads to knowing; understanding desire, pretending, intention to joke First-order TOM: knowing what another person is thinking, understand that another person may not know what you know (false beliefs]; seeing leads to knowing (e.g. looking up and away means thinking), knows someone's choice by eye gaze direction Advanced First-Order TOM: counter factual reasoning enhanced by pretense (e.g. "pretend" preparation for countcrfactual syllogism task) Second-Order TOM: knowing what another person thinks another person is thinking; belief about beliefs; false belief measures: jokes, lies Y\ i ii id Older I ike !vl:ei measure: faux pas, son in me s.n s something they should not have said, not knowing that they should not have said it Third-Order I OM: belief about belief about belief, knowing what another person thinks another person thinks he knows (e.g., lying about lying) Third-Order TOM: belief about belief about belief: strange stories, awkward moments
Pi n l o d i . I.: r u l e , :
i - 4 ;•. i-
4-5 yr 6-7 yr 9-11 yr Around I 0 yr
Adult
| H ) i : l ! - ; ; : i . ' i l d e.ll -, . i d : : ' : ' - - ; l l l f l l l ii ill ((> d e s i r e d (>h|ea
Modified from Baron Cohen ct ai. 2001; Nass and Leventhat, in press,
repetitive Stereotypic and indiscriminate sensory use of objects (mouthing, rubbing, etc.); functional object use and imitation, mechanical play with puzzles and the like; interactive play with adults like running, catching, and tickling games; and activities involving their circumscribed areas of interest (e.g., board games, computers, electronic games, or high-level word and number tasks). These activities, when engaged, may provide pleasure. Pretend play is often rudimentary even in higher functioning children, involving, for example, simple role taking (Whitehouse et al. 1996). Social Skills The hallmark of ASD is social dysfunction. The aloof child most resembles the popular notion of autism. Such children do not follow their parents around, run to greet them, or seek their comfort. Such children tend to have low intelligence, have poor verbal and nonverbal communication skills, and show little symbolic play. Passive children are generally somewhat higher functioning overall. They do not make social approaches, but will accept them when made by others. They engage in some pretend play and join in games, but take a passive role (e.g., the baby in the game of mothers and fathers). Children who are interactive but odd make spontaneous social approaches to others, but do it in a peculiar way. They tend to talk at other people, and their persistence may become annoying. Pragmatic language skills are impaired. Conversation is started with a question. Many persons on the autistic spectrum are relatively unaware of their social ineptitude except to the extent that others tease them, but some are not (Whitehouse et al. 1996). Several books written by high functioning people with ASI) highlight this lack of awareness (Willey 1999).
Restricted Range of Behaviors,
Interests, and Activities
A restricted range of behaviors, interests, and activities is the third cardinal feature of autism. In lower functioning children, these consist of repetitive, stereotyped behaviors like twirling, rocking, flapping, licking, and opening and closing doors. Overlap and comorbidity with tic disorders and obsessive-compulsive disorders are seen in higher functioning children (Gillberg and Coleman 2000; Nass and Leventhal, in press) (see Figure 67.1, Venn diagram). Many of these children have great difficulties with transitions. Not only do they not focus, but they also become overfocused. Some individuals with exceptional artistic, musical, or mathematical talents may meet other criteria for a diagnosis of an ASH or Asperger's disorder. Some of these children grow up to be singleminded, perhaps peculiar, nunsocial chess or mathematics geniuses.
Evaluation and Etiology The standard neurological examination is generally normal. The skin must be careful examined for evidence of tuberous sclerosis, the most common diagnosable disease associated with autism (Gillberg and Coleman 2000). Formal audiological assessment is required to exclude a hearing impairment. An electroencephalogram (EEG), including a sleep record or overnight video-EEG monitoring, is appropriate to exclude subclinical seizures, especially when language comprehension is impaired or developmental regression has occurred. Mild-to-severe epilepsy, partial and generalized, occurs in up to one third of patients with autism h\ early adulthood, Ir.l.ino uniantile spasinsi .ind puberty are particularly vulnerable periods. The onset of
DEVELOPMENTAL DISABILITIES seizures may play a role in adolescent deterioration. Those who arc retarded are at higher risk, hut epilepsy occurs in high-functioning children as well. Epileptiform patterns on EEG and early epilepsy occur more frequently in children who show early regression. Studies using magnetoencephalography suggest that diffuse epileptiform activity is common in children with autistic regression (Rumsey and Ernst 2000). Three major types of neuropathology have been reported in autism (Rumsey and Ernst 2000): (1) decreased development of forebrain limbic system structures {e.g., cingulate, hippocampus, amygdala), substrates for memory and emotion; (2) a decreased number of Purkinje cells in the cerebellum; and (3) age-related differences in cell size and number in cerebellar and brain stem nuclei, suggestive of a dynamic developmental process. Structural abnormalities reported in autism based on imaging studies include increased brain volume (especially males), increased ventricular volume, increased white matter volume, thin splcnium of corpus callosum, hypoplastic cerebellum (vermian lobules VI and VII), hyperplastic cerebellum (10%), and hypoplastic parietal lobes (Sparks et al. 2002). Recent imaging findings suggest that there may be differential effects driving white matter to be larger and cerebral cortex and hippocampus-amygdala to be relatively smaller (Herbert et al. 2003). Brain imaging is rarely productive in clinical practice. However, a recent metaanalysis of imaging in children with developmental delay, including autism, does demonstrate that MRI may show abnormalities in one third, especially when the neurological examination is abnormal (Shevell et al. 2003}. Most metabolic imaging studies show hypometabolism in the frontal lobes and to a lesser extent in the temporal lobes and cerebellum. Activation studies suggest an altered localization of language and cognition (theory of mind). Positron emission tomography (PET) studies suggest abnormalities of both serotonergic and dopaminergic function. Overall, the extent of metabolic workup depends on the clinical suspicions and the relevance to family counseling. Table 67.4 lists some specific causes of ASD/ PDD (pervasive developmental disorder).
Treatment Preschool children with ASD should receive special education in a therapeutic nutsery or in a home-based behavioral modification piogram. Table 67.5 lists medications that have proven helpful in some cases (Towbin 2003).
LEARNING DISABILITIES Approximately 10% of school-aged children have learning disabilities (LD), and these can affect one or more cognitive skills. The common LDs involve reading (dyslexia), motor
Table 67.4: with ASD
1797
Double syndromes: Medical disorders associated
Angel man Anorexia nervosa CHARGE association Cohen syndrome De Lange syndrome Down syndrome Ehlers-Danlos Fragile X Goldcnhar Hypomelanosis hull-: : :
Kleine Levin Ltijan-Fryns Mob ins Mucopolysaccharidosis Neurofibromatosis Norman Peroxisomal disorders PKU Rett complex Smith Magenis Steincrr myotonic dystrophyTuberous sclerosis Unilateral cerebellar hypoplasia Velocardiofacial syndrome Williams Fndocrine disorders: hypothyroidism, hypopituitarism Infections: rubella, herpes, CMV Toxins: FAS, Fetal cocaine, thalidomide Modified from Gillberg and Coleman 2000.
function (dysgraphia and dyspraxia), the spectrum of specific nonverbal LDs (mathematics, written composition, visuospatial skills, socioemotional abilities, paralinguistic communication, executive function), and attention deficit disorder (ADD) with or without hyperactivity (ADHD).
Dyslexia Ditignosis Dyslexia is the best studied and probably the most common of the learning disabilities, occurring in as many as l()% of school-aged children. This disability often has a genetic basis, and several different chromosomal loci are suspect (Fisher and DeFries 2002). The definition of developmental dyslexia, an unexpected difficulty in learning to read, has both exclusive and inclusive criteria. As with other I D, the dyslexic child should not have majot neurological abnormalities. The detection of minor abnormalities (soft signs) on examination is usual (Table 67.6). Although majot sensory function must be normal, studies of disturbed cortical visual functioning in children with reading disability are ongoing. Processing by a slow lateral geniculate magnocellular system (impottant for monitoring motion,
179S
NEUROLOGICAL DISEASES
Table 67.5:
Medications for autism
Hyperactivity and inattention Obsessive-compulsive behaviors Aggressive and impulsive behaviors Ties/stereotypies Self-mutilation Psychosis
Seizures
Psychostimulants (methylphemdate; dextroamphetamine); clonidine (Catapres) Tricyclics—Clomipramine (Anafranil); SSRI—fluoxetine (Prozac), sertraline (ZoloftJ, paroxetine (Paxil), fluvoxamine (Luvox); atypical neuroleptics—risperidone (Risperdal), olanzapine (Zyprexa), ziprasidone (Geodon) Mood stabilizers—carbamazepine (Tegretol), divalproex sodium (Depakote), gabapenten (Neurontin), topiramide (Topamax), lithium; clonidine; Beta blockers—propranolol (Inderal); anxiolytics—huspirone (BuSpar) Clonidine, clonazepam (Klonipin), pimizide (Orap), haloperidol (Haldol), risperidone (Risperdol), baclofan (Liorisol) Naloxone (Narean), propranolol, fluoxetine, clomipramine, lithium Neutoleptics: haloperidol decanoate (Haldol), risperidone (Risperdal), chlorpromazine (Thorazine), olanzapine (Zyprexa), ziprasidone (Geodon), quetiapine (Seroquel), aripipra/ole (Ability), clozapine (Clozaril) Valproate (Depakote): adrenocorticotropic hormone (ACTH)
stereopsis, spatial localization, depth, and figure-ground perception) m a y not a p p r o p r i a t e l y modify t h e information received from the fast parvoccllular system (crucial for color perception, object recognition, and high-resolution form perception) (Amity et a I. 2 0 0 2 ; Angel ique et a I. 2 0 0 2 ) . N o r m a l intelligence a n d e x p o s u r e to a social a n d educational e n v i r o n m e n t conducive to learning to read is required for diagnosis. Studies ot iiuicr-city eleinemary school children show that e n r i c h m e n t p r o g r a m s can help some n o n t e a d e r s become readers. With respect to inclusive criteria, reading t w o grades behind actual or expected g r a d e level is generally required for a diagnosis of dyslexia by educational institutions. T h e two-grades-behind criterion does n o t take into a c c o u n t the fact that different reading tests yield different reading levels and may be m o r e or less reliable m e a s u r e s a n d p r e d i c t o r s of reading ability at different ages and g r a d e levels because of ilu complex dynamics of reading acquisition. Hie agi of the child affects the inclusive criteria. Because we do n o t
Table 67.6: disabilities Cranial nerves
Motor
Cerebellar
Sensory DTK
Common soft signs associated with learning
Head turns with eyes Month opens when eyes open Difficulty with grimace Excess upper extremity posturing mi sin sseil giiil Excess overflow during finger tapping and sequencing Unsustained one-foot stand Difficulty with hopping Excess choreiform movements with arms extended Dysrhythmic rapid alternating movements Excess overflow during rapid alternating movements Ballistic finger-nose-ringer test Difficulty with tandem gait Extinction on double simultaneous stimulipoor finger localization Minor reflex asymmetries
expect children to read until first g r a d e , the strict definition m a k e s a diagnosis of dyslexia impossible before the third g r a d e . Yet a history of language delay or a family history of reading disabilities is often predictive of dyslexia, and strict adherence to the definition should not preempt considerat i o n of early i n t e r v e n t i o n . In a d d i t i o n , a 2-year discrepancy reflects n greater disability for the y o u n g e r than for t h e older child. W h e t h e r or n o t to factor intelligence into t h e diagnosis of t e a d i n g disability is d e b a t a b l e . Spelling difficulties m a y be a mild form of dyslexia t h a t persists into a d u l t h o o d or t h a t are present In g o o d readers in dyslexic families (forme fruste). Evaluation
and
Etiology
C h i l d r e n with dyslexia deserve a formal neuropsychological evaluation to determine their cognitive strengths and weaknesses a n d to identify c o m o r b i d p r o b l e m s t h a t might affect t r e a t m e n t . For e x a m p l e , dyslexia and A D H D can coexist. Deficits in phonological a w a r e n e s s frequently underlie reading difficulties and m a y petsist into adolescence (Shaywitz \999). M e a s u r e s t h a t assess p h o n o l o g i c a l functioning best differentiate dyslexic from n o r m a l readers (e.g., segmenting w o r d s , saying c o w b o y w i t h o u t the boy, saying smack w i t h o u t t h e m, w o r d a n d n o n w o r d blending, a n d s o u n d m a t c h i n g of first a n d last syllables). Few children fail to read because of visual perceptual difficulties. T h e s t a n d a r d neurological e x a m i n a t i o n is generally n o r m a l . R o u t i n e imaging is tarely a b n o r m a l a n d generally unnecessary, except p e r h a p s in children with atypical features (Table 6 7 . 7 ) . Pathological studies suggest t h a t those with dyslexia h a v e b o t h atypical p l a n u m t e m p o r a l e asymmetries a n d areas of cortical dysplasia, particularly in the left hemisphere. Specialized imaging has c o r r o b o r a t e d the m a c r o s c o p i c pathological findings. In a b o u t t w o thirds of n o r m a l a d u l t s , the left p l a n u m t e m p o r a l e is larger than the right. By c o n t r a s t , only 1 0 - 5 0 % of dyslcxics s h o w a left greater than right posterior a s y m m e t r y (Eckert and L e o n a r d 2 0 0 0 ) . Dyslexics with atypical a s y m m e t r y patterns tend to h a v e m o r e sevete language a n d / o r reading deficits. Theoretically, fluent reading requires the functional
DEVELOPMENTAL DISABILITIES Table 67.7:
Atypical features in dyslexia
Female gender Left-handed without family history Strongly left-handed, early declaration Dyslexic without family history No history of developmental language problems Large discrepancy between verbal and spatial skills Neurological abnormalities or seizures
integrity of two left-hemisphere posterior systems: a tempt)[•(jp;iru-taI system .slid a ventral occipitotemporal system, Developmental^', the temporoparietal system predominates initially and is required for learning to integrate the printed word with its phonological and semantic features. The occipitotemporal system constitutes a hue-developing rapid sight-word identification system that underlies word recognition in skilled readers. In developmental dyslexia, both posterior systems may be disrupted causing reliance on the left inferior frontal and right posterior regions of the cortex (Pugh et al. 2000). The corpus callosum, which has a role in inrerhemispheric information transfer, may he structurally different in normal versus dyslexic readers. Theoretically, the splenium is critical hecause it contains axons linking the planum temporale and angular gyrus. Metabolic imaging confirms that the left temporal lobe and the cerebellum, an area that other studies suggest is crucial for language functioning, are involved in reading (Fulbrigbt etal. 1999). Measures demanding phonological processing activate the left temporal tegion in normal conttols, but not in dyslcxics. Treatment Although dyslexia is permanent, most children with early reading problems, when identified by 8-9 years (third to fourth grade) and provided with evidence-based reading instruction, can learn to read at average to above average levels. Children diagnosed later, even when provided remediation, are likely to continue having reading problems. Seventy-five percent of children with reading problems at the end of third grade are still having trouble in seventh gtade. Dyslexic children, identified after third grade, never catch up to average or superior high school readers (Shaywitz ct al. 1999). Early identification and provision of evidence-based reading instruction reduces the percentage of children reading below grade level in fourth grade from 37% to 6%.
Nonverbal Learning Disabilities Diagnosis No generally accepted definition is available for the term nonverbal learning disabilities (NVLD), and although the
1799
diagnosis of NVLD does not yet appear in the Diagyiostic and Statistical Manual, anywhere from 1-10% of schoolaged children are thought to have problems that fall under this rubric. Many children with Asperger's syndrome have difficulties in the nonverbal domain that may manifest as learning issues in school, In contrast to children with dyslexia, children with NVLD generally have significantly higher verbal than performance IQ scores. Problem areas include: 1. Social-emotional functioning 2. Nonvcrbal/paralinguistic communication 3. Sensorimotor functioning Tactile perceptual Gross and/or fine motor (clumsy, dysgraphia, dyspraxia) Slow processing speed 4. Visuospanal processing Perceptual, motor, visual-spatial-organizational, visual-spatial working memory, visual imagery, getting gestalt .5. Executive functioning Problems in planning, organization, working memory, processing speed Attention difficulties/attention deficit hyperactivity disorder Deficits in problem solving, reasoning, concept formation, hypothesis testing, seeing the gestalt, guessing Difficulty adapting to novel (inflexible) or complex situations Motivation 6. Academics Problems with handwriting, reading comprehension, written expression, math operations and concepts, science further complicating the diagnosis of NVLD is a changing pattern of deficits with time as school demands escalate (Rourke et al. 2002). In the elementary school years, the predominant problems are social difficulties, inflexibility, writing disturbances, poor gross motor coordination, sensorimotor problems, and inattention. In junior and senior high school, academic problems become apparent in mathematics, reading comprehension, and written composition despite good verbal skills. Social skills issues continue, and problem-solving and organizational skills are relatively impaired. In young adults, emotional problems may become prominent. Evaluation
and
Etiology
In general, NVLD reflect right hemisphere dysfunction, particularly the frontal and parietal regions. Based on children at high risk for NVLD (e.g., children with closed head injuries, those treated for leukemia, and those with
1800
NEUROLOGICAL DISEASES
hydrocephalus), Rourke (Rourke et al. 2002) has suggested that NVLD result from white matter abnormalities, but imaging studies to confirm this hypothesis have yet to be done.
Table 67.8:
The development of pencil grip
Ulnar/vertical—1 % to 3 yr Radial-acceptable until 3% yr Tripod (static) 50% by 3 yr, 80% by 4 yr Tripod (dynamic) 5-6 yr
Treatment The basic management strategy is the use of verbal strengths to compensate for the visuospatial disability. Because these children have difficulties dealing with novel or complex situations, the educational process emphasizes systematic learning and appropriate strategies for troublesome, frequently occurring situations. Generalization of learned strategies should be encouraged. Appropriate nomerba; behavior to facilitate peer' interactions is learned and not instinctual. Social groups are often helpful in this regard. Sensorimotor deficits can be managed by occupational therapy, early instruction in keyboarding and minimization of the written load in school.
Developmental Disorders of Motor Function Diagnosis Among 7-year-old children, moderate coordination disturbances occur in 9% and severe disturbances in 5% (Kadesjo and Gillberg 1999). Hadders-Algra's (2002) longitudinal study suggests that the frequency of developmental coordination disability (DCD) changes with age and is affected by the presence or absence of early neurological problems. ADHD (Landgrcn et al. 2000), visual perceptual problems, and reading comprehension problems are often comorbid conditions. Several discrete types of motor skill disorders may coexist. These include clumsiness, dyspraxia, dysgraphia, adventitious movements, and anomalous dominance or handedness. Clumsiness is defined as "a slowness and/or inefficiency in performing elementary fine motor and sometimes gross motor movements. 1 ' Clumsiness is more common in children with learning disabilities (LD), and for this reason, the combination was inappropriately termed minimal brain dysfunction. Children with developmental dyspraxia have difficulty with motor learning and motor execution. Dyspraxia may be associated with clumsiness, alone or in combination with other l.D. Ideomotor and ideational dyspraxia occurs in children. Dysgraphia (difficulty with writing) can be a primary disturbance, a manifestation of clumsiness or dyspraxia, or be secondary to dyslexia as a higher order cognitive disorder (Table 67.8). Adventitious movements (i.e., synkinesis, chorea, tremor, and tic) occur normally on a developmental basis and are designated developmental soft signs when they persist beyond the age when they normally cease (Table 67.9). With regard to handedness (manual dominance), most ultimately right-handed children declare handedness after 1 year of age and before age 5 years. Strong dominance when
established belorv age 1 year should raise concern that handedness is pathological and indicates disturbed use of the other hand. Many infants may appear to be left-handed and then become right-handed. The percentage of righthanded children, and probably the strength of handedness, increases through age 5 years. Eventually, more than 9 0 % of children are right-handed. Most right-handed people are strongly right-handed, whereas most left-handed people are ambidextrous. Dexterity in left-handed and right-handed people is equal. However, the frequency of LD is greater in left-handed than right-handed people, and the frequency of left-handed people is greater among the learning disabled. Evaluation
and
Etiology
Developmental coordination disorders, because of their heterogeneity, can only be fully evaluated using a battery that taps the gamut of motor skills. In one study (Geuze et al. 2001) about 7 5 % of children who were ]udged to have DCD by a team of specialists (rehabilitation doctor, occupational therapist, and physical therapist), performed below the fifteenth percentile on a comprehensive motor battery. The remaining 2 5 % , had handwriting problems or low muscle tone issues not measured by the particular battery used. Adventitious movements arc generally assessed separately. Synkinesia is best elicited by finger tapping, finger sequencing, and stressed gait testing. Choreiform movements are best elicited by having the child stand with eyes closed, tongue out and pronated arms extended with fingers spread. Some investigators suggest that children with developmental coordination disorders have difficulty representing internally the visuospatial coordinates of intended movements. Such a deficit implicates parietal lobe dysfunction. The parietal lobe is involved in processing feed-forward information from downstream motor areas by comparing it with local visuospatial representations that specify the coordinates of the prospective actions (Wilson et al. 2002). Treatment Children with significant disorders of motor control may benefit from process-oriented occupational therapy, motor imagery intervention, and perceptual motor training (Wilson et al. 2002), Computers can facilitate output for those with poor graphomotor skills. Sometimes, these difficulties are sufficient to require a scribe in the classroom.
DEVELOPMENTAL DISABILITIES Tabic 67.9:
1801
Natural history of soft signs
Neurological system affected
Age of appearance or disappearance (yr)
Soft sign
Cranial nerves
Head does not move with eyes Sticks tongue out for 10 sec Toe-heel walk Heel walk without associated movements Hop I 0 times Hops indefinitely One-foot stand for 30 sec No longer drifts up and down with pronated and supinated arms Rigid tripod Dynamic tripod Choreiform movements Athetoid movements Tandem
Motor
Cerebellar
Ki: : n IT lli :\\ (luriiii; r.r.'kl ;i I [IT infills: m o v e men Is
Sensoi •-
Stereoagnosis, graphesthesia No longer extinguishes on double simultaneous stimulation
Visuospatial Disabilities Diagnosis Visuospatial disabilities (perceptual, organizational, memory, and motor) occur in the context of NVI.D and in isolation. They may be the underlying cause of academic difficulties in reading, writing, and mathematics. Visuospatial difficulties are usually apparent on traditional IQ testing as a large verbal performance split as several performance IQ subtests measure visual perceptual processing. Evaluation and Etiology Difficulties in the visuospatial domain that are suggested by a large verbal performance split can be corroborated by specific neuropsychological measures such as design copy and memory, picture memory, and mental rotation. Visuospatial abilities are easily assessed in the office by the simply administered "draw a person test" (Table 67.10). Studies of visuospatial disabilities have not been as extensive as studies of specific academic disabilities. Visuospatial difficulties are, however, hallmark deficits in such genetically divergent syndromes as Turner syndrome, Williams syndrome (WS), velocardiofacial (VCF)
6 to 7 6 to 7 3 5 5 7 7 3 to 4 ,5 7 to 8 7 to 10 2 to 4 6 7 to 8 6
syndrome, and neurofibromatosis (see Table 67.1). WS is perhaps the best studied by neuroimaging. Affected individuals have decreased overall brain volume, particularly in the cerebrum and brainstem with relative preservation of cerebellar and superior temporal gyrus volumes. The ratio of frontal to posterior (parietal + occipital) tissue is greater than in controls. WS has relative preservation of cerebral gray matter volume and disproportionate reduction in cerebral white matter volume. However, within the cerebral gray matter tissue compartment, the right occipital lobe shows excess volume loss, a feature that could underlie the visuospatial difficulties (Reiss et al. 2000). Treatment The treatment of visuospatial disabilities emphasizes the use of verbal strategies to navigate situations demanding visuospatial solutions. It is important to realize that visuospatial disabilities may seriously impair one's perception of the world. Insignificant tasks, like navigating the hallways at school, become difficult. Visuospatial misperceptions may lead to serious social errors.
Dyscalculia Diagnosis
Table 67.10:
"Draw a person test" scale
Humpty-Dumpty or better 50% at 3 yr, 80% at 1>\ yr Intermediate man or better 50% at 4 yr, 80% at 4/4 yr Mature man 50% at 4/4 yr I 0 part person at 5 A_ yr
Dyscalculia can involve any or all aspects of mathematics from computation to conceptualization. The prevalence of dyscalculia is approximately 6%, a figure similar to that of dyslexia and ADHD. Both genders are equally affected. Indeed, the only clear gender difference in mathematical skills is in the extremely superior range (scoring over 700 on
18(12
NEUROLOGICAL DISEASES
the math SAT in seventh grade); within this group, males out-number females by mure than 10 to 1. A developmental Gerstmann's syndrome (right-left disorientation, finger agnosia, dysgraphia, and dyscalculia) occurs in as many as 2% of school-aged children. The mean IQ of children with dyscalculia is generally normal; ADHD occurs in 2 5 % and dyslexia in 2 0 % . Dyscalculia is common in children with NVLD (Shalev and Gross-Tsur 2001). Evaluation and Etiology Children with neuropsychological evidence of either leftor right-hemisphere dysfunction can have dyscalculia. Both groups have similar problems on arithmetic batteries, but those with left-hemisphere dysfunction perform significantly worse in addition, subtraction, complex multiplication, and division and make more visuospatial errors (Shalev and Gross-Tsur 2001). Imaging studies in children with dyscalculia who had been born prematurely suggest that left-parietal abnormalities predominate (Grafman and Romero 2001). Treatment Math remediation is appropriate for the child with isolated dyscalculia or with math difficulties in combination with other learning difficulties.
Attention Deficit Hyperactivity Disorder (ADHD) Diagnosis The reported prevalence of ADHD in school-aged children ranges from 1% to 2 0 % . This wide range reflect-, (hL- lack of a biological marker for the disorder. The variation in prevalence is secondary to differing technique of ascertainment (parent, child, or teacher perspective), the diagnostic questionnaire used, age at ascertainment {standards are most clear-cut for the elementary school-aged child), and even the country of study (e.g., ADHD is more common in the United States than in the United Kingdom). Although complete recovery used to be thought the rule, it now appears that ADHD persists in 60-70% of adults diagnosed with ADHD in childhood. Almost half of such adults show significant social-emotional difficulties, and 10% show serious psychiatric or anrisocial disabilities. Assuming a prevalence of childhood ADHD of 6 - 1 0 % , the prevalence of ADHD in adults may be 2 - 7 % . ADHD is diagnosable in toddlers and may be four to eight times more common in males than females. Females, when affected, have less hyperactivity and more severe general cognitive deficits. This suggests that females with ADHD may have a gteater genetic load. Other learning difficulties as well as psychiatric disorders are commonly comorbid with ADHD (Brown 2000).
Clinical Features Practically speaking, the following symptoms define ADHD: inappropriate inattention, impulsivity, disttactibility, and hyperactivity for chronological and mental age. The current standard for diagnosis is the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (Table 67.11). Table 67.12 lists the characteristics of ADHD in preschoolers. The physical examination of the ADHD child is generally normal. Minor signs on neurological examination may include synkinesis and choreiform movements. The neuropsychological profile reveals normal IQ but low scores on the Wechsler IQ subtests that demand attention or rapid processing: digit span, coding, arithmetic, and symbol search. Also often compromised are executive-frontal lobe functions tapping the ability to initiate, inhibit, sustain, and shift attention. Evaluation
and Etiology
Although many medical causes of ADHD exist, ADHD has a substantial genetic component. Genetic factors may account for 7 0 - 9 0 % of cases. Approximately one quarter of the first-degree relatives of a child proband with ADHD also have or have had ADHD, generally the father or a maternal uncle. As many as 10% of ADHD children probably carry the Tourette gene, but may not have tics at the time of diagnosis or indeed ever. Girls with the Tourette gene more often have obsessive-compulsive disorder, whereas the combination of ADHD and tics predominate in boys. Structural imaging studies suggest atypical asymmetry
['able (S7.1 1 : Criteria lor diagnosis t)l Lirrcnuoil deficit hyperactivity disorder (ADHD) ADHD with hyperactivity, impulsiveness Fidgets with hands or feet I vavi's siha[ in classroom Runs about ot climbs excessively Has difficulty playing quietly Often on the go Talks excessively lilnrls "IK .niswL'i -. Difficulty awaiting turn Interrupts others ADHD with inattention, distractibility Has difficulty sustaining attention Does not give close attention to details Docs not seem to listen Docs not follow through Has difficulty organizing tasks Avoids engaging in tasks requiring sustained mental effort Easily distracted Forgetful in daily activities Source: Modified with permission from Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, D.C.: American Psychiatric Association, 1994,
DEVELOPMENTAL DISABILITIES Tabic 67.12: disordci
Signs of preschool attention deficit hyperactivity
High activity Poor persistence Group instruction problems Poor behavior modulation Poor social interactions Excessive aggression Silliness Mossiness Impulsiveness "Immature," not on task Inappropriate lieli.ivior Unproductive
patterns in the basal ganglia, w h e r e a s metabolic imaging studies suggest dysfunction of frontal lobes and the right sided prefrontal-striatal systems (Ernst and Rtimsey 2 0 0 0 ) . Dopaminergic dysfunction a p p e a r s to be the biochemical basis of A D H D . Genetic studies h a v e focused on c a n d i d a t e genes involved in d o p a m i n e r g i c transmission, d o p a m i n e t r a n s p o r t , a n d d o p a m i n e receptors (Solanto 2 0 0 2 ) . Treatment M e d i c a t i o n , in particular p s y c h o s t i m u l a n t s , is t h e mainstay of treatment (Table 6 7 . 1 3 ) . A p p r o x i m a t e l y 7 5 % of children r e s p o n d to stimulants. In . 5 - 1 0 % , side effects, such as weight loss, r e b o u n d depression or irritability, or flat affect limit t r e a t m e n t . N e i t h e r tics nor T o u r e t t e ' s s y n d r o m e are contraindications to stimulant use in A D H D (Nass a n d Bressman 2 0 0 2 ) . C o m o r b i d m o o d or anxiety disorders influence medication choice (Brown 2 0 0 0 ) . A t o m o x e t i n e (Strattera) a n o n s t i m u l a n t medication has recently been marketed for treating A D H D a n d m a y p r o v e effective (Ktatochvil et ah 2 0 0 2 ) and useful especially in stimulant n o n r e s p o n d c r s . O t h e r factors requiring attention are p a r e n t skills training, educational a c c o m m o d a t i o n s (extended time, separate testing site), cognitive behavioral t h e r a p y , social skills training, and behavioral modification. Behavioral modification requires setting goals, defining progress, and determining the incentives.
Table 67.13:
1803
DEVELOPMENTAL LANGUAGE DISORDERS Developmental language disorder (DLD) is t h e failure to develop language in an a g e - a p p r o p r i a t e fashion in a child with n o r m a l intelligence and h e a t i n g . M o s t children have g o o d receptive language by age 2 years, along with a 5 0 to 1 0 0 - w o r d {ot more) v o c a b u l a r y a n d s o m e t w o - w o r d phrases. Keen children w nil S'LHHI receptive skills who speak late may be at risk for c o n t i n u i n g subtle language difficulties a n d later reading a n d language-based a c a d e m i c difficulties (Rescotla et al. 1997). Lack of well-developed expressive language by age 3 years is definitely a b n o r m a l . T a b l e 6 7 . 1 4 lists a d d i t i o n a l w a r n i n g signs t h a t suggest D I D d u n i it; [he m si 3 w n r s . \ r n j u u r basis lor diagnosis is a discrepancy between nonverbal intelligence a n d language capabilities (Klcc et al. 2 0 0 0 ) . H o w e v e r , both over- a n d u n d e r d i a g n o s i s o c c u r even w h e n the best available discrepancy criteria are used. T h e difficulty in applying criteria a n d the need for strict discrepancy-based diagnostic criteria reflect, in p a r t , the large degree of individual variability in rate of l a n g u a g e acquisition (Toppleberg a n d Shapiro 2 0 0 0 ) . It is sometimes difficult to distinguish D L D from miti.il idiosyncratic delay in acquisition with eventual c a t c h - u p and ultimately n o t m a l language. T h i s p r o b a b l y a c c o u n t s in p a r t for t h e wide r a n g e ( 1 - 2 5 % ) in the r e p o r t e d prevalence of D L D in preschool children. Risk factors for D L D identified by t h e N a t i o n a l C o l l a b o r a t i v e Perinatal Project include l o w birth weight o r p r e m a t u r i t y a n d parental m e n t a l r e t a r d a t i o n . A n o t h e r risk factor is a family history of d e v e l o p m e n t a l language disorders. Increased m o n o z y g o t i c versus dizygoric twin c o n c o r d a n c e rates indicate t h a t heredity, n o t just shared e n v i r o n m e n t , is the c a u s e of t h e familial clustering (Bartlett et al. 2 0 0 2 ) . A n u m b e r of gene loci h a v e been implicated including: 13q, 16q, 19q (SLI C o n s o r t i u m 2 0 0 2 ) . In t h e three-generation KE family, half the m e m b e r s are affected with a severe speech a n d language disorder t h a t is t r a n s mitted a s a n a u t o s o m a l d o m i n a n t m o n o g e n i c t r a i t — t h e gene responsible is the F O X P 2 f o r k h e a d - d o m a i n gene. T h e first description of the language deficit in the KE family w a s of a severe form of d e v e l o p m e n t a l verbal a p r a x i a . H o w e v e r , m o s t recently investigatots a r g u e in favor of a core deficit in sequencing a n d learning of verbal and
Treatment of attention deficit hyperactivity disorder
Stimulants Alpha agonists Antidepressant Norepinephrine transport inhibirer Anti manic Mood stabilizers Beta blockers Antianxiolytic Neuroleptics
Mcthylphenidate (Ritalin), dextroamphetamine (Dexcdrinc, Adderal), pemoline (Cylert) Clonidine (Catapres), guanfacine (Tenex) Selective serotonin re-uptake inhibitors; tricyclic antidepressants; bupropion (Wellbutrin); trazodone, vcnlafaxine (Effexor); monoamine oxidase, selegiline (Deprenyl) Atomoxetine (Strattera) Lithium Carbamazepine (Tegretol), divalproex sodium (Depakote) Propranolol (Inderal), atenolol (Tenormin) Buspirone (BuSpar); clonazepam (Klonopin) Haloperidol deeanoate (Haldol); risperidone (Rispirdal); phenorhiazines
1804
NEUROLOGICAL DISEASES
Table 67.14:
Warning Tigris of ;i developmental language disorder
Limitations in expressive language Mas feeding problems related to sucking, swallowing, and chewing Fails to vocalize to social stimuli and fails to vocalize two syllables at 8 months Produces few or no creative utterances of three words ot mote by age 3 [.imitations in vocabulary Has small repertoire of words understood or used and acquires new words slowly or with difficulty Limitations in comprehending languageRelies too much on comextual cues to understand language Limitations in social interaction Rately interacts socially, except to have needs met Limitations in play Has not developed symbolic, imaginative play by age 3 Does not play interactively with peers Limitations in learning speech Expressive speech contains numerous articulation errors or is unintelligible to unfamiliar listeners Limitations in using strategics for language learning '. U-- iHinsii.il or i 11. :;.•> prop-1. ue MI.;U;;K-. :i>r .ls-.i- li-vcl, . .;•,., ••>• t i i r o iniLiuoii ii\ liohilia . does not imitate verbalizations of others (dyspraxia), does not use questions for learning ("why" questions' Limitations in attention for language activities Shows little interest in book reading, talking, or communicating with peers Source: Modified with permission from Nelson, N. W. Childhood Language Disorders in Context: infancy through Adolescence. New York: Macmillan, 1993; and Hall, N. "Developmental language disorders," Semin Pediatr Neurol, vol. 4, pp. 77-85. nonverbal associations (Watkins et al. 2002a). A recent screening of 270 4-year-olds with DLD was negative for the FOXP2 mutation (Meaburn et al. 2002). Erring on the side of overdiagnosis in the young child and initiating therapy is probably better than underdiagnosis. Hearing impairment should be ruled out by formal audiological assessment in most children presenting with language delay. The current availability of brainstemevoked responses (in addition to behavioral audiometry) makes possible an assessment of even an uncooperative young child. In view of the frequent concurrence of language disorders and epilepsy, an KEG, including a sleep record, to rule out subclinical seizures {see Verbal Auditory Agnosia, later in this chapter) is often appropriate, especially for those with impaired language comprehension.
Subtypes of Developmental Language Disorders Depending on subtype, DLD vary in their characteristic features, etiology, prognosis, and treatment response. The subtypes listed in Table 67.15 focus on psycholinguistic features that most closely approximate the adult aphasias (see Chapter 12).
Articulation and Expressive Fluency Disorders Pure Articulation
However, almost 5 0 % of children at age 4 years still have articulation difficulties. A com moo problem is defective use of th or r. At kindergarten entry, one third of children still have minor to mild articulation defects, but speech is unintelligible in less than 5 % . Stuttering and
Cluttering
Stuttering is a disorder in the rhythms of speech. The speaker knows what to say, but is unable to say it because of an involuntary, repetitive prolongation or cessation of a sound. Some degree of dysfluency is common as language skills evolve during the preschool years, particularly as mean length of utterance (MLU) reaches 6-8 words between ages 3 and 4 years. However, stuttering in contrast to developmental dysfluency is probably a linguistic disorder {errors occur at grammatically important points in the sentence). Sniftering is often a genetic trait. Although the cause of developmental stuttering is unknown, the main theories are anomalous dominance and abnormalities of iuterhemisphcric connections (Eoundas et al. 2001). Stuttering occurs more frequently in children with other DLD and with mental retardation. Cluttering, by contrast, as seen in fragile X syndrome, is characterized by incomplete sentences and short outbursts of two- to three-word phrases, along with echolalia, palilalia (compulsive repetition reiterated with increasing rapidity and decreasing volume), perseveration, poor articulation, and stuttering.
Disorders Phonological
Articulator)' skills improve with age and, as with language development, the normal range is considerable. Most children (70%) speak intelligibly by age 2 years. Unintelligible speech is the exception at age 3 years (15%).
Programming
Disorder
Children with the phonological programming disorder are fluent, and MLU approaches normal. Despite initial poor intelligibility, the achievement of serviceable speech is
DEVELOPMENTAL [)ISABILITIES
Table 67.15:
1805
Subtypes of developmental language disorders R zceptive expressive
111! Production-expressive Semantics (lexical) Syntax Phonology Fluency Pragmatics
Verbal auditory agnosia
Phonological syntactic
W
i . p
44 44 44 Nl or J.
44 4 4 Nl or 1
Expressive Verbal dyspraxia
Higher order
Phonological programming
}
•j
Nlor J.
4 Nlor 4.
Seman t itpragmatic
Lexical syntactic
44
i
44
Nl or 4 4
Nl or 4 ot 1 44
4 4
Nl = normal. Source: Modified from Rap in, i. 1996, Preschool Children with inadequate Communication. London: Mackeith Press.
expected. Language comprehension is relatively preserved. Most such children show delayed rather than deviant phonology, with improvement at 1 and 7 years after preschool diagnosis. It is debatable whether this disorder is a severe articulation problem (see Pure Articulation Disorders, earlier in this chapter) or a mild form of verbal dyspraxia (see Verbal Dyspraxia, latet in this chapter). The fact that patients witli the phonological programming disorder have more trouble learning manual signs and Bliss symbols than controls supports an association with dyspraxia. A prcrcmediation paired associate learning task may help select the best remediation method for each child because some arc better with symbols and some with signs. An adult aphasia equivalent does not exist. Verbal
Dyspraxia
The speech of children with verbal dyspraxia, also called dilapidated speech, is extremely disfluent. Utterances are short and laboriously produced. Phonology is impaired and includes inconsistent omissions, substitutions, and distortions of speech sounds. Syntactic skills are difficult to assess in the face of dysfluency. Language comprehension is relatively preserved. Many require speech and language therapy fot prolonged periods. Children with vetbal dyspraxia who do not develop intelligible speech by age 6 years are unlikely to acquire it later. The frequency with which nonverbal praxis deficits—buccal-Ungual dyspraxia (e.g., positioning muscles of articulation) and generalized dyspraxia or clumsiness—coexist with verbal dyspraxia is unknown. The presence of a more diffuse disorder of praxis has significant therapeutic implications because children with verbal dyspraxia may depend on signing and writing skills for communication. The etiology of verbal dyspraxia is unknown. The excess of males and a familial tendency support a genetic basis. Postmortem studies show either hypoplasia of the motot tract running from the Rolandic region to cranial nerve
nuclei X and XII or bilateral opercular lesions. In a few patients studied decreased cerebral blood flow in the frontal regions and failure of verbal activation to increase profusion in Broca's area have been found. Although often accompanied by more neurological symptoms, verbal dyspraxia most resembles the adult aphasia called aphemia (see Chapter 12A}.
Disorders of Receptive and Expressive Language Phonological
Syntactic
Syndrome
Phonological syntactic syndrome (also called mixed receptive expressive disorder, expressive disorder, and nonspecific formulation-repetition deficit) is probably the most common DLD. The phonological disturbances consist of omissions, substitutions, and distortions of consonants and consonant clusters in all word positions. The production of unpredictable and unrecognizable sounds makes speech impossible to understand. The syntactic impairment consists of a lack of small grammatical words (e.g., and, but) and an absence of appropriate inflected endings (e.g., -ed, -ing). The syntactic deficit is not just a developmental lag. Whereas a normal young child may say "baby cry" or "a baby crying," these children create deviant constructions, such as "the baby is cry." Telegraphic speech is common. The presence or absence of difficulties in other language areas is variable. Overall, comprehension is relatively, although not wholly, spared. Semantic skills tend to be intact. Repetition, pragmatics, and prosody may be normal. Autistic children with this DLD subtype produce a significant amount of jargon. Neurological dysfunction is especially frequent in this developmental language disorder subtype. Feeding problems related to sucking, swallowing, and chewing difficulties are common, and drooling is often persistent. The neurological examination may reveal signs of pseudobulbar palsy,
18(16
NKUROI.OGICAL DISEASES
oromotor apraxia, hypertonia, and incoordination. A single patient with the phonological syntactic syndrome and oromotor apraxia had an atypical asymmetry of the planum region and a dysplastie gyrus in the left frontal cortex. Bilateral anterior and posterior perisylvian hypoperfusion has been demonstrated in a few children with this disorder. This DLD most resembles Broca's aphasia in adults.
or a disconnection effect. Repetition strength in the setting of fluent speech with impaired comprehension characterizes the adult aphasia syndrome of transcortical sensory aphasia. Difficulties with prosody and pragmatics suggest right hemisphere dysfunction in addition to left.
Verbal Auditory Agnosia
The lexical syntactic syndrome is seen in approximately 1 5 % of children with DLD. Speech is generally dysfluent, even to the point of stuttering, because of word-finding difficulties and poor syntactic skills, with many hesitancies and false starts. Both literal and semantic paraphasias are common. Syntax is immature, not deviant. Phonology is spared, and therefore speech is intelligible. Repetition is generally better than spontaneous speech. In conversation, idiom use is better than spontaneous speech. Pragmatics may be impaired, particularly when this syndrome occurs in autistic children. Comprehension is generally acceptable, although complex questions and other linguistic forms taxing higher level receptive syntactic skills are often deficient.
Despite intact hearing, meaningful language is not understandable in verbal auditory agnosia {VAA). VAA may occur on a developmental basis and as an acquired disorder, the Landau-Kleffner syndrome (sec Chapter 73). Generalized low performance and global dysfunction are other names tor die developmental form. VAA is common in low-functioning children with autism. VAA best supports the theory that DI.D result from difficulty with processing basic sensory information entering the nervous system in rapid succession. The outcome from the developmental form of VAA is generally poor. 1 be outcome from tin- acquired disorder is better in approximately one third of patients. VAA is seen in adults with acquired bitemporal lesions.
Lexical
Syntactic
Syndrome
The neuroanatomical basis of this disorder is .llso unknown. No clear counterpart for the lexical syntactic syndrome exists among the acquired aphasias of adulthood, despite similarities with anomic aphasia, conduction aphasia, and transcortical aphasia.
Higher Order Language Disorders Semantic
Pragmatic
Syndrome
Children with the semantic pragmatic syndrome (also called repetition strength and comprehension deficit and language without cognition) are fluent speakers, even verbose. The tetm cocktail party syndrome describes the semantic pragmatic syndrome in children with hydrocephalus. Vocabulary is often large and somewhat formal. Parents are often encouraged by the child's sizable vocabulary only to find later that the verbosity did not indicate superior cognitive skills. Such children fall short in basic semantic skills required for meaningful conversation and informative exchange of ideas. They talk to talk. Phonological and syntactic skills arc generally intact, but comprehension is impaired. Pragmatic skills arc lacking and the rules that govern the use of language in conversation arc never learned. Finally, children with semantic pragmatic syndrome often show deficits in prosody. Their speech has a monotonous, mechanical, or singsong quality. They cannot convey the additional pragmatic intentions that prosody affords, such as speaking with the proper emotion or indicating by tone of voice that they are asking a question. Semantic pragmatic syndrome is often seen in higher functioning autistic children. The neuroanatomical basis of this disorder is unknown. It is reported in patients with agenesis of the corpus callosum and with hydrocephalus, which supports a possible localization in the subcortex and its connections
Ncurobtological Basis of Developmental Language Disorders Structural
Anatomy
Adult aphasia data and neurobiological theory implicate the left perisylvian regions in the processing of phonemes and linguistic information. Very few group studies have used neuroimaging to assess language-impaired children per se, other than those originally ascertained because of dyslexia. Perisylvian abnormalities of varying degrees and associated with varyingly severe language disorders are reported. Complete opercular agenesis has been reported in association with suprabulbar palsy (Worster-Drought syndrome). Poly microgyria has also been reported in the perisylvian region. Patients with the most extensive disease have the greatest language impairments, whereas those with posterior parietal polymicrogyria have milder symptoms (Nevo et a I. 2001; Gucrreiro ct al. 2002). Some children and adults with DLD (as well as relatives of DLD probands) do not have the typical planum temporale asymmetry pattern. The absence of the typical planum asymmetry may be the result of aberrant neurogenesis, which leads to reduced cell development in the perisylvian regions or atypical patterns of cell death. Caliosal si/e may be decreased in some children with DLD (Prcis ct al. 2000). An extra sulcus in the inferior frontal gyrus was statistically associated with a history of DLD (Clark and Plante 199S)
DEVELOPMENTAL DISABILITIES in a g r o u p of 41 neurological!)' n o r m a l a d u l t s . In one recent series one third of 35 children w i t h D L D h a d nonspecific M R I abnormalities including ventricular e n l a r g e m e n t (5), central volume loss (3), and white m a t t e r a b n o r m a l i t i e s (4) ( T r a u n e r et al. 2 0 0 0 ) . R a r e r e p o r t s d o c u m e n t right hemisphere abnormalities in the D L D child suggestive of a righthemisphere contribution to l a n g u a g e acquisition {Plante et al. 2 0 0 1 ) . In the KL; family (see earlier) the c a u d a t e nucleus and inferior frontal gyrus a r e reduced in size bilaterally, whereas the left frontal opercular region (pars triangularis and anterior insular cortex) and t h e p u t a m e n bilaterally have a greater v o l u m e of grey m a t t e r ( W a t k i n s et al. 2 0 0 2 b ) , An insufficient dosage of a critical f o r k h e a d transcription factors d u r i n g embryogenesis, m a y lead to m a l d e v e l o p m e n t of brain speech a n d l a n g u a g e regions of the brain (Lai et al. 2 0 0 1 ) . Despite these research results, there is no reason to image the typical D L D child in clinical practice.
1807
g r o u p s because m o s t areas implicated in A D H D research involve the c a u d a t e , frontal, a n d rerrocallosal w h i t e - m a t t e r regions. M o r e o v e r , some of these metabolic studies suggest t h a t different pathological systems may be involved, d e p e n d i n g o n t h e D L D subtype, F.lectropbysto
logy
In addition to the EEG studies m e n t i o n e d in the discussion of the VAA D L D s u b t y p e , several investigators h a v e assessed evoked responses a n d a u d i t o r y processing speed a s m a r k e r s o f l a n g u a g e d e v e l o p m e n t , n o r m a l a n d a b n o r m a l . Atypical p a t t e r n s of brain activity are docum e n t e d in children with D L D . Lateralization p a t t e r n s of electrophysiological activity m a y predict o u t c o m e in late talkers.
O u t c o m e of D e v e l o p m e n t a l L a n g u a g e Disorders Metabolic
Anatomy
Lew studies have specifically assessed children with p r i m a r y D L D (as opposed to dyslexia) (Table 6 7 . 1 6 ) . In a d d i t i o n , the comorbidity of attention deficit hyperactivity disorder ( A D H D ) in m a n y of the subjects m a k e s interpreting t h e results m o r e difficult. H o w e v e r , finding differences in the t e m p o r a l regions m a y be specific for the D L D or dyslexic
Table 67.16: \illii;
T h e occurrence of a D L D , even w h e n it a p p e a r s to resolve, may affect later social e m o t i o n a l adjustment, educational achievement, a n d v o c a t i o n a l choices. Short- a n d long-term b e h a v i o r a l , social-emotional and psychiatric p r o b l e m s a r e associated with early l a n g u a g e p r o b l e m s (Irwin et al. 2 0 0 2 ; J e r o m e et al. 2 0 0 2 ) . In o n e g r o u p of 5-year-olds w i t h speech a n d language p r o b l e m s , the frequency of A D H D
Metabolic imaging in children with developmental language disordets
Subjects 6 ADHD only 3 ADHD + MR
9 ADHD + DLD 9 controls 9 ADHD only
''.•-:1 incuboliMii byexamination of the genotype," Clin Cbim Acta, vol. 217, no. 1, pp. 3-14 Hsich, G., Sena-Esteves, M., & Breakefield, X. O. 2002, "Critical issues in gene therapy for neurological disease," Hum Gene Ther, vol. 13, no. 5, pp. 579-604 Jeng, L. B., Tarvin, R., & Robin, N. H. 2001, "Generic advances in central nervous system malformations in the fetus and neonate," Semin Fediatr Neurol, vol. 8, no. 2, pp. 89-99 Johnson, J. I.., Coyne, K. F.., Garrett, R. M., et al. 2002, "Isolated sulfite oxidase deficiency: Identification of 12 novel SUOX mutations in 10 patients," Hum Mutat, vol. 20, no. 1, pp. 74 Kaye, E. M. 2001, "Update on genetic disorders affecting white matter," Fediatr Neurol, vol, 24, pp. 11-24 Kerner, J. & Hoppcl, C. 1998, "Genetic disorders of carnitine metabolism and their nutritional management," Annu Rev Mutr, vol. 18, pp. 179-206 Khanna, A., Jain, A., Eghtesad, B., & Rakela, J. 1999, "Liver transplantation for metabolic liver diseases," Surg Clin North Am, vol. 79, no. 1, pp. 153 162 Krivit, W., Aubourg, P„ Shapiro, E., & Peters, C. 1999, "Bone marrow transplantation for globoid cell leukodystrophy, a dre no leukodystrophy, metachromatic leukodystrophy, and Hurler syndrome," Curr Opin Heinatnl. vol. 6, no. 6, pp. 377-382 Madonna, P., de Stefano, V., Coppola, A,, et al. 2002, "Hyperhomocysteinemia and other inherited prothrombotic conditions in young adults with a history of ischemic stroke," Stroke, vol. 33, no, 1, pp. 51-56 Maire, l. 2001, "Is genotype determination useful in predicting the clinical phenotype in lysosomal storage diseases?" / Inherit Metab Dis, vol. 24, Suppl 2, pp. 57-61 Mailer, A., Hyland, K., Milstien, S., et al. 1997, "Aromatic I.-a mi no acid decarboxylase deficiency: Clinical features, diagnosis, and treatment of a second family," / Child Neurol, vol. 12, no. 6, pp. 349-354 Matalon, R. & Matalon, K. M. 2002, "Canavan disease prenatal diagnosis and genetic counseling," Obstet Gynecol Clin North Am, vol. 29, no. 2, pp. 297-304
IS^I
Mayatepek, F.. 2000, "Leukotriene CA synthesis deficiency: a member of a probably underdiagnosed new group of neuromctabolic diseases," Eur J Fediatr, vol, 159, no. 1 1, pp. 811-818 Moghadasian, M, H., Salen, G., Frohlich, J. J., & Scudamore, C. H. 2002, "Cerebrotcndinous xanthomatosis: A rare disease with diverse manifestations," Arch Neurol, vol. 59, no, 4, pp. 527-529 Nuefeld, E. F. 1991, "I.ysomal storage disorders," Ann Rev Biocbcm, vol, 60, pp. 257-280 Nicolaides, P., Leonard, J., Sc Surrees, R. 1998, "Neurological outcome of methylmalonic acidaemia," Arch Dis Child, vol. 78, no. 6, pp. 508-512 Nisscnkorn, A., Michelson, M,, Ben-Zeev, B., & Lerman-Sagie, T. 2 0 0 1 , "Inborn errors of metabolism: A cause of abnormal brain development," Neurology, vol. 56, no. 10, pp. 1265-1272 Nowaczyk, M. J. & Waye, J. S. 2001, "The Smith-Lemli-Opitz syndrome: A novel metabolic way of understanding developmental biology, embryogenesis, and dysmorphology," Clin Genet, vol. 59, no. 6, pp. 375-386 Ogier de Baulny, H. 2002, "Management and emergency treatments of neonates with a suspicion of inborn errors of nu-n holism," Semin Neonatol, vol. 7, no. 1, pp. 17-26 Ogicr de Baulny, H. & Sauduhray, J. M. 2002, "Rranched-cham organic acidurias," Semin Neonatol, vol. 7, no. I, pp, 65-74 Pa stores, G. M. & Thadhani, R. 2002, "Advances in the management of Anderson-Fabry disease: Enzyme replacement therapy," Expert Opin Biol Ther, vol. 2, no. 3, PP. 325-333 Pearl, P. L. &C Krasncwich, D. 2001, "Neurological course of congenital disorders of glycosylation,"/ Child Neurol, vol. 16, no. 6, pp. 409-415 Rampoldi, L., Danek, A., & Monaco, A. P. 2002, "Clinical features and molecular bases of neuroacanthocytosis," / Mol Med, vol. 80, no. 8, pp. 475-491 Rashed, M. S. 2 0 0 1 , "Clinical applications of tandem mass spectrometry: Ten years of diagnosis and screening for inherited metabolic diseases," / Chromatogr B Biomed Sci Appl, vol. 758, no. 1, pp. 27-48 Read, C. Y. 2002, "Reproductive decisions of parents of children with metabolic disorders," C/i« Genet, vol, 6 1 , no. 4, pp. 268-276 Rush, J. S., Panneerselvam, K., Waechter, C. J., & Freeze, H. H. 2000, "Mannose supplementation corrects GDP-mannose deficiency in cultured fibroblasts from some patients with Congenital Disorders of Glycosylation (CDG)," Glycobiology, vol. 10, no. 8, pp. 829-835 Samcnuk, P. & Koffman, B. M. 2001, "Chenodeoxycholic treatment of cerebrotcndinous xanthomatosis," Neurology, vol. 56, no. 5, pp. 695-696 Sarkar, B. I 997, "Early copper histidine therapy in classic Menkes disease," Ann Neurol, vol. 4 1 , no. 1, pp. 134-136 Scaglia, F. &c Longo, N. 1999, "Primary and secondary alterations of neonatal carnitine metabolism," Semin Perinatal, vol. 2 3 , no. 2, pp. 152-161 Schaefer, F., Straube, E., Oh, J., et al. 1999, "Dialysis in neonates with inborn errors of metabolism," Nephrol Dial Transplant, vol, 14, no. 4, pp. 910-918 Scluffmann, R. & Brady, R. O. 2002, "New prospects for the treatment of lysosomal storage diseases," Drugs, vol. 62, no. 5, pp. 733-742 Schilsky, M. L. 2002, "Diagnosis and treatment of Wilson's disease," Fediatr Transplant, vol. 6, no. 1, pp. 15-19
1HM
NEUROLOGICAL DISEASES
Schneider,]. !•'., Bolcshauscr, [•'.., N'cuhaus, T. J., et al. 2 0 0 1 , " \ I R I and proton spectroscopy in Lowe syndrome," Neuropediatrics, vol, 32, no. 1, pp. 45-48 Schretten, D. J., Harris, J. G, Park, K. S., et al. 2001, "Ncurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphonbosyltransferase deficiency," / Int Neuropsychol Soc, vol. 7, no. 7, pp. 805-812 Schwartz, M, L., Cox. G. F., Lin. A. E., et al. 1996, "Clinical approach to genetic cardiomyopathy in children," Circulation, vol. 94, no. 8, pp. 2021-2038 Shapiro, E., Krivit, W., Lockman, L., et al. 2000, "Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy," Lancet, vol. 356, no. 9231, pp. 713-718 Sim, K. G,, Hammond, J., &c Wilcken, B. 2002, "Strategies for the diagnosis of mitochondrial fatty acid beta-oxidation disorders," Clin Chim Acta, vol. 323, no. 1-2, pp. 37-58 Simon, P., Weiss, F. U., Zimmcr, K. P., et al, 2001, "Acute and chronic pancreatitis in patients with inborn errors of metabolism," Paticreatology, vol. 1, no. 5, pp. 448-456 Steiner, R. D. &: Ccdcrbaum, S. D. 2001, "Laboratory evaluation of urea cycle disorders," / Pediatr, vol. 138, 1 Suppl, pp. S21-S29 SteinfeJd, R., Kohlsehurrer, A., Zschocke, J., ct al. 2002, "Tetrahydrobioptcrin monotherapy for phenylketonuria patients with common mild mutations," Eur J Pediatr, vol. 161, no. 7, pp. 403-405 StotklcrTpsiroglu, S. 1997, "Creatine deficiency syndromes: A new perspective on metabolic disorders and a diagnostic challenge," / Pediatr, vol. 131, no. 4, pp. 510-511 Snaus.ik, 1>., Mercer, J. F., Dieter, H. H., et al. 2001, "Copper in disorders with neurological symptoms: Alzheimer's,
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Volume II
Neurology in Clinical Practice The Neurological Disorders Fourth Edition Edited by
Walter G. Bradley, D.M., F.R.C.P Professor and Chairman, Department of Neurology1, University of Miami School of Medicine; Chief, Neurology Service, University of Miami-Jackson Memorial Medical Center, Miami, Florida
Robert B. Daroff", M.D. Chief of Staff and Senior Vice President for Academic Affairs, University Hospitals of Cleveland; Professor of Neurology and Associate Dean, Case Western University School of Medicine, Cleveland, Ohio
Gerald M. Fenichel, M.D. Professor of Neurology and Pediatrics, Vanderhilt University School of Medicine; Director, Division of Pediatric Neurology; Neuroiogist-in-Chief Vanderhilt Children's Hospital, Nashville, Tennessee
Joseph Jankovic, M.D. Professor of Neurology; Director, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas
With 120 contributing authors
U T T E R W O R T H E I N E M A N N An
Imprint of Elsevier
Volume II
Neurology in Clinical Practice The Neurological Disorders Fourth Edition Edited by
Walter G. Bradley, D.M., F.R.C.P Professor and Chairman, Department of Neurology1, University of Miami School of Medicine; Chief, Neurology Service, University of Miami-Jackson Memorial Medical Center, Miami, Florida
Robert B. Daroff", M.D. Chief of Staff and Senior Vice President for Academic Affairs, University Hospitals of Cleveland; Professor of Neurology and Associate Dean, Case Western University School of Medicine, Cleveland, Ohio
Gerald M. Fenichel, M.D. Professor of Neurology and Pediatrics, Vanderhilt University School of Medicine; Director, Division of Pediatric Neurology; Neuroiogist-in-Chief Vanderhilt Children's Hospital, Nashville, Tennessee
Joseph Jankovic, M.D. Professor of Neurology; Director, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas
With 120 contributing authors
U T T E R W O R T H E I N E M A N N An
Imprint of Elsevier
SLEEP AND ITS DISORDERS
presence of increased SWS after sleep deprivation. The critical role of REM sleep for CNS development in young organisms and increased protein synthesis in the brain during REM sleep may support the theory of restoration of hmin function by REM sleep. Although d/iu remain ^;im and controversial, studies of brain basal metabolism that suggest an enhanced synthesis of macromolccules during sleep, such as nucleic acids and proteins in the brain, provide an argument in favor of the restorative theory of sleep. The energy conservation theory is somewhat inadequate. The fact that animals with a high metabolic rate sleep longer than those with slower metabolism has been cited in support of this theory. It should, however, be noted that during 8 hours of sleep, only 120 calories are conserved. The adaptive theory suggests that sleep is an instinct that allows creatures to survive under a variety of environmental conditions. The memory reinforcement and consolidation theory suggests that memory reinforcement and consolidation take place during REM sleep. This theory has been strengthened by the observation that, after REM and SWS sleepdeprivation experiments in six young adults, perceptual learning during REM deprivation was significantly less than it was with SWS deprivation. These data suggest that REM deprivation affected the consolidation of the recent perceptual experience. The synaptic neuronal network integrity theory is an emerging thcor; proposing thai the primary tunciiun oi sleep is the maintenance of synaptic and neuronal network Table 74.6:
2001
integrity. Intermittent stimulation of neural network synapses is necessary to preserve CNS function. The concept of dynamic stabilization (repetitive activation of brain synapses and neural circuitry) suggests that REM sleep maintains motor circuits, whereas NREM sleep maintains nonmotor activities. The thermoregulatory function theory is based on the observation that thermoregulatory homeostasis is maintained during sleep, whereas severe thermoregulatoryabnormalities follow total sleep deprivation. The preoptic anterior hypothalamic neurons participate in thermoregulation and NREM sleep. These two processesare closely linked by preoptic anterior hypothalamic neurons but arc clearly separate. Thermoregulation is maintained during NREM sleep but suspended during REM sleep. Thermoregulatory responses such as shivering, piloerection, panting, and sweating are impaired during REM sleep. There is a loss of thermosensitivity in the preoptic anterior hypothalamic neurons during REM sleep,
PHYSIOLOGICAL CHANGES IN SLEEP Various physiological changes occur during NREM and REM sleep that are different from those noted during wakefulness (Chokroverry 2002). These changes are observed in somatic and autonomic nervous systems and include respiratory, cardiovascular, and gastrointestinal systems; endocrine, renal, and sexual function; and thermoregulation (Table 74.6).
Physiological changes during wakefulness, NREM sleep, and REM sleep
Physiology
Wakefulness
NREM sleep
REM sleep
Parasympathetic activity Sympathetic activity Heart rate Blood pressure Cardiac output Peripheral vascular resistance
++ ++
+++ +
Normal sinus rhythm Normal
Bradycardia Decreases Decreases Normal or decreases slightly Decreases Decreases
4-4-4-4Decreases or variable ( + + ) Urady tachyarrhythmia Variable Decreases further Decreases further
Respiratory rate Alveolar ventilation Upper airway muscle tone Upper airway resistance Hypoxic and hypercapnie ventilatory responses Cerebral blond flow Thermoregulation Gastric acid secretion Gastric motility Swallowing Salivary flow Migrating motor complex (a special type of intestinal motor activity) Penile or clitoral tumescence
Normal
Normal Normal Normal
++ 4-4Normal
Variable; apneas may occur Decreases furthet
+ ++4-
4-+++
Dcercases
1 :v, !V;LM-, further
1 ) u i r ; h i > n[ a b s i ' l l l
++
+ + or - H - +
4-4-4-4-
4-+
+
—
\ i i-'iiial
Normal Normal Normal
Variable 1 )t creases Decreases 1 (ecreases Slow velocity
Variable Decreases Decreases Decreases Slow velocity
Normal
Normal
Markedly increased
Noi null
NREM = non-rapid eye movement; REM = rapid eye movement; + = mild; ++ = moderate; + + + = marked; + + + + = very marked. - = absent.
2002
NEUROLOGICAL DISEASES
Somatic Central Nervous System Firing rates of many neurons in the CNS decrease during NREM sleep but increase during REM sleep.
Autonomic Nervous System During sleep, the autonomic nervous system undergoes several changes that may have implications for the pathophysiology of autonomic failure and sleep disorders in humans. Most of the autonomic changes involve respiration, circulation, thermoregulation, and the pupils (e.g., pupilloconstriction during sleep). During NREM sleep, there is an overall tonic increase in parasympathetic activity, which increases further during tonic REM sleep. In addition, during phasic REM sleep, sympathetic activity decreases. Sympathetic activity during REM sleep, however, increases intermittently, which results in swings of blood pressure and heart rhythm, causing bradytachyarrhythmias. Respiratory
Changes
Two systems—metabolic (or automatic) and voluntary (or behavioral)—control respiration during sleep and wakefulness. Both metabolic and voluntary systems operate during wakefulness, whereas only the metabolic system operates during NREM sleep. The wakefulness stimuli that act through the ARAS also act as tonic stimuli to ventilation. Activity decreases in the respiratory neurons in the parabrachial and Kolliker-Fuse nuclei in the pons, the nucleus tractus solitarius, nucleus ambiguus, and nucleus retroambigualis in the medulla. Respiratory muscle activity decreases slightly during NREM sleep but markedly during REM sleep. A marked decrement or even temporary suppression of intercostal muscle tone occurs during REM sleep, whereas tonic activity of the diaphragm diminishes and phasic activity continues. Muscle tone in the upper airway decreases in NREM sleep and disappears in REM sleep, resulting in an increase in upper airway resistance. The decreased sensitivity of the respiratory neurons to carbon dioxide, inhibition of the reticular activating system, and alteration of metabolic control of respiratory neurons during sleep result in a decrement of tidal volume, minute ventilation, and alveolar ventilation, In normal individuals, diminished alveolar ventilation causes arterial carbon dioxide tension (Pco 2 ) to rise by 2-8 mm Hg, the arterial oxygen tension (P02) to decrease by 3-10 mm Hg, and oxygen saturation (So2) to decrease by less than 2% during sleep. These blood -as changes are noted despite a fall in oxygen consumption and carbon dioxide production during sleep. Both hypercapnic and hypoxic ventilatory responses decrease during REM and NREM sleep, with a more marked decrease during REM sleep. These decrements result from a combination of
factors: fewer functional medullary respiratory neurons during sleep, decreased sensitivity of the central chemorcccptors subserving medullary respiratory neurons, and increased resistance in the upper airway. Arousal responses also decrease, particularly during REM sleep. The voluntary respiratory control system may be active during some portion of REM sleep. Respiration is therefore vulnerable during sleep in normal individuals. Mild respiratory irregularity- with few apneic episodes (apnea index **~~ o-L———
-^^^
^ •—~
"—
100-1
2003
synthesized and released by the pineal gland and derived from serotonin, begins to rise in the evening, attaining maximal values between 3:00 AM and 5:00 AM, and decreases to low levels during the day. Other endocrine changes include a maximum rise of aldosterone jusl before awakcnmi" in the carl; hours oi the morning and a marked decrease of plasma renin activity during REM sleep. Sexual
Function
The most striking finding is increased penile tumescence in men during REM sleep. In women, there is increased clitoral tumescence during REM sleep. Them toregulatio n iVuk rcMnuT.mnv has k v n linked intimately to the sleepwake cycle, but it follows a circadian rhythm that is independent of the sleep-wake rhythm. At the onset of sleep, body temperature begins to fall. Body temperature reaches its lowest point during the third sleep cycle. Thermoregulation is maintained during NREM sleep but is nonexistent in REM sleep, and experimental animals become poikilothcrmic. Thus physiological responses (e.g., shivering, panting, sweating, and piloerection) to thermal stimuli are depressed or absent during REM sleep.
Sleep Deprivation and Sleepiness
FIGURE 74.4 Schematic diagram to show plasma levels of hormones during 8 hours of sleep in an adult. {ADH = antidiuretic hormone; ALD = aldosterone; COR = Cortisol; GDI! = gonadotropic hormone; GH = growth hormone; MLT = melatonin; PRO = prolactin; TES = testosterone; TSH = thyroid-stimulating hormone. Zero indicates lowest secretory episode, and 100 indicates peak secretion.J (Reproduced with permission from Chokrovcrty, S. 1999, "Physiological changes in sleep," in Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, ed S. Chokrovcrty, Butterworth-Heinemann, Boston.)
Sleepiness is determined by both circadian and homcostatic factors. The circadian phase is determined by the suprachiasmatic nuclei, and it works in a biphasic manner. There arc two phases when an individual has the maximal sleepiness propensity: One phase that is intense is around 3:00-5:00 AM, and the other, which is less intense, is around 3:00-5:00 PM. In addition, there are two forbidden or dead zones. The individual is wide awake and is unable to sleep, noted around late morning and early evening. Homeostasis refers to a balance between sleep and wakefulness. After prolonged wakefulness, there is an intense desire to sleep. REM sleep is influenced by the circadian rhythm, whereas SWS is influenced by homeostasis. Much is known about the physiology of circadian rhythm, but the neurobiology of the homeostatic influences remains largely unknown. Excessive sleepiness, therefore, may result from both circadian dysrhythmia and disruption of homeostasis of the body. A large segment of the population working different shifts and having irregular sleep-wake schedules is chronically sleep deprived (Bonnet and Arand 1995). The at-risk groups include doctors, nurses, firefighters, interstate truck drivers, police officers, overnight train drivers, and high school and college students. Compared with a survey conducted in the beginning of the last century and another
2004
NEUROLOGICAL DISEASES
toward the end of the century, modern America is sleep deprived by approximately 1.5 hours of sleep (Harrison and Home 1995). This does not necessarily mean that the sleep requirement is less today, but, simply, it means that people are sleep deprived. However, there may be a sampling error in these two surveys: for example, 2000 people were sampled in the earlier survey versus 311 in the later survey. Increased environmental light and sound, industrialization. increasing r, umber i of people work in L: in various shifts, and the advent of television and radio are cited as some of the factors responsible for this reduction of total sleep hours. Harrison and H o m e (1995), however, argued that most people are not chronically sleep deprived but have the capacity to take more sleep. In one epidemiological study, sleepiness in Western society was estimated to be found in 5-36% of the total population. Experiments have been conducted to study the consequences of total, partial, and selective sleep deprivation. These experiments have shown clearly that in animals sleep is necessary for survival, but studies of complete sleep deprivation for prolonged periods (e.g., weeks to months) cannot be conducted in humans from a practical point of view. Experiments in rats using a carousel device have provided evidence that sleep is essential for survival. All rats deprived of sleep for 10-30 days died after having lost weight despite increasing food intake. The rats also lost temperature control. It took longer for rats deprived of REM sleep to die than those deprived of SWS.
deprivation. The REM sleep percentages also increase during the recovery sleep after a prolonged period of sleep deprivation, but this increment of REM sleep percentage was not shown after short periods of sleep deprivation for 4 days. These facts might suggest that different mechanisms regulate NREM and REM sleep. Partial and Selective Steep Deprivation Measurements of mood and performance after partial sleep deprivation (e.g., restricting sleep to 4.5-5.5 hours for 2-3 months) showed minimal deficits in performance, which may have been related to decreased motivation. After selective REM deprivarion, PSC studies showed increased REM pressure (i.e., earlier and more common onset of REM sleep during successive nights) and REM rebound (i.e., quantitative increase of REM pcrcenrages during recovery sleep). The observation of a psychotic reaction after REM deprivation as noted by Dement was proved to be inaccurate in subsequent investigations. Similar ro REM deprivation, after stage IV NREM sleep deprivation for two consecutive nights, there is an increase in stage IV sleep during the recovery night. It is more difficult to deprive a person of stage IV NREM sleep than of REM sleep. In summary, these experiments have proven conclusively that sleep deprivation causes sleepiness and impairment of performance, vigilance, attention, and concentration but does not cause permanent memory or other CNS changes,
Total Sleep Deprivation Consequences of Excessive Daytime Sleepiness One of the earliest experiments in sleep deprivation in humans was in 1896 (Chokroverty 1999a). The effects of a 90-hour period of sleep deprivation were studied in three healthy young men. All subjects had difficulty staying awake, hut they felt totally refreshed and rested after they were allowed to sleep for 10 hours. One of them, however, had sensory illusions that disappeared completely after icon, LTV i>' sleep period, hi I Vfi.S, a spectacular experiment was conducted when a 17-year-old California college student named Randy Gardner (Chokroverty 1999a) tried to set a new world record for staying awake. He remained awake for 264 hours and 12 minutes and then slept for 14 hours and 14 minutes, after which he recovered fully. Thus the conclusion of the experiment was that it was possible to deprive people of sleep for a prolonged period without causing serious mental impairment. Other important observations include frequent occurrence of ''microsleep 1 ' episodes (i.e., brief episodes of NREM sleep) and loss of performance that may have been caused by the loss of molivation. Several order cvpcriiticnls Liter in humans showed no permanent adverse effects after sleep deprivation. However, sleep deprivation increases the daytime tendency to sleep as proven by multiple sleep latency tests in such subjects. The percentage of SWS increases considerably during the tccovery sleep period after sleep
Consequences of EDS (Table 74.7) are discussed under the following four headings: (1) performance and productivity ,u work and school; ;1 Imnur cerebral functions; (3) quality of life and social interactions; and (4) morbidity and mortality (Roth and Roehrs 1996). Performance and Productivity at
Work and School
Impaired performance and reduced productivity at work for shift workers, reduced performance in class for school and college students, and impaired job performance in patients with narcolepsy, sleep apnea, circadian rhythm disorders, and chronic insomnia are well-known adverse effects of sleep deprivation and sleepiness. Sleepiness and .issoi.-i.ilcd rn irhuiil v are worse- in niejit sliiti workers, older workers, and female shift workers. Table 74,7:
Consequences of excessive daytime sleepiness
Impaired performance and productivity Impaired short-term memory, attention, conception, and cognition Impaired quality of life Psychological stress Increased morbidity and mortality: i.e., increased likelihood of accidents
SLEEP AND ITS DISORDERS
Higher Cerebral Functions Sleepiness interferes with higher cerebral functions, causing impairment of short-term memory, concentration, attention, cognition, or intellectual performance. Psychometric tests document increased reaction time in patients with excessive sleepiness. These individuals make increasing numbers of errors, and they need increasing time to reach the target in reaction time tests (Dinges 1995). Sleepiness also can impair perceptual skills and new learning. Insufficient sleep and excessive sleepiness may cause irritability, anxiety, and depression. Learning disabilities and cognitive impairment due to impaired vigilance also have been described (Roth and Rochrs 1996). Quality of Life and Social Interaction People complaining of F.DS are often under severe psychological stress. They are often wrongly perceived as dull, lazy, and downright stupid. Excessive sleepiness may cause severe marital and social problems. Individuals with this problem have serious difficulty with interpersonal relationships. In a survey of 180 narcoleptic patients, one third thought that they were misunderstood because of their symptoms. Shift workers constitute approximately 2 0 - 2 5 % of the work force in America (i.e., approximately 20 million). A majority of them have difficulty with sleeping, and sleepiness as a result of insufficient sleep and circadian dysrhythmia. Many of them have an impaired quality of life, marital discord, and gastrointestinal problems. Increased Morbidity and Mortality Persistent daytime sleepiness causes individuals to have an increased likelihood of accidents. Estimates by the U.S. National Highway Traffic Safety Administration showed that approximately 56,000 police-reported crashes per year resulted from drivers who were "asleep at the wheel" (Knipling and Wang 1994). New York police estimate that 3 0 % of all fatal crashes along the New York Thruway occur because the driver fell asleep at the wheel. Approximately 1 million crashes annually (one sixth of all crashes) are thought to be produced by driver inattention or lapses. Sleep deprivation and fatigue make such lapses more likely to occur. Truck drivers are especially susceptible to fatiguerelated crashes (Lyznicki et al. 1998). Many truckers drive during the night while they are sleepiest. Truckers also may have a high prevalence ol sleep apnea. The I ".S. Department of Transportation estimates that 200,000 automobile accidents each year may be related to sleepiness. Nearly one third of all trucking accidents that are fatal to the driver are related to sleepiness and fatigue. The presence of sleep disorders (see Primary Sleep Disorders Associated with Excessive Daytime Sleepiness, later in this chapter) increases the risk of crashes.
2005
Individuals with untreated insomnia, sleep apnea, and narcolepsy and shift workers, all of which cause excessive sleepiness, have more automobile crashes than other drivers (Costa de Silva et al. 1996). A 1991 Gallup organization national survey found that individuals with chronic insomnia report 2.5 times as many fatigue-re la ted automobile accidents than did those without insomnia. The same 1991 Gallup survey found serious morbidity associated with untreated sleep complaints as well as impaired ability to concentrate and accomplish daily tasks, impaired memory, and interpersonal difficulties. A 1994 telephone survey of drivers by the New York State Task Force estimated that approximately 2 5 % reported that they had fallen asleep at the wheel at some time. Young male drivers are especially susceptible to crashes caused by falling asleep as documented in a study in North Carolina in 1990, 1991, and 1992 (e.g., in 5 5 % of the 4333 crashes, the drivers were predominantly male and 25 years of age or younger). In the October 1995 Gallup poll, 5 2 % of all adults surveyed said that in the past year they had driven a car or other vehicle while feeling drowsy, 3 1 % of adults admitted dozing off while at the wheel of a car or other vehicle, and 4% reported having had an automobile accident because of tiredness during driving. A number of national and international catastrophes involving industrial operations, nuclear power plants, and all modes of transportation have been related to sleepiness and fatigue (Dinges 1995): for example, the Exxon Valdez oil spill in Alaska; the nuclear disaster at Chernobyl in the former Soviet Union; the near-nuclear disaster at Three Mile Island in Pennsylvania; the gas leak disaster in Bhopal, India, resulting in 25,000 deaths; and the Challenger space shuttle disaster.
Causes of Excessive Daytime Sleepiness Excessive sleepiness may result from both physiological and pathological causes (Table 74.8). Physiological
Causes of Sleepiness
Sleep deprivation and sleepiness because of lifestyle and habits of going to sleep and waking up at irregular hours can be considered to result from disruption of the normal circadian and homeostatic physiology. Groups who are excessively sleepy because of lifestyle and inadequate sleep include young adults and elderly individuals, workers at irregular shifts, health care professionals (e.g., doctors, particularly the house staff, and nurses), firefighters, police officers, train drivers, pilots and flight attendants, commercial truck drivers, and those individuals with competitive drives to move ahead in life, sacrificing hours of sleep and accumulating sleep debt. Among young adults, high school and college students are particularly at risk for sleep deprivation and sleepiness. The reasons for excessive
2006
NEUROLOGICAL DISEASES
Table 74.8:
Causes of excessive daytime sleepiness
Physiological causes Sleep deprivation and sleepiness related to lifestyle and irregular sleep-wake schedule Pathological causes Primary sleep disorders Obstructive sleep apnea syndrome Central sleep apnea syndrome Narcolepsy Idiopathic hypersomnolence Circadian rhythm sleep disorders Jet lag Delayed sleep phase syndrome Irregular sleep-wake pattern Shift work sleep disorder Noii-24-hour sleep-wake disorders Periodic limb movement disorder Restless legs syndrome Insufficient sleep syndrome Inadequate sleep hygiene Recurrent or periodic hypersomnia Kleine-Levin syndrome Idiopathic recurrent stupor Catamenial hypersomnia Seasonal affective depression Occasionally due to insomnia General medical disorders Hepatic failure Renal failure Respiratory failure Electrolyte disturbances Cardiac failure Severe anemia Endocrine causes
I lypothyroidism Acromegaly Diabetes mcllitus Hypoglycemia Hyperglycemia Psychiatric or psychological causes Depression Psychogenic unresponsiveness or sleepiness Neurological causes Brain tumors or vascular lesions affecting thalamus, hypothalamus, or brainstem Post-traumatic hypersomnolence Multiple sclerosis Encephalitis Icthargica and other cnccphalitidcs and encephalopathies including Wernicke's encephalopathy Cerebral trypanosomiasis (African sleeping sickness) Neurodegenerative disorders Alzheimer's disease Parkinson's disease Multiple system atrophy Myotonic dystrophy and other neuromuscular disorders causing sleepiness secondary to sleep apnea Medication-related hypersomnia
sleepiness in adolescents and y o u n g adults include both biological a n d psychosocial factors. Some of the causes for later bedtimes in these g r o u p s include social interactions Willi peers, h o m e w o r k in the evening, sports, employment or other extracurricular activities, early w a k e - u p times to start school, and a c a d e m i c obligations requiring additional school or college w o r k at night. Biological factors m a y play a role but are n o t well studied. For e x a m p l e , teenagers may need extra h o u r s of sleep. Also, the circadian timing system may change with sleep phase delay in teenagers. EDS associated with shift w o r k is described (see P r i m a r y Sleep Disorders Associated with Excessive D a y t i m e Sleepiness, later in this chapter).
upper brainstem) m a y p r o d u c e excessive sleepiness. P r o l o n g e d h y p e r s o m n i a m a y be associated with t u m o r s in t h e region of the third ventricle. S y m p t o m a t i c narcolepsy resulting from c r a n i o p h a r y n g i o m a a n d o t h e r t u m o r s of the h y p o t h a l a m i c and pituitary regions has been described (Aldrich 1993). C a t a p l e x y associated with sleepiness, sleep paralysis, a n d h y p n a g o g i c hallucinations h a s been described in patients with rostral brainstem g l i o m a s with or w i t h o u t infiltration of the walls of the third ventricle. N a r c o l e p s y - c a t a p l e x y also h a s been described in a H L A D R 2 a n t i g e n - n e g a t i v e patient with a p o n t i n e lesion d o c u mented by magnetic r e s o n a n c e imaging ( M R I ) .
Pathological
Causes
of
Sleepiness
Neurological Causes of Excessive Sleepiness. Tumors and vascular lesions affecting the ascending reticulat activating arousal system a n d its projections to t h e p o s t e r i o r h y p o t h a l a m u s and t h a l a m u s lead to daytime sleepiness (Aldrich 1993). It should be n o t e d t h a t lesions of this system often cause c o m a rather than just sleepiness. Brain t u m o r s (e.g., a s t r o c y t o m a s , suprasellar cysts, metastases, l y m p h o m a s and h a m a r t o m a s affecting the posterior h y p o t h a l a m u s , pineal t u m o r s , and a s t r o c y t o m a s of the
Benzodiazepines
Nonbcnzodiazepine hypnotics, e.g., phenobarbital, Zolpidem Sedative antidepressants, e.g., tricyclics, trazodone Antipsychotics Nonbcnzodiazepine anxiolytics, e.g., buspirone Antihistamines Narcotic analgesics including tramadol (Ultram) Beta blockers Toxin and alcohol-induced hypersomnolence
O t h e r neurological causes of EDS include bilateral p a r a m e d i a n thalamic infarcts (Bassctti et al. 1996), p o s t - t r a u m a t i c h y p e r s o m n o l e n c e , a n d multiple sclerosis. N a r c o l e p s y - c a t a p l e x y has been described in occasional patients with multiple sclerosis a n d a r t e r i o v e n o u s malform a t i o n s in the d i e n c e p h a l o n (Calvelou ct al. 1995). EDS has been described in association w i t h encephalitis lethargica a n d o t h e r encephalitides as well as e n c e p h a l o p athies including W e r n i c k e ' s e n c e p h a l o p a t h y . It w a s n o t e d t h a t the lesions of encephalitis Icthargica described by Von E c o n o m o in the beginning of this c e n t u r y , which severely affected the posterior h y p o t h a l a m i c region, were associated w i t h the clinical manifestation of e x t r e m e s o m n o l e n c e .
SLEEP AND ITS DISORDERS
These lesions apparently interrupted the ascending arousal systems projecting to the posterior hypothalamus. Encephalitis lerhargica is now extinct. Cerebral sarcoidosis involving the hypothalamus may cause symptomatic narcolepsy. Whipple's disease of the nervous system involving the hypothalamus may occasionally cause hypcrsomnolence. Cerebral trypanosomiasis, or African sleeping sickness, is transmitted to humans by tsetse flies: Trypanosoma gambiense causes Gambian or West African sleeping sickness, and Trypanosoma rbodesiense causes East African sleeping sickness. Certain neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple system atrophy also may cause EDS. The causes of EDS in Alzheimer's disease include degeneration of suprachiasmatic nucleus resulting in arcadian dysrhythmia, associated sleep apnea-hypopnea, and periodic limb movements in sleep, In Parkinson's disease, excessive sleepiness may be due to the associated periodic limb movements in sleep, sleep apnea, and depression. EDS in multiple system atrophy associated with cerebellar parkinsonism or parkinsoniancerebellar syndrome and progressive autonomic deficit (Shy-Drager syndrome) may be caused by the frequent association with sleep-related respiratory dysrhythmias and possible degeneration of the reticular activating arousal systems (Chokrovcrty 1999b). Sleep disorders are being increasingly recognized as a feature of Parkinson's disease and other parkinsonian disorders. Although some studies have attributed the excessive daytime drowsiness and irresistible sleep episodes ("sleep attacks") to anti-parkinsonian medications (Ondo et al. 2001), sleep disturbances are also an integral parr of Parkinson's disease (Arnulf et al. 2002). In one study of 303 patients with Parkinson's disease, 2 1 % reported falling asleep while driving (Ondo et al. 2002). Several studies also reported a relatively high incidence (10-20%) of symptoms of restless legs syndrome in patients with Parkinson's disease (Ondo et al. 2002; Krishnan et al. 2003). There is also increasing awareness about the relationship between parkinsonian disorders and REM sleep behavior disorder (RBD), and RBD may be the presenting feature of Parkinson's disease, multiple system atrophy, and other parkinsonian disorders (Gagnon et a I. 2002). These and other studies provide evidence supporting the notion that dopamine activity is normally influenced by circadian factors (Rye and Jankovic 2002). For example, tyrosine hydroxylase levels fall several hours before waking and their increase correlates with motor activity. The relationship between hypocretin and sleep disorders as so ciated with Parkinson's disease is currently being explored (Overeem et al. 2002). Myotonic dystrophy and other neuromuscular disorders may cause EDS due to associated sleep apnea-hypopnea syndrome and hypoventilation. In addition, in myotonic dystrophy, there may be involvement of the ARAS as part of the multisystem membrane effects noted in this disease.
2007
Excessive Daytime Sleepiness Associated with General Medical Disorders. Several systemic diseases such as hepatic, renal, or respiratory failure and electrolyte disturbances may cause metabolic encephalopathies that result in FDS. Patients with severe EDS drift into a coma. The other medical causes for EDS include congestive heart failure (CHE) and severe anemia. Hypothyroidism and acromegaly also may cause EDS due to the associated sleep apnea syndrome. Hypoglycemic episodes in diabetes mellitus and severe hyperglycemia arc additional causes of EDS. Primary Steep Disorders Associated with Excessive Daytime Sleepiness. A number of primary sleep disorders cause excessive sleepiness (Tables 74.8 and 74.9). The most common cause of FJDS in the general population is insufficient sleep syndrome associated with sleep deprivation. The next most common cause is obstructive sleep apnea syndrome (OSAS); narcolepsy and idiopathic hypersomnolence are other common causes of EDS. Most patients with EDS referred to the sleep laboratory have OSAS. Other causes of EDS include circadian rhythm sleep disorders, periodic limb movement disorder, and restless legs syndrome, some cases of chronic insomnia, and inadequate sleep hygiene (sec later). Many sedatives and hypnotics cause EDS. In addition to the benzodiazepine and nonbenzodiazepine hypnotics and sedative anti-depressants (e.g., tricyclic antidepressants and trazodone) as well as nonbenzodiazepine neuroleptics {e.g., buspirone), antihistamines, antipsychotics, and narcotic analgesics including tramadol (Ultram) cause EDS. Beta blockers for treatment of the hypertension also may cause excessive sleepiness. Toxin and alcohol-related hyper somnolence can occur as well. Many industrial toxins such as heavy metals and organic toxins (e.g., mercury, lead, arsenic, and copper) may cause EDS. These may sometimes also cause insomnia. Individuals working in industrial settings using toxic chemicals routinely are ar risk. These toxins also may cause systemic disturbances such as alteration of renal, liver, and hematological function. There may be an impairment of nerve conduction. Chronic use of alcohol ar bedtime may produce alcohol-dependent sleep disorder. Usually, this causes insomnia, but sometimes the patients may have excessive sleepiness in the daytime. Many of these patients suffer from chronic alcoholism. Acute ingestion of alcohol causes transient sleepiness.
CLASSIFICATION OF SLEEP DISORDERS The original diagnostic classification of sleep and arousal disorders by the Association of Sleep Disorder Centers categorized sleep-wake disorders into four classes: (1) disorders of initiating and maintaining sleep, (2) disorders of excessive somnolence, (3) disorders of sleep-wake schedule, and (4) dysfunctions associated with sleep,
2008
NEUROLOGICAL DISEASES
Tabic 74.9:
International classification of sleep disorders
Dyssomnias Intrinsic sleep disorders Psychophysiological insomnia Sleep-state mis perception Idiopathic insomnia Narcolepsy Recurrent hypersomnia Idiopathic hypersomnia Obstructive sleep apnea syndrome Central sleep apnea syndrome Central alveolar hypoventilation syndrome Periodic limb movement disorder Restless legs syndrome Intrinsic sleep disorders NOS Extrinsic sleep disorders Inadequate sleep hygiene Environmental sleep disorder Altitude insomnia Adjustment sleep disorder Insufficient sleep syndrome Limit-setting sleep disorder Sleep-onset association disorder Food allergy insomnia Nocturnal eating (drinking) syndrome Hypnotic-dependent sleep disorder Stimulant-dependent sleep disorder Alcohol-dependent sleep disorder Toxin-induced sleep disorder Extrinsic sleep disorders NOS Circadian rhythm sleep disorders Time-zone (jet lag) syndrome Shift work sleep disorder Irregular sleep-wake pattern disorder Delayed sleep-phase syndrome Advanced sleep-phase syndrome Non-24-hour sleep-wake disorder Circadian rhythm sleep disorders NOS Parasomnias Arousal disorders Confusional arousals Sleepwalking Sleep terrors Sleep-wake transition disorders Rhythmic movement disorders Sleep starts Sleep talking Nocturnal leg cramps Parasomnias usually associated with REM sleep Nightmares Sleep paralysis Impaired sleep-related penile erections
Sleep-related painful erections REM sleep-related sinus arrest REM sleep behavior disorder Other parasomnias Sleep bruxism Sleep enuresis Sleep-related abnormal swallowing syndrome Nocturnal paroxysmal dystonia Sudden unexplained nocturnal death syndrome Primary snoring Infant sleep apnea Congenital central hypoventilation syndrome Sudden infant death syndrome lii'iiis'.ii univ II.d .'.li :p niyci. onus
Other parasomnias NOS Sleep disorders associated with medical or psychiatric disorders Mental disorders Psychoses Mood disorders Anxiety disorders Panic disorders Alcoholism Neurological disorders Cerebral degenerative disorders Dementia Parkinsonism Fatal familial insomnia Sleep-related epilepsy Electrical status epilepticus of sleep Sleep-related headaches Other medical disorders Sleeping sickness Nocturnal cardiac ischemia Chronic obstructive pulmonary disease Sleep-related asthma Sleep-related gastroesophageal reflux Peptic ulcer disease Fibromyalgia Proposed sleep disorders Short sleeper Long sleeper Subwakefulness syndrome Fragmentary myoclonus Sleep hypcrhidrosis Menstrua I-associated sleep disorder Pregnancy-associated sleep disorder Terrifying hypnagogic hallucinations Sleep-related neurogenic tachypnea Sleep-related laryngospasm Sleep choking syndrome
NOS = not otherwise specified; REM = rapid eye movement.
sleep stages, or partial arousals ( p a r a s o m n i a s ) . T b i s classification has been supplanted by the 1 9 9 0 International Classification of Sleep Disorders (ICSD), which w a s revised slightly in 1 9 9 7 . T h e ICSD system is the one used by sleep specialists; it lists 84 sleep disorders in tour b r o a d catcgories: d y s s o m n i a s , p a r a s o m n i a s , sleep disorders associated
with medical or psychiatric disorders, a n d p r o p o s e d sleep d i s o r d e r s (see T a b l e 7 4 . 9 ) . D y s s o m n i a s are subdivided into intrinsic, extrinsic, a n d c i r c a d i a n r h y t h m sleep disorders. Intrinsic disorders result from causes in the b o d y , w h e r e a s extrinsic disorders a r e primarily caused by e n v i r o n m e n t a l factors. C i r c a d i a n
SLEEP AND ITS DISORDERS
rhythm disorders result from disruption of sleep-wake schedule changes. Parasomnias arc characterized hy abnormal movements and behavior intruding into sleep without necessarily disturbing sleep architecture. These consist of arousal and sleep-wake transition disorders, REM-related parasomnias, and others. Medical or psychiatric sleep disorders include those attributable to another condition; they are caused by mental (psychiatric), neurological, and other medical disorders. Proposed sleep disorders include disorders for which inadequate or insufficient information is available to substantiate with certainty the existence of that particular disorder. The ICSD includes descriptive details, specific diagnostic criteria, severity, and duration. There is also coding information for clinical and research purposes. In addition to the ICSD two other systems are used: the International Classification of Diseases (ICD), ninth revision, clinical modification, and the ICD, tenth revision [ICD-10). The 1CD-10NA is an expansion of ICD-10 with alphanumeric codes for every neurological disease, including specific sleep disorders. There has been no study to assess the validity and reliability of any classification of sleep disorders.
Approach to a Patient with Sleep Complaints The approach to a patient with a sleep complaint must begin with a clear understanding about sleep disorders as listed in the ICSD. Some common sleep complaints are trouble falling asleep and staying asleep (insomnia); falling asleep during the day (daytime hypersomnolence); and inability to sleep at the right time (circadian rhythm sleep disorders). Other common complaints are thrashing and moving about in bed with repeated leg jerking (parasomnias and other abnormal movements, including nocturnal seizures) and restless legs syndrome (RLS). Cardinal manifestations in a patient complaining of insomnia include all or some of the following: difficulty falling asleep; frequent awakenings, including earlymorning awakening; insufficient or total lack of sleep; daytime fatigue, tiredness, or sleepiness; lack of concentration, irritability, anxiety, and sometimes depression and forget fulness; and preoccupation with psychosomatic symptoms, such as aches and pains. Cardinal manifestations of hypersomnia include EDS, falling asleep in an inappropriate place and under inappropriate circumstances, no relief of symptoms after additional sleep at night, daytime fatigue, inability to concentrate, and impairment of motor skills and cognition. Additional symptoms depend on the nature of the underlying sleep disorder (e.g., snoring and apneas during sleep witnessed by a bed partner in patients with OSAS; attacks of cataplexy, hypnagogic hallucinations, sleep paralysis,
2009
automatic behavior, and disturbed night sleep in patients with narcolepsy). Sleeplessness and EDS are symptoms; therefore, every attempt should be made to find a cause for these complaints. Insomnia may be due to a variety of causes. The etiological differential diagnosis for EDS may include OSAS; central sleep apnea (C'SAt; narcolepsy; idiopathic hypersomnia; several psychiatric, neurological, and other medical illnesses; drug or alcohol abuse; and periodic hypersomnolence (e.g., Kleine-Levin syndrome, idiopathic recurrent stupor, and caramenial hypersomnolence). Sometimes a patient with RES may complain of f'.DS. Abnormal movements and behavior during sleep include REM and NREM sleep parasomnias and other abnormal movements (e.g., periodic limb movements in sleep [PLMS]), some daytime movement disorders that persist during sleep, and nocturnal seizures. The physician must evaluate the patient first on the basis of the history and physical examination before undertaking laboratory tests, which must be determined by the clinical diagnosis (Chokroverty 1999a). The first step in the assessment of a sleep-wakcfulncss disturbance is careful evaluation of the sleep complaints. The history should include information on the patient's entire 24 hours and must include a detailed sleep history, with a sleep questionnaire as well as a sleep log or diary. It must also include psychiatric, neurological, medical, drug alcohol, and family and past histories. The history must be followed by a physical examination to uncover medical or neurological causes of insomnia, hypersomnia, and parasomnias. Physical examination of patients with OSAS may uncover upper airway anatomic abnormalities. It is advisable to interview the bed partner, caregiver, or parents of children to get an adequate history, particularly the history during sleep at night, which may have an effect on daytime functioning. A sleep questionnaire containing a list of pertinent questions relating to sleep complaints; sleep hygiene; sleep patterns; medical, psychiatric, and neurological disorders; and drug and alcohol use may be filled out by the patient to save time during the history taking. A sleep log kept over a 2-weck period also is a valuable indicator of sleep hygiene. Such a log should include information on bedtime, arising time, daytime naps, amount of time needed to go to sleep, number of nighttime awakenings, total sleep time, and feelings on arousal. 0 L l L ' s t i° l l s should be asked regarding the patient's mood and naps during the daytime, hi women, the relation of sleepiness to the menstrual cycle also should be ascertained. Pertinent questions can help diagnose primary sleep disorders. For example, a history of snoring and apneas witnessed during sleep at night would suggest OSAS. Unusual movements during sleep at night may suggest periodic limb movement disorder. A history of short sleep attacks, cataplexy, hypnagogic hallucinations, sleep paralysis, and disturbed night sleep in a young adult suggests narcolepsy. Nonrefreshing sleep or no benefit from
2010
NEUROLOGICAL DISEASES
additional sleep may suggest sleep apnea syndrome and idiopathic hypersomnolence. Identification of an irregular sleep-wake schedule and delayed sleep onset and awakening and inquiry into the patient's lifestyle to uncover sleep deprivation and insufficient sleep are important for the diagnosis of sleepiness. Paresthesias and uncontrollable limb movements at sleep onset or in the early evening may suggest RLS. A family history is important in primary sleep disorders such as narcolepsy, RLS, and OSAS, which may be responsible for EDS.
Subjective Measures of Sleepiness A variety of scales have been developed to assess the subjective degree of sleepiness. The Stanford Sleepiness Scale (Table 74.10) is a seven-point scale to measure subjective sleepiness but may not be reliable in patients with persistent sleepiness (Robinson and Guilleminault 1999). Another scale is the visual analogue scale of alertness and well-being. In this scale, subjects are asked to indicate their feelings on an arbitrary line. This scale has been used successfully in circadian rhythm disorders. The Epworth Sleepiness Scale evaluates general level of sleepiness (Johns 1998). The patient is rated on eight situations with a score of 0-3 (3 being the highest chance of dozing off). The maximum score is 24, and a score greater than 10 suggests the presence of excessive sleepiness (Table 74.11). This scale has been weakly correlated with the multiple sleep latency test (MSIT) scores.
CLINICAL PHENOMENOLOGY In this section, the clinical characteristics of selected sleep disorders arc described.
Insomnia Insomnia is a symptom rather than a disease and is characterized by an inadequate amount of sleep or impaired quality of sleep (Chesson et al. 2000; Satei et al. 2000).
Table 74.10:
Stanford sleepiness scale
1. Wide awake, active, and alert 2. Awake and able to concentrate but not functioning at peak 3. Relaxed, awake, and responsive but not fully alert 4. Feeling a little foggy 5. Difficulty staying awake 6. Sleepy, prefer to lie down 7. Cannot stay awake; sleep onset is imminent Source: Modified with permission from Hoddes, E., Zareone, V,, Smythe, H., et a\. 1973, "Quantification of sleepiness: A new approach," Psychophysiology, vol. 10, pp. 431-436.
Table 74.11:
Epworth sleepiness scale
Eight situations
Scores*
1. Sitting and reading 2. Watching television 3. Sitting in a public place (e.g., a theater or a meeting) 4. Sitting in car as a passenger for ;iu In iLLi• v. iihtuii .i break 5. Lying down to rest in the afternoon 6. Sitting and talking to someone 7. Sitting quietly after a lunch without alcohol 8. In a car, while stopped for a few minutes in traffic
— — — — — — —
*Scale to determine the total scores: 0 = would never doze; 1 = slight chance of dozing; 2 = moderate chance of dozing; 3 = high chance of dozing. Source: Modified with permission from Johns, M. W. 1991, "A new method for measuring daytime sleepiness: The Epworth sleepiness scale," Sleep, vol, 14, pp. 540-545.
People with insomnia complain of difficulty initiating or maintaining sleep, which causes sleep that does not restore or refresh and impairment of daytime functioning. The National Institute of Mental Health (NIMH) consensus conference in 1984 divided insomnia (Chokroverty 2003b) into transient (1 week), short-term (1—3 weeks), and chronic (>3 weeks). The ICSD includes 14 categories that may have insomnia as a prominent complaint (included under the category of dyssomnias) and can occur in intrinsic, extrinsic, and circadian rhythm sleep disorders. Insomnia is the most common sleep disorder in the population. In one survey, 3 5 % of adults between the ages of 18 and 79 years complained of insomnia in the past year (Chokroverty 2003b). In the NIMH Epidemiological Catchment Area Study (1981-1985), 1 0 % of the subjects responding to a sleep questionnaire had had problems sleeping for 2 weeks or more in the preceding 6 months; the problems were not related to neurological or psychological conditions. Other surveys have confirmed that insomnia affects about one third of the adult population in the United States at one time or another, and in 10%, it is a persistent problem {Leger et al. 2000; Ohayon and Guilleminault 1999). The prevalence of insomnia increases with age, and symptoms were more prevalent in women than in men. There is also a higher prevalence of insomnia among persons of lower socioeconomic status; in divorced, widowed, or separated individuals; and in those experiencing recent stress, depression, drug or alcohol abuse and anxiety disorder (Kirsti et al. 2003). Clinical
Manifestations
of Insomnia
The symptoms of insomnia often interfere with interpersonal relationships or job performance. Decrements in daytime task performance and prolonged reaction times have been reported in patients complaining of insomnia (Chokroverty 2003b). Formal cognitive and motor skill
SLEEP AND ITS DISORDERS tests generally do not detect objective evidence of impairment. The NIMH Epidemiological Catchment Area Study, however, indicated an increased risk of major depression in those with chronic insomnia. A 1991 Gallup survey found that patients who report sleep deprivation due to chronic insomnia have 2.5 times as many automobile accidents as those who report fatigue from other causes. Some of these excessive risks may relate to the increasing proportion of drug or alcohol abuse with insomnia. Long-term detrimental health effects due to insomnia have not been documented, but one prospective study reported an increased chance of deaths from cancer, stroke, or heart disease among persons who reported sleeping for less than 4 hours or more than 10 hours per night (Chokroverty 1999a). These results have not been corroborated and may have been confounded by several factors. Objective tests for sleepiness (e.g., the MSI.T) document that people with insomnia are no more sleepy than age-matched normal control subjects; in fact, those with insomnia are less sleepy than normal control subjects, which suggests a hyperarousal state. These findings may also be due to an impaired perception of sleep. In one study, more than 7 0 % of patients with chronic insomnia and more than 30% of normal subjects reported being awake if awakened from stage II NREM sleep (Mahowald et al. 1997) and patients wirh insomnia tend to overestimate sleep latency (the deviation of time between lights-out and the onset of sleep) after nocturnal awakenings. Patients with insomnia also tend to mispcrceive prior sleep as wake time, thus underestimating total sleep time (Mercer et al. 2002). Causes of Insomnia Insomnia is a heterogeneous condirion that may result from a wide variety of factors. Multiple causes may contribute to insomnia in an individual, and different causes may be responsible for different types of insomnia (transient, shortterm, and chronic). Transient and Short-Term Insomnia. Factors that can result in transient or short-term insomnia are similar, but the disturbances that produce short-term insomnia are of greater magnitude. Causes of transient and short-term insomnia arc listed in Table 74.12. Tabic 74,12:
Causes of transient and short-term insomnia
A change of sleeping environment (the most common cause of transient insomnia, the so-called first night effect) Jet lag Unpleasant room temperature Stressful life events (e.g., loss of a loved one, divorce, loss of employment, preparing to take an examination) Acute medical or surgical illnesses (including intensive care units) Stimulant medications (e.g., theophylline, beta blockers, corticosteroids, thyroxine, bronchodilators, or withdrawal of central nervous system depressant medications)
2011
Jet lag is experienced after travel through several time zones, which disrupts the synchronization between the body's inner clock and external cues (Bearpark 1994). Some of these sleep problems result from "jet" factors and others from "lag" factors. Jet factors that may be detrimental to sleep include long periods of travel with limited mobility, dryness of the eyes, headache, fatigue, gastrointestinal disturbances, and nasal congestion. Lag factots result in dyssynchrony berween the body's internal clock and the sleep schedule of the new environment. Symptoms are usually most pronounced when travel is from west to east and are more severe in elderly individuals. Readjustment and resynchronization occur at a rate of about 1 hour per day when one travels eastward and 1.5 hours per day when one travels westward (Bearpark 1994). Shift work may affect up to 5 million workers in the United States; it can cause sleep disruption, chronic fatigue, gastrointestinal symptoms (including peptic ulcer), an increased chance of traffic accidents, and increased errors on the job. Drug-related insomnia includes rebound insomnia on discontinuation of short- and intermediateacting hypnotics. Other drugs that may be responsible for insomnia are listed in Table 74,12. Chronic Insomnia. Chronic insomnia can be caused by the chronic use of drugs or alcohol; various medical, neurological, or psychiatric disorders; or a variety of primary sleep disorders (Table 74.13). Persistent insomnia can result directly from a medical illness (Table 74.14) or indirectly from the medications required for treatment of that illness. For example, sleep disruption may be caused by paroxysmal nocturnal dyspnea in patients with untreated CHF, whereas treatment with diuretics may disturb sleep by causing nocturia. Similar situations occur with nocturnal angina, chronic obstructive pulmonary disease (COPD), and bronchial asthma. Asthma may be exacerbated at night, with coughing and wheezing, which is related to several circadian factors {Chokroverty 1999c). Table 74.13:
Causes of chrome insomnia
General medical disorders Neurological disorders, including fatal familial insomnia and post-traumatic insomnia Psychiatric disorders Drug- or alcohol-related insomnia Primary sleep disorders Primary or idiopathic (used to be called childhood-onset insomnia) Psychophysiological insomnia Circadian rhythm disorders associated with insomnia Sleep-state misperceprion Restless legs syndrome Periodic timb movements in sleep Inadequate sleep hygiene Altitude insomnia Insufficient sleep syndrome Central sleep apnea-insomnia syndrome
2012
NEUROLOGICAL DISEASES
Tabic 74.14:
Medical causes of insomnia
Congestive heart failure Ischemic heart disease Nocturnal angina Chronic obstructive pulmonary disease Bronchial asthma including nocturnal asthma Peptic ulcer disease Reflux esophagitis Rheumatic disorders, including fibromyalgia syndrome Lyme disease Acquired immunodeficiency syndrome Chronic fatigue si ndrome
Neurological disorders causing insomnia are listed in T a b l e 7 4 . 1 5 . T h e pathogenesis of insomnia in neurological disorders may be related to direct or indirect m e c h a n i s m s . For e x a m p l e , lesions of the h y p n o g e n i c n e u r o n s in t h e hypothalamic-preoptic nuclei and the lower b r a i n s t e m area in the region of t h e nucleus tractus solitarius can alter the balance between w a k i n g and sleeping brain, causing sleeplessness. O t h e r neurological conditions can p r o d u c e pain, confusional episodes, changes in the s e n s o r i m o t o r system, or m o v e m e n t disorders t h a t interfere with sleep. Insomnia in some n e u r o m u s c u l a r diseases m a y be d u e to sleep-related hypoventilation with c o n s e q u e n t sleep fragmentation. Insomnia may also be due lo medications used to treat neurological illnesses (e.g., a n t i c o n v u l s a n t s , d o p a minergic agents, and anticholinergic drugs). Insomnia c o m m o n l y coexists with or precedes the development of a n u m b e r of psychiatric illnesses. A large epidemiological study found t h a t individuals with i n s o m n i a at baseline were a b o u t 34 rimes m o r e likely than n o r m a l subjects to develop a n e w psychiatric disorder w i t h i n a year c o m p a r e d with individuals w i t h o u t insomnia ( C h o k r o v e r t y 2 0 0 3 b ) . T h o s e with insomnia are also a b o u t 4 0 times m o r e likely t h a n n o r m a l subjects to develop a n e w episode of major depression within 6 m o n t h s . Individuals with insomnia that resolved within 1 year had a similar incidence of subsequent psychiatric disorders c o m p a r e d with n o r m a l individuals. Specific e x a m p l e s of psychiatric disorders t h a t m a y be associated with insomnia include depression, anxiety disorders, and schizophrenia. There is a high prevalence of depression a m o n g elderly individuals c o m p l a i n i n g of insomnia. Early m o r n i n g Table 74.15:
Neurological disorders causing insomnia
Cerebral hemispheric and brainstem strokes Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease Brain tumors Traumatic brain injury causing post-trauma tie insomnia Neuromuscular disorders, including painful peripheral neuropathies Headache syndromes (migraine, cluster, hypnic headache, and exploding head syndromes) Fatal familial insomnia, a rare prion disease
a w a k e n i n g is considered to be t h e biological h a l l m a r k of depression. Adolescents a n d y o u n g adults with depression, in c o n t r a s t , m a y r e p o r t difficulty in initiating sleep. Characteristic findings in sleep disorders associated with depression a r e a s h o r t R E M latency and maldistribution of R E M cycle d u r a t i o n , with the longest n o c t u r n a l R E M cycle o c c u r r i n g in t h e first o n e third of t h e night. Anxiety d i s o r d e r s a r c the m o s t c o m m o n psychiatric disorders a n d include panic, p h o b i c , obsessive-compulsive, p o s t - t r a u m a t i c stress, and generalized anxiety disorders. Sleep m a y be disrupted by p a n i c a t t a c k s , n i g h t m a r e s , or flashbacks, d e p e n d i n g on the u n d e r l y i n g anxiety disorder. M a j o r depression coexists in m a n y patients. In a recent telephone interview of a representative s a m p l e of the general p o p u l a t i o n in several E u r o p e a n countries O h a y o n a n d Roth ( 2 0 0 3 ) concluded t h a t chronic i n s o m n i a can be a residual s y m p t o m of a previous m o o d or a n x i e t y disorder, a n d subjects with these disorders have a higher risk of relapse. In s c h i z o p h r e n i a , the severity of sleep disturbances is related to t h e intensity of psychotic s y m p t o m s . T h e r e is often extremely p r o l o n g e d sleep-onset latency during the acute illness, with a reduction of total sleep time. Primary Chronic
Sleep Disorders Insomnia
Associated
with
Some patients w i t h c h r o n i c i n s o m n i a h a v e either idiopathic or psychophysiological insomnia or insomnia as a s y m p t o m of a n o t h e r p r i m a r y sleep disorder. I d i o p a t h i c I n s o m n i a . Idiopathic or primary insomnia, previously called c h i l d h o o d - o n s e t i n s o m n i a , is defined as a life-long difficulty in initiating a n d m a i n t a i n i n g sleep, resulting in p o o r d a y t i m e functioning. T h e cause of this s y n d r o m e is u n k n o w n , but a n e u r o c h e m i c a l i m b a l a n c e , either in the a r o u s a l (hyperactivity) or s l e e p - p r o m o t i n g n e u r o n s (hypoactivity), has been suggested but n o t p r o v e d . Onset occurs in early c h i l d h o o d , and sometimes the s y n d r o m e rims in families. This c o n d i t i o n s h o u l d only he diiisMosi'd .ifrer •.•wln-ann of c o n c o m i t a n t medical, neurn logical, and psychiatric or o t h e r psychological p r o b l e m s . Psychophysiological Insomnia. Psychophysiological i n s o m nia is defined as chronic i n s o m n i a resulting from learned, sleep-pre venting associations and increased tension or agitation. It is estimated t h a t a b o u t 1 5 % of all individual with i n s o m n i a a t t e n d i n g sleep disorder centers h a v e psychophysiological i n s o m n i a . Affected individuals a r e overly concerned a n d overly focused on the p r o b l e m of sleep but do n o t have generalized anxiety, p h o b i c , or o t h e r psychiatric disorders. O n s e t of these s y n d r o m e s often occurs in y o u n g a d u l t h o o d , and s y m p t o m s persist for decades. First-degree relatives m a y h a v e similar sleep p r o b l e m s , suggesting a possible genetic c o m p o n e n t . nia
I be chanickTiNUc t e n u r e i>' psychophysiological IKMIIII is d e v e l o p m e n t of c o n d i t i o n e d responses t h a t a r e
SLEEP AND ITS DISORDERS
incompatible with sleep. The disorder begins in some patients during an initial period of stressful events, but the insomnia persists even after the inciting stressors have resolved. The combination of excessive worry, fear, and frustration about being unable to initiate and maintain sleep and the identification of the bedroom as a signal for arousal contribute to negative conditioning and sleeplessness. Affected patients tend to sleep poorly during PSG study, although occasional patients sleep better because they are removed from their usual sleep environment. This condition is distinguishable from generalized anxiety disorder because patients with psychophysiological insomnia have anxiety confined to issues relating to sleep. The condition tends to have a later onset than idiopathic insomnia, which typically begins in childhood. Sleep-State Misperception. In this disorder, subjects complain of sleeplessness hut without objective evidence (e.g., PSG recording of a sleep disorder). Despite complaints of no sleep or poor sleep over many years, actigraphy (a technique that measures patient activity and permits an objective assessment of sleep time) or PSG recordings document a normal sleep pattern (Saadch et al. 1995). Inadequate "Sleep Hygiene". Good sleep hygiene measures promote sleep. These include avoidance of caffeinated beverages, alcohol, and tobacco in the evening; avoidance of intense mental activities and vigorous exercise close to bedtime; avoidance of daytime naps and excessive time spent in bed; and adherence to a regular sleep-wake schedule. Insufficient Sleep Syndrome. Insufficient sleep is probably the most common cause of sleepiness in the general population. The whole society appears to be sleep deprived (bonnet and Arand 1995), which results from various factors, such as lifestyle, competitive drive to perform that sacrifices sleep, and environmental light and sound. Chronic sleep deprivation may lead to daytime sleepiness, irritability, lack of concentration, decreased daytime performance, muscle aches and pains, or depression. Altitude Insomnia, Altitude insomnia refers to sleeplessness that develops in some individuals on ascent to altitudes higher than 4000 m in conjunction with other features of acute mountain sickness, such as fatigue, headache, and loss of appetite (Coote 1994). The severity of the sleep disturbance is directly proportional to the height of ascent. Those who live at higher altitudes become acclimatized and tend to sleep normally, but in some, chronic mountain sickness may develop, causing sleep disturbance. Affected patients have periodic breathing (Ghcync-Stokes asthma) due to the stimulation of peripheral chemoreceptors by hypobaric hypoxemia. This causes hyperventilation, hypocapnia, and a respiratory alkalosis that suppresses ventilation. The abnormal breathing pattern causes repeated awakenings and sleep fragmentation, which may
2013
be exacerbated by stress, an uncomfortable sleeping environment, and cold temperature. The best treatment for altitude insomnia is aceta/olamidc, which promotes a mild metabolic acidosis that compensates for the hypoxemiadriven respiratory alkalosis. RLS, periodic limb movement disorder, and circadian rhythm disorders are some of the other causes of persistent insomnia. In some patients, CSA may cause insomnia.
Narcolepsy In 1880, the French physician Gelineau coined the term narcolepsy and gave a classic description of irresistible sleep attacks (Bassetti 2003). He also described "astasia," which had all the clinical features of what was later termed cataplexy. Before Gelineau's description, however, there were isolated instances of hypersomnolence, many of which resembled narcolepsy (although some may have been EDS associated with sleep apnea). In the last century, reports of large series of patients brought the entity of narcolepsy to the attention of the medical profession (Bassetti 2003; Overeem et al. 2001). In 1957, Yoss and Daly listed the narcoleptic tetrad of sleep attacks, cataplexy, sleep paralysis, and hypnagogic hallucinations (Bassetti 2003). The modern era of narcolepsy research began in 1960 with Vogel's discovery of sleep-onset REMs (SOREMs) in the narcolepsy syndrome. The observation by Honda and coworkers of the presence of HLA DR2 and DQwl (now called DQwl5) antigens in 100% of Japanese narcoleptic patients brought narcolepsy research to the field of molecular neurobiology (Mignot 1998; Overeem et al. 2001). Epidemiology, Genetics, and Family Studies in Narcolepsy There is wide variation in the prevalence of narcolepsy throughout the world, and good epidemiological studies are lacking. In the United States, the prevalence is 3-6 per 10,000; in Japan, it is 1 per 600; and in Israel, it is only 1 per 500,000. Both genetic and environmental factors contribute to the development of narcolepsy. About 1-2% of firstdegree relatives of narcoleptic patients manifest the illness, compared with 0.02-0.18% of the general population (a difference of 10-40 times) (Mignot 1998; Overeem et al. 2001). Several reports of familial narcolepsy have appeared in the literature since the first report in 1877. A positive family history of hypersomnolence and, less commonly, of cataplexy was reported in up to 5 0 % of relatives of narcoleptic patients in the early studies. Early reports were based on symptoms only and not on PSG studies; therefore, cases of sleep apnea causing EDS may have been misdiagnosed as narcolepsy. Reports show that 4.7% of first-degree relatives of people with narcolepsy-cataplexy
2014
NEUROLOGICAL DISEASES
complain of F.DS (Billiard et al. 1994). In view of the fact that the prevalence of EDS in the general population may be abonl 1 1%, M can he concluded tliat IMOSI "slccp>'" relatives
of patients with narcolepsy do not have narcolepsy. The mode of inheritance is thought to be autosomal dominant in humans, recessive in Doberman pinschers {canarc-1) and Labrador retrievers, and multifactorial in poodles. Narcolepsy lias been linked io dys:uiiclii'r: ol ;lie hypocretin (orexin) peptide system. Lin and colleagues (1999) found deletions in the transcripts of the hypocretin receptor 2 {HcrtrZ) gene in narcoleptic Doberman pinschers and Labrador retrievers. Chemelli and colleagues (1999) created a knockout of the orexin gene in mice, which exhibited a phenotype strikingly similar to that in human narcolepsy patients and canarc-1 mutant dogs. Orexincontaining neurons are located exclusively in the lateral hypothalamus with projections throughout the CNS, including the major nuclei implicated in sleep regulation. These two studies implicate hypocretins as major sleepmodulating neurotransmitters, which are closelv linked to the pathophysiology of narcolepsy. Twin studies in narcolepsy do not suggest a strong genetic influence. Approximately 2 5 - 3 1 % of monozygotic twins are concordant, but the majority are discordant for narcolepsy, which suggests the influence of environmental factors in the etiology of narcolepsy. Because most monozygotic twin pairs are discordant for narcolepsy-cataplexy and three discordant dizygotic twins were identified in a sample of 11,354 twins in the Finnish study, there may be an interaction of environmental and genetic factors in the development of narcolepsy (Mignot 1998; Overeem et al. 2001). Honda and co-workers first directed attention to an association between HLAs of the major histocompatibility complex for narcolepsy-cataplexy. The haplotypes DR15 subtype of DR2 and DQ6 subtype of DQ1 are closely associated with narcolepsy in 95-100% of white and Japanese patients (Mignot 1998; Overeem et al. 2001). In blacks with narcolepsy, the DR2 antigen is found in only 65% of patients, but the DQ1 antigen is present in more than 90%. It has been established that the HLA allele DQB1*0602 is the narcolepsy subtype gene along with the allele DQA1*0102 located nearby on chromosome 6 in all ethnic groups (Mignot 1998; Overeem et al. 2001). However, cases of patients with narcolepsy not carrying HLA DR2 or DQ1 antigens have been reported (Mignot 1998; Overeem et al. 2001}. Also, 1 2 - 3 5 % of the general population carry the same HLA alleles, but narcolepsy is present in only 0.02-0.18% of the population. Therefore, the alleles DQB1*0602 and D Q A l ' 0 1 0 2 are neither necessary nor sufficient for development of narcolepsy. Clinical
Manifestations
The syndrome of narcolepsy is a lifelong neurological condition that generally begins in an adolescent or young
adult with EDS and sleep attacks. Peak incidence occurs during the teens and early 20s (mostly at ages 15-20 years); another peak is seen aftct the second decade. Rare occurrences have been described in patients younger than 5 years of age and older than age 50. In modern demographic studies, there is no difference in prevalence between men and women. Many precipitating factors have been described, but most of them are probably incidental. After a variable interval of mouths to years, at least 7 0 % of patients develop the second characteristic feature, cataplexy, which is followed by other symptoms in a certain percentage of patients. Narcolepsy begins before age 10 in about 5 - 1 5 % of patients and after age 50 in about 5% of patients. In about 10% of patients, cataplexy precedes EDS by a few months and rarely b>T as much as 28 years. Any of the other major symptoms may rarely he the first symptom before narcoleptic sleep attacks and cataplexy (Bassetti 2003; Overeem et al, 2001). Clinical manifestations of narcolepsy syndrome may be described under three headings; major, minor, and miscellaneous. Major manifestations are narcoleptic sleep attacks and EDS, cataplexy, sleep paralysis, hypnagogic hallucinations, disturbed night sleep, and automatic behavior. Narcoleptic Sleep Attacks. The patient complains of EDS and characteristic sleep attacks, which are manifested by an irresistible desire to fall asleep. The attacks may come under inappropriate circumstances Mid in inappropriate places: during driving, talking, eating, playing, walking, running, working, class time, sexual intercourse, watching television, sitting, and conditions of boredom and monotony. Attacks are generally brief, lasting for a few minutes to 15-30 minutes, and on awakening, the patient usually feels fresh, although occasionally, the patient feels tired and drowsy. The incidence of attacks varies widely from one or more attacks daily to attacks weekly or monthly. Sometimes they occur once every few weeks to months and, occasionally, once every year to every few years. The attacks persist throughout life, although there may be fluctuations and, rarely, temporary remissions. Because of these sleep attacks, EDS, and the common occurrence of microsleep episodes, performance at school and work declines, resulting in a variety of psychosocial and socioeconomic difficulties, Cataplexy. Lowenfeld coined the term cataplexy (Bassetti 2003). Cataplexy is characterized by sudden loss of tone in the voluntary muscles, except for respiratory and ocular muscles. The cataplectic attacks are often {>95% of the time) triggered by emotional factors, such as laughter, rage, and anger. The attacks may be complete or partial and, rarely, unilateral (0.5-1.0% of patients). The patient completely loses tone in the limb muscles and falls to the ground. Knees may buckle, there may be head nodding, sagging of the jaw, dysarthria, or loss of voice, and in rare unilateral cases, there may be a loss of power in one arm
SLEEP AND ITS DISORDERS
or leg. These attacks generally last for a few seconds to a minute and sometimes a few minutes. Consciousness is retained completely during the attacks, and there is never any jerking of the limbs or head. Physical examination during these brief spells reveals flaccidity of the muscles and absent or markedly diminished muscle stretch reflexes. The H-reflcx, which is the electrical counterpart of the muscle stretch reflex, and F responses arc decreased or absent. Cataplexy is the second most important manifestation of narcolepsy syndrome and is present in 6 0 - 1 0 0 % of patients with narcolepsy. In most patients, cataplexy appears months to years after onset of the sleep attacks, but occasionally, cataplexy may be the initial presentation, which causes diagnostic confusion. At the onset, the patient may have attacks daily or weekly; gradually, they occur less often and may even disappear in old age. Rarely, particularly after withdrawal of tricyclic medications, patients may develop status cataplecticus. The EEG recording shows wakefulness during the brief cataplectic spells, but if these arc prolonged to 1-2 minutes, shows REM sleep and all its manifestations. Sleep Paralysis, Sleep paralysis is the third major manifestation of narcolepsy. It occurs months to years after onset of narcoleptic sleep attacks and is seen in about 2 5 - 5 0 % of patients. There is sudden apparent unilateral or bilateral paralysis or paralysis of one limb, cither during sleep onset at night (hypnagogic) or while awakening (hypnopompic) in the morning. The patient is conscious during these paralytic attacks but is unable to move or speak and is often frightened and fearful. As the patient experiences more and more of these episodes, he or she overcomes the fear and anxiety. Hypnagogic Hallucination. Hypnagogic hallucination is the fourth major manifestation of narcolepsy syndrome and may occur cither at the onset of sleep or during awakening early in the morning. The hallucination manifests as vivid, often fearful, visual imagery but sometimes has auditory, vestibular, or somesthetic hallucinatory phenomena. These hallucinations may occur years after the onset of sleep attacks in 2 0 - 4 0 % of narcoleptic patients. Narcoleptic sleep attacks, cataplexy, and sleep paralysis or hypnagogic hallucination are seen in about 3 0 % of patients; all four major features (narcoleptic tetrad) may occur together in about 10% of patients. Disturbance of Night Sleep. Disturbance of night sleep, together with the four major manifestations, may be termed the narcoleptic pentad. PSG findings showing disturbed night sleep are seen in 72-H0% of patients (see Laboratory Assessment of Sleep Disorders, later in this chapter). Automatic Behavior. Automatic behavior is included under major manifestation and is found in a large percentage of patients ( 2 0 ^ 0 % ) . During these episodes,
2015
the patient performs the same function repetitively, speaks or writes in a meaningless manner, drives on the wrong side of the toad, or drives to a strange place and then forgets the episodes. The behavior resembles a fuguelikc state and may result from partial sleep episodes, frequent lapses, or microslccp episodes. Minor
Manifestations
In addition to major manifestations, many patients have other minor clinical featutes. These may include psychosocial disturbances, anxiety, depression, morning headache, impotence in men, frigidity and lack of orgasm in women, and recent memory impairment. Miscellaneous Man ifes tat ions Patients with narcolepsy syndrome may also have sleep apnea and PLMS, which often aggravate their sleep attacks. The incidence of associated sleep apnea in narcolepsy varies, but about 3 0 % of narcoleptic patients may have sleep apnea, which is most commonly central but it may be obstructive or mixed. It is important to recognize obstructive sleep apnea (OSA) in narcoleptic patients because they may need additional treatment with continuous positive airway pressure (CPAP) for relief of apneas and EDS. The third important miscellaneous manifestation is RBD, which Schenck and Mahowald reported in 17 patients in whom the diagnosis was made by established criteria for narcolepsy and RBD. These patients ranged in age from 8 to 74 years, and 7 1 % were men. Narcolepsy and RBD most commonly emerged in tandem. In three patients, treatment of narcolepsy-cataplexy with stimulants and tricyclic medications either induced or exacerbated RBD. Differential
Diagnosis
Narcoleptic sleep attacks should be differentiated from other causes of EDS. These include sleep deprivation and insufficient sleep syndrome; OSAS; alcohol- and drugrelated hypcrsomnolcnce; other medical, neurological, and psychiatric disorders causing hypersomnolence; idiopathic hypersomnia; and circadian rhythm sleep disorders. OSAS (see Sleep Apnea Syndrome, later in this chapter) is the most common cause of EDS in patients referred to a sleep laboratory for evaluation and is characterized by repeated episodes of obstructive and mixed apneas during NREM and REM sleep in overnight PSG recordings. These patients have prolonged daytime sleep episodes, followed by fatigue and drowsiness on awakening, which contrasts * with a fresh feeling in narcoleptic patients on awakening from brief sleep attacks. All patients with hypersomnolence can he excluded after careful history and physical elimination and overnight PSG recording. Idiopathic hypersomnia (see Idiopathic Hypersomnia, later in this chapter) closely resembles narcolepsy syndrome.
2016
NEUROLOGICAL DISEASES
In contrast to narcolepsy, the sleep episodes in idiopathic hypersomnia arc prolonged, and the sleep is not refreshing. PSG recordings and MSLT scores do not show SORF.Vts but do show pathological sleepiness. There is no disturbance of REM-NREM organization on PSG recordings. Sun:-: patients with idiopathic hypersomnia ma) have a positive family history. Cataplexy may be mistaken for partial complex seizure, absence spells, atonic seizures, drop attacks, and syncope. During partial complex seizure, there is an altered state of consciousness, but in cataplexy, patients retain consciousness. Patients with partial complex seizures may have secondary generalized tonic-clonk movements and postictal confusion, and EEG recordings may show characteristic epileptiform discharges in the anterior and midtemporal regions. Absence spells arc characterized by staring and vacant expression lasting for a few seconds to 30 seconds and an altered state of alertness accompanied by characteristic 3-Hz spike-and-wavc discharges on the EEG recording. Atonic seizures are accompanied by transient loss of consciousness, and the EEG findings may show slow spike-and-wavc or polyspike-and-wave discharges. Drop attacks may occur in vertebrobasilar insufficiency {transient ischemic attacks), and the patient may have other evidence of brainstem ischemia, such as vertigo, ataxia, or diplopia. Syncope results from Transient loss of consciousness and may have resulted from cardiogenic or other causes, including neurogenic orthostatic hypotension. Sleep paralysis in narcolepsy should be differentiated from isolated and physiological sleep paralysis and familial sleep paralysis. In all these conditions, other manifestations of narcolepsy are absent, Automatic behavior and fugue states should be differentiated from the automatism seen in partial complex seizure and psychogenic fugue. History, physical exanima tion, and the EEG findings are helpful in the differentiation. Differential diagnosis should also include neurological conditions that were thought to be associated with secondary or symptomatic narcolepsy. Secondary narcolepsy has been controversial, and many cases of hypcrsomnolence resulting from CNS lesions have been described in the past as narcolepsy. Most of these are atypical sleep attacks and did not have the classic features of narcolepsy. Occasional cases of true narcoleptic sleep attacks and cataplexy have been described, however, in association with diencephalic and midbrain tumors. Multiple sclerosis and narcolepsy may occasionally be seen in the same individual and are associated with a 111.A DR2 antigen positi vity. Pathophysiological
Mechanisms
Physiological, neurochemical, genetic, and environmental factors all play distinct roles in the pathogenesis of narcolepsy syndrome. Physiological abnormalities in narcolepsy suggest a disturbance of REM-NREM sleep-wake
state boundaries. The hallmark of physiological testing in narcolepsy is the presence of SOREMs (i.e., the onset of REM sleep at sleep onset or within 15 minutes of sleep onset). In most patients, this sign is found in two of four to five nap recordings in MSLT scores and in approximately 5 0 % of PSG recordings. Other features point to dissociation of REM sleep and intrusion into wakefulness. During cataplexy, there is muscle atonia of REM sleep without other REM features during a wakeful electroencephalogram. If the episode is prolonged, however, the patient develops full REM sleep. Similarly, in sleep paralysis, muscle atonia is similar to the REM sleep atonia. REM sleep intrusion with dream imagery without other features of REM sleep is noted in hypnagogic hallucinations, In many of these episodes, the sleep state is intermediate between REM and NREM sleep. Many patients also have microsleep episodes during the daytime. The time -is o la tion laboratory experiments conducted by Pollak and coworkers showed strong evidence for circadian disorganization in narcoleptic patients. Although the total 24-hour sleep, as welt as the percentage of REM sleep, is norma! in narcoleptic patients, the intrusion of REM sleep atonia into wakefulness suggests the dissociation of REM sleep regulation. Occasional occurrence of RBD in some narcoleptic patients may be cited as evidence favoring an impairment of state boundary theory in narcolepsy. Neurochemical
Mechanisms
The neurochemical basis of narcolepsy is not well understood. Injection of cholinergic drugs (e.g., physostigmine) in narcoleptic dogs (Doberman pinschers are good models of narcoleptic dogs with an autosomal recessive inheritance) increases the cataplectic episodes, whereas atropine and scopolamine (muscarinic receptor-blocking agents) decrease cataplectic episodes (Guilleminault et al. 1998). M2 subtypes of muscarinic cholinergic receptors are found to be upregulated in the pontine reticular formation of narcoleptic dogs {Guilleminault et al. 1998). Postmortem studies have also shown increased muscarinic Mj receptor binding in the basal ganglia and the amygdala. These findings, in conjunction with the pharmacological experiments, suggest hypersensitivity of the muscarinic cholinergic system in the cataplectic dog brain. There is also c villi lice In s u g g e s t .1 d e U \ I in i r . o m >.i i;ii[n-r;;ic t i : ;;uLiUii!i oi
the REM sleep mechanism contributing to narcoleptic symptoms. REM-off cells (serotonergic cells in the raphe and noradrenergic cells in the locus ceruleus) are completely inactive during REM sleep and appear to play a permissive role by modulating cholinergic activity. It has been postulated that an imbalance of the chemical regulation between the cholinergic and monoaminergic neurons may play a role in narcoleptic symptomatology. The stimulants (amphetamine and others) used for effective treatment of sleepiness in narcolepsy increase the synaptic availability of monoamines. Tricyclic antidepressants used in the
SLEEP AND ITS DISORDERS
treatment of cataplexy decrease the reuptake of norepinephrine; fluoxetine decreases the reuptake of serotonin, thus increasing the availability of both of these monoamines. Modafinil, the wake-promoting agent used in the treatment of narcolepsy, may exert its effect by promoting dopaminergic transmission (Nishino and Mignot 1997; Wisor et al. 2001). Documentation of an abnormality in the hypocretin (orexin) neurons in the lateral hypothalamus in patients with narcolepsy-cataplcxy is the most exciting recent development in its pathogenesis (Siegel 1999, 2002). This condition can be considered a hypocretin (orexin) deficiency syndrome. Such a hypothesis is supported by the following observations: induction of narcolepsy-like symptoms after preprohypocretin gene knockout in mice and mutation of the hypocretin receptor 2 gene in dogs (Chemelli etal. 1999; Lin etal. 1999); decreased hypocretin 1 levels in the cerebrospinal fluid of patients with narcolepsy-cataplexy (Nishino et al. 2000, 2001; Mignot et al. 2002); postmortem documentation of decreased numbers of hypocretin neurons in brains from narcoleptic individuals (Thannickal ct al. 2000); and identification of a prep ro hypocretin gene mutation in a child with severe narcolepsy and a generalized absence t hypocretin peptides in the brain (Peyron et al. 2000). Genetic
and Environmental
factors
Genetic and environmental factors in narcolepsy are described briefly under Epidemiology. Genetics, and family Studies in Narcolepsy, earlier in this chapter. The exact environmental factors in narcolepsy are unknown. The question of autoimmunity in narcolepsy is the subject of speculation, but no definite evidence has been uncovered (Overeem e t a l , 2001).
2017
seen in these patients, and they may have automatic behavior with amnesia tor the events. Physical examination uncovers no abnormal neurological or other findings. This is a very disabling and lifelong condition. The MSLT shows evidence of pathological sleepiness without SOREMs. The differential diagnosis of idiopathic hypersomnia should include other causes of EDS, such as classic narcolepsy-cataplexy, upper airway OSAS, CSA syndrome, upper airway resistance syndrome (UARS), insufficient sleep, drug-induced hypersomnia, and other medical or psychiatric disorders, particularly mood disorders. Posttraumatic hypersomnia, chronic fatigue syndrome, delayed sleep-phase syndrome (DSPS), and long sleeper syndrome should also be included in the differential diagnosis. Based on a retrospective review of clinical and PSG features as well as questionnaire results derived from a database of 3618 patients evaluated between 1985 and 1993 at a sleep disorder center, Aldrich (1996) suggested that idiopathic hypersomnia is a heterogeneous syndrome. I le contradicted some of the previously reported findings, and in his analysis, these patients did not exhibit prolonged night sleep or sleep drunkenness. Aldrich also questioned the validity of using prolonged or "deep" sleep as a diagnostic criterion for idiopathic hypersomnia. He suggested that clinical heterogeneity may reflect differences in etiologies, such as reports of preceding Epstein-Barr viral infection, infectious mononucleosis, Guillain-Barre syndrome, or human immunodeficiency virus (HIV) infection. The author argued for revaluation of the diagnostic criteria for idiopathic disorders of sleepiness not associated with cataplexy. Some of these patients may have a positive family history, but the mode of inheritance is unknown. Unlike narcolepsy, there is no clear association between idiopathic hypersomnia and HLA antigens.
Idiopathic Hypersomnia
Sleep Apnea Syndrome
ICSD (1997) defines idiopathic hypersomnia as a disorder of excessive sleepiness of presumed (but not proved) CNS cause that is associated with normal or prolonged (1-2 hours) NREM sleep episodes. The syndrome has been described under a variety of labels, including NREM narcolepsy, idiopathic CNS hypersomnia, and functional, mixed, or harmonious hypersomnia. Idiopathic hypersomnia (Billiard and Dauvillicrs 2001) occurs insidiously, generally between the ages of 1.5 and 30 years. It closely resembles narcolepsy and sleep apnea. Although sometimes it is very difficult to distinguish from narcolepsy syndrome, the sleep pattern is different from that in narcolepsy or sleep apnea (Bassetti and Aldrich 1997). A patient with idiopathic hypersomnia generally sleeps for hours, and the sleep is not refreshing. The patient does not give a history of cataplexy, snoring, or repeated awakenings throughout the night. Sleep drunkenness (i.e., confusional arousal) is often
Sleep apnea syndrome encompasses both obstructive and central apneas as well as hypopnca. OSAS is very common but remains underdiagnosed, whereas CSA syndrome is uncommon in the general population. OSAS is the most common sleep disorder studied in the sleep laboratory by overnight PSG recording done to assess EDS, In the general population, however, sleep deprivation or insufficient sleep syndrome is the most common cause of EDS today. The reason for underdiagnosis of OSAS is inadequate awareness and insufficient knowledge about the serious consequences of this disorder among ' physicians and the public. OSAS causes significant morbidity and mortality, and it is important to diagnose the condition because effective treatment is available for most individuals who have it. To understand the condiiiuii, definition ol sever.:.! terms related to sleep disordered breathing (SDB) is necessary.
2018
NEUROLOGICAL DTSF.ASF.S
Sleep-Disordered
Breathing:
Terminology
Apnea (obstructive, central, or mixed), hypopnea, hypoventilation, paradoxical breathing, periodic breathing, increased upper airway resistance, dysrhyrhmic breathing, apneustic breathing, inspiratory gasps, and nocturnal stridor may all be grouped under SDB. Figure 74,5 shows some patterns of SDB. The term sleep apnea refers to temporary cessation or absence of breathing during sleep. Analysis of the breathing pattern has revealed the presence of three types of sleep apnea: upper airway obstructive, central, and mixed. Normal individuals may experience a few episodes of sleep apnea, particularly central apnea at the onset of NREM sleep and during REM sleep. To be of pathological significance, the sleep apnea should last at least 10 seconds, the apnea index (number of episodes of apnea per hour of sleep) should be at least 5, and the patient should have at least 30 episodes during 7 hours of all-night sleep, Cessation of aitflow with no respiratory effort constitutes central apnea; diaphragmatic and intercostal muscle activities arc absent, as is air exchange through the nose or mouth. Upper airway OSA is characterized by cessation of airflow through the nose or mouth with persistence of diaphragmatic and intercostal muscle activities. Mixed apnea is manifested as an initial cessation of airflow with no respiratory effort {central apnea) followed by a period of upper airway OSA. Sleep-related hypopnea is defined by the American Academy of Sleep Medicine Task Force (1999) as a reduction in the breathing signal to less than one half the volume measured during the preceding or following respiratory cycle with 3% or more oxygen desatitration or EEG arousal. The Sleep Heart Health Study reported by
Shahar et al. (2001) defines hypopnea as a 3 0 % or greater reduction in thoracoabdominal exertion or flow limitation associated with 4% or greater oxygen desaturation. The respiratory disturbance index (RDI) or apneahypopnea index (AHI} is defined as the number of apneas and hypopneas per hour of sleep. A normal index is less than 5, but most investigators consider AHI or RDI of 10 or more significant. Apneas and hypopneas are accompanied by oxygen desaturation and are terminated by an arousal, which is defined as transient (lasting 3-14 seconds) return of alpha activities in the EEG recording. Repeated arousals causing sleep fragmentation may be the main contributing cause to EDS. Arousals along with repeated hypoxemias are also the most important factors for long-term cardiovascular consequences of OSAS. During paradoxical breathing, the thorax and abdomen move in opposite directions, thereby indicating increased upper airway resistance. This type of breathing may be noted in patients with OSAS as well as in some patients with UARS. Periodic breathing includes Cheync-Stokes breathing and the Cheyne-Stokes variant pattern of breathing. Cheyne-Stokes breathing is a special type of central apnea manifested as cyclic changes in breathing, with a crescendo-dccrescendo sequence separated by central apneas. The Cheyne-Stokes variant pattern of breathing is distinguished by the substitution of hypopneas for apneas. Cheyne-Stokes breathing and the variant pattern arc most commonly noted in CHF and neurological disorders. Dysrhythmic breathing is characterized by nonrhythmic respiration of irregular rate, rhythm, and amplitude that becomes worse during sleep. This type of breathing may
FIGURE 74.5 Patterns of sleepdisordered breathing: (A) central apnea; (B) upper airway obstructive apnea; (C) mixed apnea (initial central apnea followed by obstructive apnea); (D) paradoxical breathing; (E) Cheyne-Stokes bn.1:!tiling; (f:) ('heytie-Stokes variant pattern; (G) dysrhythmic breathing; (H) apneustic breathing; (1) inspiratory gasp, (Reproduced with permission from Chokroverty, S. 1999, "Sleep, breathing, and neurological problems," in Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, ed S. Chokroverty, Bu rter worthI leinvituiiiri, Huston,)
SLEEP AND ITS DISORDERS
result from an abnormality in the automatic respiratory pattern generator in the brainstem. Apneustic breathing is characterized by prolonged inspiration with an increase in the ratio of inspiratory to expiratory time. This type of breathing may result from a neurological lesion in the caudal pons disconnecting the apneustic center in the lower pons from the pneumotaxic center in the upper pons. Inspiratory gasp is characterized by short inspiratory time and a relatively prolonged expiration and has been noted after a lesion in the medulla. Hypoventilation refers to a reduction of alveolar ventilation accompanied by hypoxemia and hypercapnia without any apnea or hypopnea; it may be noted in patients with neuromuscular disorders and kyphoscoliosis and those with underlying lung or chest wall abnormalities that impair gas exchange during wakefulness.
2019
Patients with UARS show subtle airflow limitations due to increased upper airway resistance followed by repeated arousals during sleep at night. This subtle aitflow limitation cannot be identified by the usual recording of respiration using an oronasal thermistor or inductance plethysmography to register chest and abdominal wall motions. Nasal pressure monitoring with a nasal cannula is more sensitive than use of a thermocouple or thermistor in detecting airflow limitation and increased upper airway resistance (Ayappa et al. 2000), Intraesophageal balloon manometry, however, is the gold standard for detecting upper airway resistance, and this reveals increasing efforts, with increasing intraesophageal pressure, leading to arousal but without any apneas or hypopneas (Figure 74.6). These patients may or may not snore; they do have EDS and all its consequences, as seen in OSAS. Epidemiology
of Obstructive Sleep
Apnea
Syndrome
Upper Airway Resistance Syndrome There is a general gradation from increasing upper airway resistance, which is found in normal individuals during sleep, to the limitation of airflow in subjects with loud snoring to a stage of UARS followed by the next stage of complete airway occlusion, seen in patients with OSAS.
No study has been specifically designed to determine the incidence of OSAS in a previously healthy population. Based on a definition of at least five apneas or hypopneas per hour of sleep accompanied by EDS {Young et al. 1993), however, the prevalence of OSAS is 4% in men and 2% in women between 30 and 60 years of age. There is a strong
FIGURE 74.6 Polysomnography recording of a patient with upper airway resistance syndrome. Note that peak increase in effort (solid arrow) is associated with a small drop in peak flow and tidal volume causing a transient arousal on the electroencephalogram. ECG = electrocardiogram; EMGIJCJ;,] = facial muscle
electromyogram; EOG = electrooculogram (right and left); FLOW = pneumotac ho meter to quantity airtli >-.>.-; Pes = esophageal manometry to record esophageal pressure; RESPmm=respiratory effort; Sao2 = oxygen saturation. (Reproduced with permission from Robinson, A. & Guilleminault, C, 1999, in Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, ed S. Chokroverty, Butte i worth-Hcinemann, Boston.)
2020
NEUROLOGICAL DISEASES
association between OSAS and male gender, increasing age, and obesity. The condition is common in men older than 40 years of age, and among women the incidence of OSAS is greater after menopause. About 8 5 % of patients with OSAS are men, and obesity is present in about 7 0 % of OSAS patients. There is an increased prevalence of OSAS in those with a thick neck and large abdomen. Men with a neck circumference measuring more than 17 inches and women with a neck measuring more than 16 inches are at risk for OSAS. Race may be a factor, given that a high ptevalence of SD13 is noted in Pacific Islanders, Mexican-Americans, and African-Americans. There are also family aggregates of OSAS. Other factors with a high association are alcohol, smoking, and drug use. Consequences of Obstructive Sleep Apnea Syndrome Short-term consequences of OSAS include impairment of the quality of life and increasing traffic accidents; longterm consequences include cardiovascular and neurological dysfunction. OSAS is associated with increased morbidity and mortality (Robinson and Guilleminault 1999; Flemons 2002). Prevalence of hypertension in untreated OSAS exceeds 40%, whereas 30% of patients with idiopathic hypertension have OSA (Fletcher 2000; Robinson and Guilleminault 1999). Recent prospective and community-based studies have confirmed the previous suggestion of a clear relationship between hypertension and OSAS including mild OSAS (Peppatd et al. 2000; Nieto et al. 2000). Improvement of hypertension after treatment of OSA (Peppetell et al. 2002; Faceenda et al. 2001; Hla et al. 2002) further supports a causal relationship between OSAS and hypertension. A significant relationship between hypertension and the RD1 exists even after obesity and other confounding factors are eliminated. Factors responsible for hypertension in OSAS include repeated hypoxemia during sleep at night and increased sympathetic activity. Cardiac arrhythmias, pulmonary hypertension, and cor pulmonale, which are noted in patients with severe OSAS, may be related to severe hypoxemia during sleep. There is also a strong relationship between snoring, myocardial infarction, and stroke. The association of supratentorial infarction, mfratentonal infarction, and transient ischemic attacks with snoring and sleep apnea has been clearly documented (Basserti and Chervin 2000). Neuropsychological measurements document that cognitive dysfunction in patients with OSAS improves after treatment (Fugleman et al. 2000; Kim et al. 1997). Pathogenesis of Obstructive Sleep Apnea Syndrome The pathogenesis of OSAS includes local anatomical factors as well as neurological factors (Douglas and Polo 1994; Robinson and Guilleminault 1999). Collapse of the
pharyngeal airway is the fundamental factor in OSA. During sleep, muscle tone decreases, including that of the upper airway dilator muscles, which maintain upper airway patency. As a result of this decreased tone, these muscles relax, causing increased upper airway resistance and narrowing of the upper airway space. This effect becomes more marked during REM sleep because of marked muscle hypotonia or atonia of muscles at this stage. This generates turbulent flow and vibration, causing snoring; in some individuals, there may be significant narrowing or occlusion, causing apnea. Episodes of upper airway narrowing causing apneas, hypopneas, or increased upper airway resistance that are terminated by arousals and sleep fragmentation, with repetition of the cycles numerous times throughout the night, are responsible for the daytime symptoms in OSAS. The site of narrowing in most individuals is at the level of the soft palate. Therefore, decreased tone in the palatal, genioglossal, and other upper airway muscles, causing increased upper airway resistance and decreased airway space, plays an important role in upper airway obstruction in OSAS. Obesity associated with increased fat deposition in the region of the pharynx and soft palate, abnormal facial features (e.g., rctrognathia or micrognathia), and other conditions (e.g., myxedema or acromegaly) that cause fatty tissue deposit in the pharyngeal region predispose individuals to upper airway narrowing and OSA. Imaging studies of the upper airway region have shown that in OSA, upper airway space is narrower than in those who do not have apnea or hypopnea. )n addition to the smaller airway space in OSAS, the activity of the genioglossus muscle is found to be higher than normal during wakefulness in these patients; this may be considered a compensatory mechanism to keep the upper airway patent. Other anatomical abnormalities include adenotonsillar enlargement in children and craniofacial dysostosis. Defective upper airway reflexes may also play a role in upper airway occlusion. In some family members, abnormal facial structures, a narrow upper airway, and long uvula have been found. Neural factors responsible for OSAS include abnormalities of respiratory control in the medullary respiratory neurons. The output of sleep-related medullary respiratory neurons is thought to decrease in normal individuals during sleep. This reduction of the medullary respiratory neuronal activity in sleep causes a loss of tonic and phasic motor output to the upper airway dilator muscles, resulting in an increase in airway resistance. 1 [ypoxic and hypercapnic ventilatory responses, however, are found to be normal in OSAS, but in obesity-hypoventilation syndtomc (pickwickian syndrome), which may be considered a very advanced stage of OSAS in obese patients, these responses are depressed, causing hypercapnia and hypoxemia even during wakefulness. Thus a complex intetaction of peripheral upper airway and central neural factors combine to produce the full-blown syndrome of OSAS.
SLEEP AND ITS DISORDERS
Symptoms Symptoms of OSAS (Flemons 2002; Robinson and Guilleminault 1999) can be divided into two groups (Table 74.16): those occurring during sleep (nocturnal events) and those occurring during the daytime (diurnal events). Nocturnal sleep symptoms of OSAS include loud snoring (often with a long history), choking, cessation of breathing (apneas witnessed by the bed partner), sitting up fighting for breath, abnormal motor activities with thrashing about in bed, severe sleep disruption, gastroesophageal reflux, nocturia and nocturnal enuresis (seen mostly in children), and occasionally hyperhidrosis, The major daytime symptom of OSAS is F.DS. Patients fall asleep during the day at inappropriate times and in inappropriate places and may be involved in driving accidents. They cannot function adequately during the day, and some patients may complain of morning headaches and forgetfulncss; men may report impotence. The prolonged duration and the unrefreshing nature of the EDS attacks differentiate them from narcoleptic sleep attacks. Table 74.16: syndrome
Symptoms and signs in obstructive sleep apnea
Nocturnal symptoms during sleep Loud snoring (often with a long history) Choking during sleep Cessation of breathing (apneas witnessed by bed partner) Sitting up or fighting for breath Abnormal motor activities (e.g., thrashing about in bed) Severe sleep disruption Gastroesophageal reflux causing heartburn Nocturia and nocturnal enuresis (mostly in children) Insomnia (in some patients} Excessive nocturnal sweating (in some patients) Daytime symptoms Excessive daytime somnolence Forget fulness Personality changes Decreased libido and impotence in men Dryness of mouth on awakening Morning headache (in some patients) Automatic behavior with retrograde amnesia Hyperactivity in children Hearing impairment (in some patients) Physical findings Obesity in the majority of patients Increased body mass index (body weight in kg/height in m2) >25 Increased neck circumference (>17 in. in men and >16 in. in women) In some patients: Large edematous uvula Low-hanging soft palate Large tonsils and adenoids (especially in children) Retrognathia Micrognathia Hypertension Cardiac arrhythmias Evidence of congestive heart failure
2021
Snoring is present in most patients, and there is often a gradation from mild snoring for many years to very loud snoring for a period and then to the development of daytime symptoms. A histoty of apneas witnessed by a bed partner is a strong indicator of the presence of sleep apnea. Occasionally, patients may complain of difficulty falling asleep and numerous awakenings during the night. Excessive sweating in some patients may be related to the increased muscle activity related to abnormal motor activities during sleep at night. Increased release of atrial natriuretic peptide during sleep may be responsible for natriuresis, diuresis, and nocturnal enutcsis. Some patients may complain of hearing impairment related to a history of loud snoring for many years. Other complaints include memory impairment, automatic behavior with retrograde amnesia, dryness of mouth on awakening in the morning, decreased libido, personality changes, and hyperactivity in children. Factors that may aggravate symptoms of OSA include alcohol intake, CNS depressants, sleep deprivation, respiratory allergies, and .smoking.
Signs Physical examination should include assessment of respiratory, oropharyngeal, neurological, hematological, and cardiovascular funcrions. Examination of the oropharyngeal region may detect redundant oropharyngeal tissues, such as large edematous uvula, redundant mucosal folds of the pharyngeal walls, low-hanging long soft palate, or large tonsils and adenoids, especially in children. Other findings may include microglossia, micrognathia, and rerrognarhin. Body weight and height measurements are important. Neck circumference correlates with SDB. Physical examination reveals obesity in about 7 0 % of patients. Physical examination may also uncover the risk factors associated with repeated hypoxemia and apnea during sleep, such as hypertension, cardiac arrhythmias, and evidence of CHF, Evaluation
and
Assessment
Evaluation and assessment are the same as those for other sleep disorders. Particular attention should be paid to the detailed sleep history as well as the daytime history, and careful physical examination should be focused on specific associated and risk factors. The laboratory assessment and management are described later in this chapter, under Laboratory Assessment of Sleep Disorders.
Restless Legs Syndrome Clinical
Manifestations
Thomas Willis gave a graphic clinical description of RLS more than 300 years ago. More than 50 years ago, Ekbom brought the entity to the attention of the medical
2022
NEUROLOGICAL DISEASES
community (Chokroverty et al. 2003). RLS remains largely underdiagnosed or undiagnosed. The exact prevalence of RLS is not known because definitive population-based study has been inadequate. Ekbom gave a prevalence rate of 5%, but in several contemporary population surveys using the International Restless Legs Syndrome Study Group (IRLSSG) criteria (Walters et al. 1995; International Restless Legs Syndrome Study Group 2003) the prevalence of RLS has been estimated to be about 10% for all adult populations, particularly those of European descent (Chokroverty et al. 2003). In some surveys from \w„. • w i • • i -..i U-: i.. .• i•-, < urciucb lew . suggesting .i possible ethnic and racial difference in prevalence of RLS. RLS is a lifelong condition that may begin at any age but is most severe in middle-aged and elderly persons, in whom it has a chronic progressive course. The fundamental problem in RLS is a complex sensorimotor disorder involving the legs predominantly (Allen ct al. 2001, 2003). The essential clinical diagnostic features as revised (Allen et al. 2003) from the previous IRLSSG criteria (Walters et al. 1995) are listed in Table 74.17. RLS is idiopathic in most patients, but it also may result from conditions such as iron deficiency, uremia, or polyneuropathy (Chokroverty and Jankovie 1999). The hallmarks of idiopathic or primary RLS are intense, disagreeable, creeping sensations (paresthesia or dysesthesia) in the lower extremities that arc relieved by moving the legs (Allen et al. 2003). The symptoms are worse when the patient is lying down in bed in the evening and occur most commonly at sleep onset. The sensory manifestations include intense, disagreeable feelings that are generally different from the usual paresthesias or dysesthesias encountered in common polyneuropathies or radiculopathies.
Table 74.17: Clinical diagnostic criteria for idiopathic restless legs syndrome Essential criteria An urge to move the legs usually accompanied or caused by uncomfortable sensations in the legs The urge to move or unpleasant sensations beginning or worsening during periods of rest or inactivity such as lying or sitting The urge to move or unpleasant sensations are partially or totally relieved by movements, MI eh as walking or stretching, at least as long as the activity continues The urge to move or unpleasant sensations arc worse in the evening or night than during the day or only occur in the evening or night Supportive features Dopaminergic responsiveness Presence of periodic limb movements in sleep or in wakefulness Positive family histoty Associated features Usually progressive clinical course Normal neurological examination in the idiopathic fotm Sleep disturbance
These creeping sensations occur mostly between the knees and the ankles, causing an intense urge to move the limbs, which relieves the feelings. Occasionally, patients complain of pain. Affected patients generally have severe difficulty in initiating sleep due to paresthesias and restlessness of the legs. Severely affected individuals may also have paresthesias during the day when resting or sitting quietly, Motor manifestations of RLS can be divided into three groups: voluntary urge to move the legs causing restlessness, involuntary movements in wakefulness, and PLMS. The restlessness is seen mostly in the legs but occasionally also in the arms. The movements arc usually symmetrical but sometimes may be seen asymmetrically and asynchronously. Motor restlessness generally comprises tossing and turning in bed, floor pacing, leg stretching, leg flexion, foot rubbing, and occasionally marching in place and body rocking. The involuntary movements during relaxed wakefulness include myoclonic jerks and dystonic movements. These movements may be periodic, and these are called periodic limb movements in wakefulness (PLMW). The myoclonic jerks can also be aperiodic or may occur in clusters. The dystonic movements are more sustained and prolonged in duration than the myoclonic jerks. The salient features of PLMS (Table 74.18) are seen in at least 80% of patients with RLS. PLMS are mostly dystonic and rarely myoclonic, based on the EMG criteria of duration of the muscle bursts. Neurological examination in the idiopathic form of RLS is generally normal because movements arc usually noted in the evening, when the patients are resting in bed. In sevctc cases, however, the movements may be noted during the day while subjects are sitting or lying down, and both voluntary and involuntary movements may be seen during neurological examination. In secondary forms of RLS, clinical signs of associated abnormality may be present. The course is gcnetally chronic and progressive, but remissions sometimes occur. The condition may be exacerbated during pregnancy or by caffeine or iron deficiency. Family history may be positive in 4 0 - 5 0 % of the patients, which suggests a dominant mode of inheritance.
["able 4, IK:
Features of pcriodie limb movements in sleep
Repetitive, often stereotyped movements during NREM sleep Usually noted in the legs and consisting of extension of the great toe, dorsiflexion of the ankle, and flexion of the knee and hip; sometimes seen in the arms Periodic or quasi periodic at an average interval of 20-40 sec (range 4-90 sec) with a duration of 0.5-5.0 sec and as part of at least four consecutive movements Occurs at any age but prevalence increases with age May occur as an isolated condition or may be associated with a large number of other medical, neurological, or sleep disorders and medications Seen in at least 80% of patients with restless legs syndrome NREM = non—rapid eye movement.
SLEEP AND ITS DISORDERS Tabic 74.19: syndrome
Causes of symptomatic or secondary restless legs
Neurological disorders Polyneuropathies Lumbosacral radiculopathies Amyotrophic lateral sclerosis Myelopathies Multiple sclerosis Parkinson's disease Poliomyelitis
Isaac's syndrome Hyperexplexia (startle disease) Medical disorders Anemia: iron and folate deficiency Diabetes mcllitus Amyloidosis Uremia Gastrectomy Cancer Chronic obstructive pulmonary disease Peripheral vascular (arterial or venous) disorder Rheumatoid arthritis Hypothyroidism Drugs and chemicals Caffeine Neurolepsy Withdrawal from sedatives or narcotics Lithium C.ikmm ..'vniivi nir,u;nriiits e.g., nifedipine
Differential diagnosis of RLS m a y be considered u n d e r t w o categories: secondary RLS a n d the entities t h a t m a y mimic RLS. In secondary or s y m p t o m a t i c RLS, several conditions m a y be associated with RLS or may cause symptomatic RLS (Table 7 4 . 1 9 ) . T h e entities t h a t mimic RLS are listed in T a b l e 7 4 . 2 0 . An i m p o r t a n t a n d often difficult condition to differentiate from RLS is akathisia. Essential features of akathisia t h a t differentiate it from RLS a r e listed in T a b l e 7 4 . 2 1 . Pathoph ysio logy T h e physiological m e c h a n i s m or the a n a t o m i c a l locus responsible for RLS-PLMS is u n k n o w n . Pathophysiological
Table 74.20:
Entities that may mimic restless legs syndrome
NkamilqruL-n'.dikvU .lkaihsia Syndrome of painful legs and moving toes Muscular pain-fasciculation syndrome Myokymia Causalgia-dystonia syndrome Painful nocturnal leg cramps Myoclonus (essential myoclonus) Hypnic jerks ("sleep starts") Anxiety-depression Growing pains
2023
Table 74.21: Pertinent features of akathisia that differentiate it from restless legs syndrome Inner restlessness, fidgetiness with jittery feelings, or generalized restlessness Common side effect of neuroleptic drugs Can he acute, chronic, or tardive Characteristic motor restlessness consists of swaying or rocking movements of the body; marching in place; crossing and uncrossing of the legs; shifting body positions in chair; inability to sit still; rhythmic or nonrhythmic, synchronous or asynchronous, symmetrical or asymmetrical limb movements; movements resemble chorea rather than the voluntary movements of restless legs syndrome Motor restlessness present mostly during the day but may be worse when sitting or standing in one place for a long time Polysomnography study shows no distinctive features and rarely may show evidence of mild sleep disturbance and periodic limb movements in sleep No relevant family history Neurological examination reveals evidence of akathisia and sometimes drug-induced extrapyramidal manifestations Involuntary movements (e.g., myoclonic jerks) are uncommon and not a prominent feature Best treated with anticholinergics or ^-adrenergic antagonists
e l m s may be derived from electrophysiological a n d i m a g i n g studies as well as from s t a t e - d e p e n d e n t and circadian factors {Hening et al. 1999; T r e n k w a l d c r and W i n k e l m a n n 200.5; C h o k r o w r t y el al. 200,51. D o p a m i n e r g i c a n d peptidergic theories a r e based on pharmacological responses. On t h e basis of implications derived from s e c o n d a r y RLS, a vascular hypothesis, a p e r i p h e r a l n e u r o p athy h y p o t h e s i s , a n d deficient a n d toxic states have been suggested as etiologies, b u t n o n e has been satisfactory. T h e most likely hypothesis is a functional alteration in the b r a i n s t e m region, b u t the e x a c t location is u n d e t e r m i n e d . Several studies have found inconsistent s u p p o r t for the presence of some hyperexcitable b r a i n s t e m reflexes. Based on t h e absence of cortical prepofentials in a jerk-locked back averaging study, it is unlikely t h a t the cortex is the g e n e r a t o r of P L M S . Studies h a v e s h o w n t h a t RLS w a s m a x i m u m during the falling p h a s e of a b o d y t e m p e r a t u r e c u r v e , w h i c h suggests t h a t there is a circadian factor t h a t m o d u l a t e s severity of R L S , i n d e p e n d e n t of activity state. A functional MR1 study s h o w e d increased activity in the c o n t r a l a t e r a l t h a l a m u s a n d in the red n u c l e u s , bilateral cerebellum, and brainstem reticular formation in patients with P L M S a n d sensory s y m p t o m s (Bucher et al. 1997). Two positron emission tomography (PF.T) studies (Turjanski et al. 1999\ R u o t t i n e n et al. 2 0 0 0 ) and t w o single p h o t o n emission c o m p u t e d t o m o g t a p h y (SPECT) studies (Staedt et al. 1 9 9 5 ; M i c h a u d et al. 2 0 0 2 ) suggested small but significant striatal d o p a m i n e a b n o r m a l i t i e s . H o w e v e r , the small m a g n i t u d e of these o b s e r v a t i o n s a n d r e p o r t s of s o m e negative d o p a m i n e system imaging studies ( T r e n k w a l d e r et al. 1 9 9 9 ; Eisensehr et al. 2 0 0 1 ) raise s o m e
2024
NEUROLOGICAL DISEASES
pertinent questions about whether these abnotmalities arc primary rather than epiphenomcna. The most exciting current development in RLS research is the hypothesis that brain iron depletion causes alteration of brain dopaminergic system thereby producing symptoms of RLS (Allen and Earley 2003). Periodic Limb Movements hi Sleep PI.MS is a PSG finding and is characterized by periodically recurring limb movements during NREM sleep; most commonly, patients dorsiflex the ankles and flex the knees and hips every 20-40 seconds (tange 4-90) seconds. ( )cc.iMOiiali\, I'l MS i- noted ill [lie n p ; v r li:r.;v,. ]:, .,i
least 80% of patients with RLS, PLMS is also seen, whereas RLS is found in about 3 0 % of patients with PLMS. Additional criteria for PLMS are listed in Table 74.18. Limb movements may be accompanied by partial arousal, causing sleep fragmentation. A PLMS index fnumbci ul I1! MS per hour ol sleep) ol S is considered within normal range. PLMS is seen most commonly in RLS but may also occur in a large number of othet medical, neurological, and sleep disorders (Montplaisir et al. 2000), and in association with medications (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, and r dopa . Whether PI MS occurs as a primary condition unassociated with RLS causing repeated awakenings and sleep fragmentation as described in the ICSD under the heading of PLMD remains controversial. There is a growing body of evidence that PLMS may not have a specific clinical significance and is simply a PSG observation seen in a wide variety of sleep disorders but is present in most patients with RLS (Montplaisir et al. 2000; Mahowald 2002).
this disorder have great difficulty in functioning adequately in the daytime if they have to wake up early in the morning to go to school or work. They have severe sleep-initiation difficulty and cannot function normally in society because of the disturbed sleep schedule. They often try a variety of hypnotic medications or alcohol in an attempt to initiate sleep sooner. Sleep architecture is generally normal if these individuals are allowed to follow their own uninterrupted sleep-wake schedule. DSPS may represent 5-10% of complaints of insomnia in some sleep disorders centers. Onset occurs during childhood or adolescence. Sometimes there is a history of DSPS in other family membets. Some patients may have depression. Primary DSPS results from an unusually long intrinsic circadian period due to abnotmalities in • In- biological clock in the Si \. Aclii;rapliic recordings over several days document the charactetistic sleep schedule. Advanced
Sleep-Phase
Syndrome
Advanced sleep-phase syndrome (ASPS) is the converse of DSPS: The patient goes to sleep in the early evening and wakes up earlier than desired in the morning (e.g., 2:004:00 AM). If these patients do not go to sleep at an early hour, they experience sleep disruption and daytime sleepiness. Occasional familial cases have been described. ASPS is most commonly seen in elderly individuals. The basic mechanism is thought to be an inherent shortening of the endogenous circadian timing. The diagnosis is based on sleep logs and characteristic actigraphic recordings over several days. ASPS is easy to distinguish from the early morning awakening of depression because sleep architecture is normal and does not exhibit the shortened REM latency and other REM sleep abnormalities seen in depressed patients.
(arcadian Rhythm Sleep Disorders Hypernychthemeral Orcadian rhythm sleep disorders result from a mismatch between the body's internal clock and the geophysical environment (Mahowald et al. 1997; Dagan 2002) either because of a malfunction in the biological clock (primary circadian rhythm disorders) or because the clock is out of phase due to a shift in environment (secondary circadian dysrhythmias). Jet lag and shift work are two common sources of secondary circadian dysrhythmias resulting from exogenous factors. Delayed Sleep-Phase Syndrome The ICSD defines DSPS as a condition in which the major sleep episode is delayed in relation to the desired clock time. This causes symptoms of sleep-onset insomnia or difficulty awakening at the desired time. Typically, the patient goes to sleep late (e.g., 2:00-6:00 AM) and awakens in the late morning or afternoon (e.g., 10:00-2:00 PM), Patients with
Syndrome
Hypernychthenteral syndrome, also cailed non-24-hour sleep-wake disorder, is characterized by an inability to maintain a regular bedtime. Sleep onset wanders around the clock. Affected patients have a gradually increasing delay in sleep onset by about 1 hour per sleep-wake cycle, causing eventual progression of sleep onset through the daytime hours and into the evening. These individuals fail to be entrained or synchronized by usual time cues, such as sunlight or social activities. Hypernychthemeral syndrome is an extremely uncommon disorder and is most often associated with blindness. Approximately one third of blind individuals are affected because of impairment of the retinohypothalamic pathway, which normally cues circadian patterns. The syndrome also may be associated with hypothalamic tumors. Sometimes depression and anxiety disorders are associated with this syndrome.
SLEEP AND ITS DISORDERS
Neurological Disorders and Sleep Disturbance Sleep disorders are very common in neurological illnesses, which ma; adversely affect punnus' •deep. llm.s (here is an interrelationship between sleep and neurological disorders. Sleep dysfunction may result from central or peripheral somatic and autonomic neurological disorders. Neurological diseases may cause insomnia or EDS as well as parasomnias. Neurological causes of excessive sleepiness have been described previously, and neurological disorders that cause insomnia are described under Insomnia, earlier in this chapter. Sleep and Epilepsy There is a distinct and reciprocal relationship between sleep and epilepsy (Chokroverry and Quinto 1999; Dinner 2002). Sleep affects epilepsy, and epilepsy affects sleep. In the beginning of the last century, before the availability of encephalography, several authors emphasized that many seizures are predominantly nocturnal and occur at certain times at night. The modern era of combining the clinical and EEC findings on sleep and seizures began with the observation of Gibbs and Gibbs in 1947 that EEG epileptiform discharges were seen more often during sleep than during wakefulness (Chokroverry and Quinto 1999). A basic understanding of the mechanism of epileptogenesis and sleep makes it clear why seizures are often triggered by sleep. The fundamental mechanism for epileptogenesis includes neuronal synchronization, neuronal hypcrexcitability, and a lack of inhibitory mechanism. During NREM sleep, there is an excessive diffuse cortical synchronization mediated by the thalamocortical input, whereas during REM sleep, there is inhibition of the thalamocortical synchronizing influence in addition to a tonic reduction in the interhemispheric impulse traffic through the corpus callosum. Factors that enhance synchronization are conducive to active ictal precipitation in susceptible individuals. NREM sleep thus acts as a convulsant by causing excessive synchronization and activation of seizures in an already hyperexeitable cortex. In contrast, during REM sleep, there is attenuation of epileptiform discharges and limitation of propagation of generalized epileptiform discharges to a focal area. Sleep deprivation is another important seizure-triggering factor, and the value of sleep-deprived ERG studies in the diagnosis of seizures is well known. Sleep deprivation increases epileptiform discharges, mostly during the transition period between waking and light sleep. Sleep deprivation causes sleepiness, which is one factor for activation of seizures, but it probably also increases cortical excitability, which triggers seizures. However, in a recent report on 84 patients with medically refractory partial epilepsy with secondary generalization undergoing inpatient monitoring, Malow ct al. (2002) noted that acute sleep deprivation did not affect seizure incidence.
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Biorhythmic classification of seizures has shown inconsistencies and contradictions. Seizures have been shown to occur predominantly during sleep (nocturnal seizures), predominantly in the daytime (diurnal seizures), or both during sleep at night and daytime (diffuse epilepsy). Taking into consideration different series, the incidence of sleep epilepsy has been quoted to be 2 2 % , but most of these statistics were obtained before the advent of electroencephalography. The most likely figure for nocturnal seizures is aboul 10%. Because of inconsistencies in biorhythmic classification, modern epilcptologists use the International Classification of Epilepsy, which divides seizures into primarily generalized and partial seizures with or without secondary generalization. Effect of Sleep on Epilepsy, True nocturnal seizures (Malow and Plazzi 2003; Chokroverry and Quinto 1999) may include tonic seizures, benign focal epilepsy of childhood with rolandic spikes or occipital paroxysms, juvenile myoclonic epilepsy, electrical status epilepticus during sleep or continuous spikes and waves during sleep, generalized tonic-clonic seizures on awakening, nocturnal frontal lobe epilepsy including nocturnal paroxysmal dystonia (NPD), and a subset of patients with temporal lobe epilepsy (nocturnal temporal lobe epilepsy). Many patients with generalized tonic-clonic and partial complex seizures also have predominantly nocturnal seizures, Nocturnal seizures may be mistaken for motor and behavioral parasomnias or other movement disorders that persist during sleep or reactivate during stage transition or awakenings in the middle of the night. Tonic Seizure. Tonic seizures are characteristic of Lcnnox-Gastaut syndrome, which may also include other seizure types, such as myoclonic, generalized tonic-clonic, atonic, and atypical absence. Tonic seizures are typically activated by sleep, occur much more often during NREM sleep than during wakefulness, and are never seen during REM sleep. The typical EEG finding consists of slow spikes and waves intermixed with trains of fast spikes as intcrietal abnormalities during sleep. Benign Rolandic Seizure. Benign rolandic seizure is a childhood seizure disorder seen mostly during drowsiness and NREM sleep and is characterized by focal clonic facial twitching, often preceded by perioral numbness. Many patients may have secondary generalized tonic-clonic seizures. The characteristic EEG finding consists of centrotemporal or rolandic spikes or sharp waves and sometimes occipital spikes. Seizures generally stop by the 15-20 years of age without any neurological sequela. Juvenile Myoclonic Epilepsy. Onset of myoclonic epilepsy of Janz usually occurs between 13 and 19 years of age and
2026
NEUROLOGICAL DISEASES
is manifested by massive bilaterally synchronous myoclonic jerks. The seizures increase shortly after awakening in the morning and occasionally on awakening in the middle of the night. A typical electroencephalogram shows synchronous and symmetrical polyspikes and spike-and-wave discharges. The intericta) discharges predominate at sleep onset and then on awakening but are virtually nonexistent during the rest of the sleep cycle. Nocturnal Frontal Lobe Epilepsy. Nocturnal frontal lobe epilepsy includes (Provini et al. 1999; Malow and Plazzi 2003) nocturnal paroxysmal dystonia, paroxysmal arousals and awakenings, episodic nocturnal wanderings, and autosomal dominant nocturnal frontal lobe epilepsy. These disorders all share common features of abnormal paroxysmal motor activities during sleep and respond favorably to anticonvulsants. They most likely represent partial seizures arising from discharging foci in the deeper regions of the brain, particularly the frontal cortex, without any concomitant scalp EEC evidence of epileptiform activities. The relationship to seizures, particularly partial complex seizures of temporal or extratcmporal origin, however, remains controversial. Nonepilepric seizures or pseudoseizures are not common during sleep at night but sometimes can occur and be mistaken for true nocturnal seizures, and it is important to differentiate these from true seizures because of difference in management. hive patients were originally described who had episodes of abnormal movements that were tonic and often violent during NREM sleep almost every night. Ictal and interictal EEG findings were normal. Later, 12 patients were described with NREM sleep-related choreoathetotic, dystonic, and ballismic movements each night, often occurring many times during the night for many years. The term nocturnal paroxysmal dystonia {NPD) was coined for this entity (Table 74.22). The disorder in all patients responded to carbamazepine therapy, and the spells lasted less than 1 minute. It was suggested that these spells were a type of unusual nocturnal seizure. Later, patients with NPD showed IT(. evidence ot epileptiform abnormalities arising from the frontal lobes. A study comparing groups of
Table 74.22:
Features of nocturnal paroxysmal dystonia
Onset: infancy to fifth decade Usually sporadic; rarely familial Sudden onset from non-rapid eye movement sleep Two clinical types: Common [ype is short-lasting (15 sec to ). Respiratory muscle
function of individuals with neuromuscular disorders should be specifically assessed, and it is important to measure the maximal static inspiratory and expiratory pressures. Finally, chemical control of breathing (hypercapnic and hypoxic ventilatory responses) may be needed to assess respiratory functions and control systems in patients with various neurological disorders causing dysfunction of the metabolic respiratory controllers as well as in patients with obcsity-hypoventilation {pickwickian) syndrome.
Elcctrodiagnosis of the Respiratory Muscles FMG recordings of the upper airway and diaphragmatic and intercostal muscles may detect affection of these muscles in various neurological diseases. A laryngeal EMG recording may detect laryngeal paresis in patients
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NEUROLOGICAL DISEASES
with VISA with laryngeal stridor. A phrenic nerve and intercostal nerve conduction study may detect phrenic and intercostal neuropathy, which may cause diaphragmatic and intercostal muscle affections in some patients with neurological disorders.
the problem, however, treatment should be focused on specific sleep disturbance. Certain general principles of treatment should apply to treatment of any sleep disorders. It is beyond the scope of this chapter to discuss management of various medical, psychiatric, and neurological disorders. General sleep hygiene measures are listed in Table 74.28.
Other Laboratory Tests Steep Apnea Syndrome Appropriate laboratory tests should always be performed to exclude any suspected medical disorders that may be the cause of patients' insomnia or hypersomnia. These tests may include blood analysis and urinalysis, EGG, Holter ECG, chest radiography, and other investigations to rule out gastrointestinal, pulmonary, cardiovascular, endocrine, and renal disorders. In rare patients, when autonomic failure causes a sleep disturbance or sleep-related breathing disorder, autonomic function tests may he required for the diagnosis of the primary condition. In patients with narcolepsy, 1 1LA typing may be performed because most of the patients with narcolepsy show positivity for HLA DR2 DQ1, and DQB1*0602 antigens (Mignot 1998, 1999). Another important test is measurement of cerebrospinal fluid hypocretin 1 levels, which arc found to be low (below 110 pg/mL) in patients with narcolepsycataplexy who are HI.A D Q B D 0 6 0 2 positive (Mignot et al. 2002). In selected patients suspected of having a psychiatric cause of EDS, neuropsychiatry testing (e.g., the Minnesota Multiphasic Personality Inventory) may be helpful. In patients with RLS, EMG and nerve conduction studies are important to exclude polyneuropathies or lumbosacral radiculopathies and other lower motor neuron disorders that may be associated with RLS or cause symptoms resembling idiopathic RLS. Other important laboratory tests in patients with RLS include those necessary to exclude diabetes mellitus, uremia, anemia, and other associated conditions. It is particularly important to obtain levels of serum iron (including serum ferritin and transferrin), serum folate, fasting blood glucose, blood urea, and creatinine. The role of nerve biopsy remains controversial. In the vast majority of patients, a nerve biopsy is not necessary, but it may be obtained for research purposes and when there is a strong suspicion of polyneuropathy.
Management of Sleep Disorders It is important to determine a cause for sleep disturbances so that the primary condition can be adequately treated. Treatment of secondary sleep disturbances is unlikely to be successful unless the primary cause is properly diagnosed and treated. Treatment of an underlying cause may resolve the sleep disturbance. If satisfactory treatment is not available for the primary condition or does not resolve
The objective of management of sleep apnea syndrome is to improve the quality of life by improving the quality of sleep and to prevent life-threatening cardiac arrhythmias, pulmonary hypertension, CHF, and stroke, which arc related to SDK. Treatment of sleep apnea syndrome includes (Table 74.29) general measures, pharmacological agents, mechanical devices, and surgical treatment (Robinson and Guilleminault 1999). Genera) measures include avoidance ot sedative-hypnotics and alcohol, which can aggravate sleep-related breathing disorders, and reduction of body weight in obese patients, Pharmacological Treatment. Pharmacological treatment has not been very helpful in OSAS. The agents that have been partially successful in treatment of mild sleep apneahypopnea syndrome are protriptyline and acetazolamidc. There have been isolated reports of the use of selective serotonin reuptake inhibitors, theophylline and medroxyprogesterone acetate, without much benefit as well as topical nasal corticosteroids for OSAS in children with minimal benefit. Acetazolamide, a carbonic anhydrase inhibitor, produces metabolic acidosis, causing a shift in the CO2 apnea threshold, and has been used with some success to treat central apnea at high altitude. In a subset of patients with OSAS who were receiving CPAP treatment, modafinil, a novel wake-promoting agent, has been useful as adjunct treatment for residual daytime sleepiness. Mechanical Devices. Nasal CPAP is an important therapy for treating OSAS. CPAP opens up the upper airway passage so that obstructive apneas and hypopneas,
Table 74,2H:
Sleep hygiene measures
Sleep only as much as you need to feel rested Keep a regular sleep schedule Avoid forcing sleep Exercise regularly for at least 20 min, preferably 4-5 hr before bedtime Avoid caffeinated beverages after lunch Avoid alcohol near bedtime: no nightcap Avoid smoking, especially in the evening Do not go to bed hungry Adjust bedroom environment Deal with your worries before bedtime
SI.ELLP AND ITS DISORDLKS
Table 74.29:
Treatment of sleep apnea syndrome
General measures Avoid alcohol, particularly in the evening Avoid sedative-hypnotics Reduce body weight Pharmacological treatment (in mild cases) Protnptyline Acctazolamide (central apnea at high altitude) Mechanical devices Nasal continuous positive airway pressure for OSAS Bilevel positive airway pressure for OSAS Intermittent positive pressure ventilation for hypoventilation in neuromuscular disorders Dental appliances in some mild to moderate OSAS Tongue-retaining device for OSAS (unpredictable) Surgical treatment Uvulopalatopharyngoplasty (UPP), including laser-assisted and radiofrcquency UPP Major maxillofacial surgical procedures Tonsillectomy and adenoidectomy Diaphragm pacing (central sleep apnea) Tracheostomy (rarely performed nowadays) OSAS = obstructive sleep apnea syndrome. hypoxemias, snoring arousals, and sleep fragmentation are eliminated. The optimal (TAP pressure is first determined in the laboratory during overnight an PSG study, and the patient can purchase home units ro use nightly during sleep. Instead of CPAP, some patients may require bilevel positive airway pressure, which delivers a higher pressure during inspiration and a lower pressure during expiration. It is important to follow-up with such patients for the purpose of compliance and to identify patients who did not have adequate benefit and may require repeat titration. All patients do not comply with the CPAP regimen because of various problems, such as difficulty with the mask, claustrophobia, air leaks between the mask and face, and nasal congestion. The compliance vaties from 6 0 % to 70% of patients. Further study is needed to determine the factors for compliance and noncompliance and to understand the long-term effect on the natural history of OSAS. The role of nasal CPAP in CSA syndrome is highly controversial. In a subgroup of patients with CSA who show narrowing or occlusion of the upper airway on fiberoptic scope, nasal CPAP may reverse the apneic episodes. Surgical Treatment. In a few patients with severe OSAS in which CPAP therapy fails, UPP, including laser-assisted and radiofrequency UPP, and other upper airway surgical procedures have been tried with variable success (Sher 2002). Significant improvement is noted in approximately 5 0 % of patients after UPP, and many of those who show improvement may still need (TAP for elimination of residual apneas. An overnight PSG study must always be performed before UPP is undertaken because it may eliminate snoring without adequately relieving OSAS. Other surgical approaches may be needed in patients with severe disease, including maxillofacial surgery, such as
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hyoid myotomy and suspension or mandibular osteotomy with genioglossus muscle advancement, although their role remains uncertain (Sher 2002). Tracheostomy may still be needed in an occasional patient as an emergency measure during severe respiratory compromise or severe apnea associated with dangerous cardiac arrhythmias causing a life-threatening situation. Tracheostomy for such severe cases of OSAS appears to be effective and well tolerated in the long term (Thatcher and Maisel 2003). Some patients may later be weaned from the tracheostomy and move to CPAP treatment, which has replaced tracheostomy for obstructive or mixed apneas. In patients with respiratory center involvement with CSA syndrome, diaphragm pacing or electrophrenic respiration has been used successfully, particularly for those who require ventilatory assistance during both day and night. Other Ventilatory Supports. In patients with neuromuscular disorders, including those with AI.S, poliomyelitis, and postpolio syndrome, ventilatory support is often needed with either negative pressure or positive pressure ventilators ((^hokrovcrty 1999b; Guilleminault and Shergill 2002; Gonzalez et al. 2002). Intermittent positive pressure ventilation (IPPV) can be administered through a nasal mask. Negative pressure ventilation can be delivered from a tank respirator or from a cuirass. With ventilatory support, patients with neuromuscular disorders often obtain relief of daytime hypcrsomnolence and show improvement in sleep architecture. A combination of a nasal mask and positive pressure ventilation may be needed. When OSA complicates sleep hypoventilation, IPPV through a nasal mask during sleep may be a better treatment than negative pressure ventilation and may obviate the need for tracheostomy or diaphragm pacing. Negative-pressure ventilation may improve these patients' nocturnal ventilation during NREM sleep but can produce upper airway obstructive apnea during REM sleep, causing severe hypoxemia and hypercapnia. Patients with respiratory muscle weakness, including diaphragmatic muscle weakness, may require a combination of CPAP, cuirass ventilation, and later IPPV at night. Patients with motor neuron disease and associated sleep-related hypoventilation and apnea have been treated with cuirass ventilators, CPAP, and later IPPV at night with considerable symptomatic relief. Patients with poliomyelitis or postpolio syndrome who require ventilatory support to maintain respiratory homeostasis generally show improvement in sleep architecture and respiratory function after mechanical ventilation via nasal mask. Obstructive or mixed apneas respond to CPAP.
Other Treatment Modalities. Dental appliances can reduce snoring and help patients with mild sleep apnea, but at present, it is not possible to predict which patients will respond to such treatment. A tongue-retaining device is another unpredictable measure for treating sleep apnea.
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NEUROLOGICAL DISEASES
Narcolepsy The administration of stimulants, such as modafinil, NKilivlplH-r.ulaU'. pemoline, dextroamphetamine, or mcthamphetamine, is the treatment of choice (Table 74,30) for narcoleptic sleep attacks (Bassetti 2003). In 6 5 - 8 5 % of patients, a significant improvement of EDS can be obtained. Modafinil, a novel wake-promoting agent, or methylphenidate is the drug most commonly used initially in patients with newly diagnosed narcolepsy. Because of hepatotoxicity pemoline is rarely used at present. The longterm efficacy and safety of modafinil fot the treatment of excessive sleepiness and sleep attacks associated with narcolepsy have been well established (Moldofsky et al. 2000; Mitlet et al. 2000). The starting dose is 100-200 mg daily and may be increased to 400 nig daily in two divided doses if needed. Methylphenidate treatment may be started with 5-10 mg two to three times daily. To avoid insomnia, the last dose should not be taken aftet 4:00 PM. In patients whose narcolepsy docs not respond to modafinil or methylphenidate, treatment with dextroamphetamine or mcthamphetamine can be administered, starting with 5-10 mg in the morning or twice a day. The maximum acceptable doses of stimulants for treatment of narcolepsy may include up to 50 mg daily (rarely 100 mg) for methylphenidate and 50 mg daily for both dextroamphetamine and methamphetamine. The most common side effects of the stimulants include nervousness, tremor, insomnia, irritability, palpitations, headache, and gastrointestinal symptoms. Another problem is tolerance, which may be noted in many patients, particularly with increasing doses. The treatment of cataplexy and other auxiliaty symptoms of narcolepsy (see Table 74.30) consists of administration of tricyclic antidepressants, such as protriptyline (starting with 5 mg per day), imipramine (25-200 mg per day), and clomipramine (10-200 mg per day). Specific serotonin reuptake inhibitors, such as fluoxetine (20-80 mg per day), have been used with success. Recently sodium oxybatc (y-hydroxybutyrate) in two divided nightly doses
Table 74.30:
Drug treatment for narcolepsy syndrome
For sleep attacks Modafini!: 200 mg/day Methylphenidate (Ritalin): 5 mg bid, 30 min before meals to a maximum of 30 mg, rarely 100 mg/day IV\m>nmphi'iamine (Dcxcdrine): 5 mg qd or hid, up to 50 mg/day Y t e r r i a m p r i o r n m u H ' : X I . • -11 L~L 31- i - . - • 5 N I L ; qd nr h i d , up r
50 mg/day Mazindol: 2 mg qd or bid, up to 8 mg/day For cataplexy, sleep paralysis, and hypnagogic hallucinations Imipramine: 75-150 mg/day Clomipramine: 75-125 mg/day Fluoxetine: 20 mg qd, up to 80 mg/day Viloxazine: 150-200 mg/day Sodium oxybate: 3-9 g nightly
of 3-9 g has been found to be an effective drug for treating cataplexy and narcoleptic sleep attacks (US Xyrctn Multicenter Study Group 2003). Nonpharmacological treatment of narcolepsy includes general sleep hygiene measures, short daytime naps, and participation in narcolepsy support groups. Idiopathic
Hypersomnia
The treatment of idiopathic hypersomnia is generally unsatisfactory and is similar to the stimulant treatment for narcolepsy. Parasomnias No special treatment is needed for most ot the parasomnias. The subjects with partial arousal disorders (e.g., sleepwalking and sleep terrors) must he protected from injury to self or others by arranging furniture, using a padded mattress, and paying particular attention to doors and windows. If attacks of sleepwalking or sleep terrors are frequent, . realrr.eni v. uli ..u: aniulepirss.im e.g.. imipr.i mule or small doses of a benzodiazepine (e.g., clonazepam) may be tried for a short period. Most RBDs respond dramatically to small doses of clonazepam (e.g., 1-2 mg at night). Occasional patients may need other drugs {e.g., melatonin). Circadian Rhythm Sleep Disorders Orcadian rhythm sleep disorders may be treated by the use of chronotherapy, phototherapy, or both. Chronotherapy refers to the intentional delay of sleep onset by 2-.y hours on successive days until the desired bedtime has been achieved. After this, the patient strictly enforces the sleepwake schedule. One study reported a high success rate among patients with DSPS even when the disorder had been present for many years. After several months, however, the patient generally becomes less adherent to the schedule and begins to lapse into his or her original sleep habits. Exposure to bright light on awakening is effective in altering sleep onset and in synchronizing body temperature rhythm in patients with DSPS. The patient sits in front of a 10.000-lux light for 30^10 minutes on awakening; in addition, room lighting must be markedly reduced in the evening to achieve the desired results, A response is LU.Tiei,;lly (.vide:u Lillet 2-3 weeks- bin maintenance "l the response often requires indefinite treatment. This treatment is still evolving, and no large-scale study with adequate follow-up has been conducted to assess the long-term effect of phototherapy in DSPS. In patients with ASPS, bright light exposure in the evening has been successful in delaying sleep onset. Melatonin (0,5-7,5 mg/day), taken orally in the evening or at bedtime, has been reported to be effective in some blind people with hypernychthemeral syndrome.
SLEEP AND ITS DISORDERS SiToml.m circuliau rhythm disorders (e.g., jet lag and effects of shift work) may be treated with benzodiazepine or /olpidem. Phototherapy has been tried, but its effectiveness has not been determined. Melatonin is being evaluated for treatment of arcadian rhythm disorders. Restless Legs Syndrome and Periodic Limb in Sleep
Movements
hour major groups of drugs have been used to treat RLS and PLMS (Table 74.31): dopaminergic agents, benzodiazepines, gabapentin, and opiates (Hcning et al. 1999). The typical dose for carbidopa/L-dopa (Sinemet) is 25/100 to 100/400 mg taken in divided doses before bedtime and during the night, Pergolide can be started at 0.05 mg and gradually increased to 0.2-0.5 mg taken in divided doses. One dose is taken 1 hour before bedtime and, depending on severity, another dose may be needed earlier in the evening or during the middle of the night on awakening. Another dopamine agonist, bromocriptine, may be tried, beginning with 2.5 mg and gradually increasing to a maximum of 15 mg per day. Bromocriptine has not been found to be as useful as pergolide or carbidopa/i.-dopa. Sometimes, a long-acting drug (e.g., Sincmct-CR) may be combined with short-acting carbidopa/L-dopa for maximum effect. Problems with the use of dopaminergic medications include abdominal pain, nausea, recurrence of RLS symptoms, poor sleep quality during the last part of the night, and the development of rebound or augmentation, consisting of symptoms of RLS-PLMS developing earlier in the day and more severely than before treatment. Nausea, vomiting, and headache also may occur after treatment with carbidopa/L-dopa, whereas nasal stuffiness, hypotension,
Tabic 74.31:
Drug treatment of restless legs syndrome
Major drugs Dopaminergic agents Carbidopa/L-dopa Pergolide
Bromocriptine Pramipexole Ropinirole Benzodiazepines Clonazepam Temazepam Gabapenrin ( Ipiati-f,
Codeine Propoxyphene Oxycodone Methadone Minor drugs Tramadol Baclofen
Carbamazepine Clonidine
Propranolol
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and nightmares have been reported after treatment with pergolide. Two new nonergot dopamine agonists, pramipexole and ropinirole, have been available in recent years. The safety and efficacy of these agonists in the treatment of RLS have been proven by several clinical trials. Most physicians now begin treating RLS with one of these agents. Pramipexole should be started at 0.125 mg I hour before bedtime and then gradually increased every 5-7 days as needed. The average dose is about 0.5-0.75 mg and may be increased up to 1.0-1.5 mg a day. Ropinirole should be started at 0.25 mg 1 hour before bedtime and gradually increased to an average dose of 1.5-2.5 mg. Side effects of these two drugs include nausea, sleepiness, dizziness, and peripheral edema. Another long-acting dopamine agonist, cabergolinc, has been used successfully to treat RLS, but this drug is very expensive and generally not used in the United States. Clonazepam (0.5-2.0 mg per day at bedtime) or temazepam (15-30 mg at bedtime) may be useful in treating RLS-PLMS. Medications should be started with the lowest dose and gradually increased to obtain maximum benefit with minimal side effect. These agents may produce daytime sleepiness or confusional episodes, particularly in elderly patients. Gabapentin is an anticonvulsant that has been found to be beneficial in mild-to-moderate RLS-PLMS. Divided doses of 300-1800 mg per day may be helpful but can produce somnolence, dizziness, ataxia, or fatigue in more than 10% of patients. Opiates are effective for treating RLS-PLMS but are a less desirable alternative because of their proclivity to produce constipation and their potential fot addiction. Codeine, propoxyphene, oxycodone, and methadone have all been used for this purpose. Tramadol, a non-narcotic agent with activity at the opiate mu-receptor, also has been used with some success in patients with RLS-PLMS. For mild RLS-PLMS, the physician may start with gabapentin. In moderate-to-severe conditions, most physicians start with pramipexole or ropinirole. In patients with refractory disease, one may have to use a combination of two to three drugs. In summary, the principle of treatment of RLS-PLMS is to start with the lowest possible dose and then increase by 1 tablet every 5-7 days until a maximum therapeutic benefit is reached or the side effects are noted. The dose can be divided and given 1-2 hours before bedtime. If necessary, for some patients with severe conditions, a daytime dose may be needed. Other minor drugs (see Table 74,31) that have been helpful in occasional patients with RLS-PLMS include baclofen (10-60 mg daily), carbamazepine {200-600 mg daily), clonidine, an adrenergic agent (0.1-0.9 mg daily), and propranolol (80-120 mg daily). In secondary RLS, the primary condition should be treated and the deficiency states, including the iron deficiency, should be corrected. The patient should also follow general sleep hygiene measures. Finally, the patients
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NEUROLOGICAL DISEASES
should avoid certain medication and agents that might aggravate RLS, including neuroleptics, tricyclics, selective serotonin re-uptake inhibitors, other antidepressants, certain antinausea medications, calcium-channel blockers, caffeine, alcohol, and smoking. Insomnia Insomnia is a syndrome and not a specific disorder, and therefore treatment depends on the underlying cause of the syndrome. Treatment of secondary insomnia is unlikely to be successful unless the primary cause of the disturbance is diagnosed and properly treated. Both nonpharmacological and pharmacological therapies may be useful in the management of insomnia (Morin ct al. 1999, 2001; Espie ct al. 2001). Nonpharmacological Treatment. The mainstay of treatment for patients with chronic insomnia is the use of nonpharmacologic.il measures in conjunction with the judicious, intermittent use of hypnotics. Nonpharmacological interventions include relaxation therapy and biofeedback; stimulus-control therapy; sleep restriction; and patient education about sleep hygiene, sleep habits, attitudes toward sleep, and the role of autonomic and cognitive arousals (Table 74.32). Sleep hygiene measures are listed in Table 74.28. Relaxation therapy involves progressive muscle relaxation and biofeedback to reduce somatic arousal. One small study of several relaxation procedures found a 4 2 % improvement in self-reported sleep complaints after 1 year of relaxation therapy. Stimulus-control therapy may also be useful in patients with chronic insomnia. Bootzin's stimulus-control technique is focused on discouraging the learned
Tablt 74.32:
Treatment of insomnia
Nonpharmacological treatment Relaxation therapy, including biofeedback Stimulus-control therapy Sleep-restriction therapy Sleep hygiene measures Chronotherapy (for circadian rhythm disorders) Phototherapy (for circadian rhythm disorders) Pharmacological treatment Benzodiazepines Flurazepam: 15-30 mg Estazolam: 1-2 mg Clonazepam: 0.5-2.0 mg Lorazepam: 1-2 mg Temazepam: 15-30 mg Triazolam: 0.125-0.250 mg Nonbenzodiaiepines Zolpidem: 5-10 mg Zalcplon 5-10 mg Antihistamines Sedative antidepressants Melatonin
association between the bedroom and wakefulness and reestablishing the bedroom as the major stimulus for sleep. These techniques have been reported to lessen complaints of insomnia in approximately 5 0 % of individuals after 1 year. Sleep-restriction therapy may improve sleep efficiency by restricting the total time in bed for sleep. Once this has occurred, gradually increasing the time allocated to sleep may improve the level of daytime functioning and the overall quality of sleep. Roughly one fourth of patients with insomnia may benefit from such a regimen. The relative efficacy of these various nonpharmacological approaches has not been well established. One metaanalysis involving 2102 patients in 59 trials found that sleep-restriction and stimulus-control therapies were more effective than relaxation techniques used alone (Smith et al. 2002). The use of sleep hygiene measures alone was not effective. The extent to which the concomitant use of nonpharmacological therapy augments the performance of pharmacological treatment is also unclear. Pharmacological Therapy. Hypnotic medications have generally not been the first choice of treatment for chronic insomnia (see Table 74.32). When they are prescribed, they should he used intermittently and always combined with nonpharmacological therapies. Judicious use of hypnotics may be helpful in treating transient or short-term, idiopathic, and psychophysiological insomnia, but their use should be restricted to less than 4 weeks' duration. Intermittent use of hypnotic medications (e.g., 1-2 nights per week) may be necessary in some patients with chronic idiopathic or psychophysiological insomnia whose insomnia does not respond adequately to nonpharmacological treatment, although the drugs should not be the main component of therapy. Hypnotic medications are contraindicated in pregnancy because of data showing an increased risk of fetal malformations with diazepam or diazoxide if used during the first trimester. The drugs should also he avoided or used judiciously in patients with alcoholism or renal, hepatic, or pulmonary disease. A combination of alcohol and hypnotics is absolutely contraindicated. The drugs should also be avoided in patients with sleep apnea syndrome. Benzodiazepine drugs (temazepam, flurazepam, triazolam, and estazolam) and two nonbenzodiazepine drugs (/olpidem and zalcplon) are commonly used as hypnotics; two other benzodiazepine drugs (lorazepam and clonazepam) are also often used for this indication (Morin et al. 2001; Walsh and Schweitzer, 1999; Walsh et al. 2000; Danjou et al. 1999). Triazolam is no longer available in Great Britain because of reports of serious side effects, such as amnesia, rebound insomnia, and anxiety. The selection of a specific hypnotic agent should be based primarily on the elimination half-life. Short-acting drugs, such as temazepam, estazolam, triazolam, and Zolpidem, are generally preferable because they produce less residual sleepiness the morning after use. However, these drugs,
SI.F.F.P AND ITS DISORDERS
particularly triazolam, may have a high incidence of amnesia and rebound insomnia and should be used cautiously in patients with anxiety disorders. Adjustment in dosage may be necessary in patients who have prolonged drug elimination half-lives due to age or impaired renal or hepatic function. Dependence and tolerance arc the major disadvantages of long-term use of hypnotics. The drugs should be discontinued gradually rather than abruptly to avoid precipitating symptoms of withdrawal. Sedating antidepressants (e.g., amitriptyline and trazodone) are most useful in the management of patients in whom depression and insomnia coexist but are of limited usefulness in nondepressed patients because of rapidly developing tolerance to the sedative effects. Many overthe-counter sleep aids conrain the sedating antihistamine diphenhydramine or doxylaminc. These medications are generally not helpful in the management of chronic insomnia. Melatonin, a normal product of the pineal gland, is sold as a food supplement and an orphan drug in the United States, but over-the-counter sales are banned in the United Kingdom. Data on the efficacy and safety of melatonin are minimal, but the hormone does not appear to be a potent hypnotic for most patients with chronic insomnia. However, a subgroup of elderly patients with low melatonin levels have benefited from melatonin treatment, and it also is useful in some patients with jet lag, DSPS, and hypernychthcmeral syndrome. Sleep Disturbances in Neurological llhess Treatment of neurological illnesses causing sleep-related dysrhythmias have been described (see Sleep Apnea Syndrome, earlier in this chapter). Nocturnal seizures should be treated with standard anticonvulsant medications. Sleep disturbances in these patients often resolve after effective therapy for seizures, Trearment of acute confusional states associated with dementia should be focused on the precipitating or causal factors for such episodes. Often, episodes are precipitated when the patient is transferred from home to an institution. As much as possible, the home environment of such patients should be preserved. The darkness of night often precipitates episodes, so a night light is helpful. Medication that could have adverse effects on sleep and breathing should be teduced in dose or changed. Associated conditions that could interfere with sleep {e.g., pain due to arthritis and other causes) should be treated with analgesics. Depression is often an important feature in patients with AD, and a sedative antidepressant may be helpful. Frequency of urination in such patients may result from infection or an enlarged prostate gland and may disturb sleep at night. Appropriare treatment should be used for such conditions. Patients should be encouraged to develop good sleep habits. They should be discouraged from taking daytime haps and should be encouraged to exercise (e.g., walking) during the day. They should not drink caffeine in
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the evening before bedtime. For sleeplessness, a trial with intermediate-acting benzodiazepines, Zolpidem or zaleplon, should be tried for a short period. For extreme agitation, patients should be given small doses of high-potency antipsychotics, such as halopendol or thiothixene, or atypical antipsychotics (e.g., risperidone, olanzapine, quetiapine), which have less side effects than halopcridol or thiothixene. In some patients, appropriately timed exposure to bright light may be helpful. Treatment of PD improves sleep inconsistently. In patients who have reactivation of parkinsonian symptoms during sleep at night, adjustment in the timing and choice of medication may be helpful. Some patients may benefit from an evening or bedtime dose. Longer-acting preparations of L-dopa also may help when taken near bedtime. Dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, and ropinirole) with their sustained actions may benefit sleep in some patients. Antihistamines such as diphenhydramine may promote sleep in addition to giving a modest antiparkinsonian effect. A small dose of carbidopa/ L-dopa, with a second dose later at night if the patient awakens, may sometimes help those with insomnia. In some patients, selegiline may improve sleep. Nocturnal dyskinesias related to i.-dopa and causing insomnia may respond to a reduction in the dose of dopamine agonists or by addition of a small dose of benzodiazepine. In patients with nocturnal hallucinations and nightmares, including nocturnal vocalizations and RBD, clonazepam (0.5-1.0 nag) at bedtime may be beneficial. Nocturnal hallucinations and psychosis in patients with PD have been treated successfully with clozapine or the newer drug olanzapine. During clozapine treatment, the usual precautions of monitoring blood count and testing liver function should be taken. Rivastigmine, a cholinesrerasc inhibitor, has been beneficial in improving sleep disturbance cognition and hallucinations in some patients with PD.
CONCLUSION There has been an explosion of knowledge in our understanding of sleep and its disorders stretching from the gene to pathophysiology and phenomenology. The field of sleep medicine is beginning to take its rightful place as a distinct subspecialty in medicine. Sleep disorders affect multiple systems and result from dysfunction of almost every system in the body. It is therefore important to have a basic understanding of the physiological changes during sleep and the clinical phenomenology of sleep disorders. In this chapter, I briefly summarize the essential physiological changes during sleep, which are quite different from those during wakefulness as well as circadian rhythms, the function of sleep, and neurobiology of slcep-wakefulness. Clinical manifestations of many primary and secondary sleep disorders, methods of laboratory investigation, and management are also briefly reviewed. Sleep is a function of
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the brain and patients with neurological disorders a r e particularly susceptible to disorders of sleep. Sleep adversely affects neurological illnesses, a n d neurological disorders in turn adversely affect the quality a n d quantity of sleep. Therefore, it is i n c u m b e n t u p o n neurologists to h a v e a basic understanding of disorders of sleep because sleep dysfunction encroaches on almost every aspect of n e u r o l o g y .
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Mignot, E, 1999, "Genetics in sleep disorders," in Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, ed S. Chokroverty, Butterworth-Heinemann, Boston Mignot, E., I.ammers, G. J., Ripley, B., et al. 2002, "The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias," Arch Neurol, vol. S9, pp. 1553-1562 Mitlcr, M. M„ Harsh, J., Flirshkowitz, M., et al. 2000, "U.S. Mndalinil in NjivnlepM Mu.u^-iikT Stsnu Croup: Long u :III efficacy and safety of modafinil (Provigil) for the treatment of excessive daytime sleepiness associated with narcolepsy," Sleep Med, vol. 1, pp. 231-243 Mitler, M. M., Poceta, J, S„ & Rigby, B. G. 19V9, "Sleep scoring technique," in Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, ed S. Chokroverty, Butterworth-Heinemann, Boston, pp. 245-262 Moldofsky, H., Broughton, R. J., & Hill, J. D. 2000, "A randomized trial nl the long term coin inm-J el'i.jey and safety of modafinil in narcolepsy," Sleep Med. vol. 1, pp. 109-116 Montagna, P., Gambetti, P., & Lugaresi, E. 2003, "Fatal familial insomnia," in Sleep and Movement Disorders, eds S. Chokroverty, W. Hening, & A. Walters, Butterworth/ Heinemann-Elsevier Science, Philadelphia, pp. 362-372 Mompl.usir, U .Muli.uid, \ 1 . , [>L-::esle, K.. ei il. 2000, "Periodic leg movements are not more prevalent in insomnia or hypersomnia but are specifically associated with sleep disorders involving a dopaminergic impairment," Sleep Med, vol. 1, PP. 163-167 Monn, C. M., Colecchi, C, Stone, J., & Sood, R, M. 1999, "Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial, "JAMA, vol. 28 I, pp. 991-999 Morin, C. M., Daley, M., & Oucllct, M. C. 2001, "Insomnia in adults," Curr Treat Options Neurol, vol. 3, pp. 9-18 Nieto, F. J., Young, T. B., Lind, B. K., et al. 2000, "Association of sleep-disordered breathing, sleep apneas, and hypertension in a large community-based study: Sleep Heart Health Study," JAMA vol. 283, pp. 1829-1836 \isliino, S.. e< Mignot, I. 1997, -'Pharmacological axpecls of human and canine narcolepsy," Prog Neurobiol, vol. 52, pp. 27-78 Nishino, S., Ripley, B., Overeem, S., et al. 2000, "Hypocretin (orexin) deficiency in human narcolepsy," Lancet, vol. 355, no. 9197, pp. 39-40 Nishino, S., Ripley, B., Overeem, S., et al. 2001, "Low cerebrospinal fluid hypocrerin (orexin) and altered energy homeostasis in human narcolepsy," Ann Neurol, 2 0 0 1 , vol. 50, pp. 381-388 Ohayon, M. M., &: Guilleminault, C. 1999, "Epidemiology of sleep disorders," in Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, ed S. Chokroverty, Butterworth-Heinemann, Boston, pp. 301-316 Ohayon and Roth (2003) Olson, E. J., Boeve, B. F., & Silber, M. H, 2000, "Rapid eye movement sleep behavior disorder: demographic, clinical and laboratory findings in 93 cases," Brain, vol. 123, pp. 331-339 Olson, E. [., Boeve. B, F„ & Silber, M. H. 2000, "Rapid eye movement sleep behavior disorder: demographic, clinical and laboratory findings in 43 cases." brain, vol. 123, pp. 331-339 Ondo, W. G., Vuong, D. K., & Jankovic, J. 2002, "Exploring the relationship between Parkinson's disease and restless legs syndrome," Neurology, vol. S9, pp. 421 -424
SLEEP AND ITS DISORDERS Ondo, W. G„ Vuong, K. V., Khan, H., et al. 2001, "Daytime sleepiness and other sleep disorders in Parkinson's disease," Neurology, vol. 57, pp. 1392-1396 Orr, W.C. 2001, "Gastrointestinal functioning during sleep: A new horizon in sleep medicine," Sleep Med Rev, vol. 5, pp. 91-101 Overeem, S., Mignot, E., Van Dijk, et al. 2001, "Narcolepsy: Clinical features, new pathophysiologic insights and future perspectives," j Clin Neurophysiol, vol. 18, pp. 78-105 Overeem, S., van Hilten, J. J., Ripley, B., et al. 2002, "Normal hypocretin-1 levels in Parkinson's disease patients with excessive daytime sleepiness," Neurology, vol. 58, pp. 498-499 Pepperd, P. E„ Young, T., Palta, M., et al, 2000, "Prospective study of the association between sleep-disordered breathing and hypertension," N Engl J Med, vol. 342, pp. 1378 1384 Pcpperell, J. C, Davies, R. J. O., & Srradling, J. R. 2002, "Systemic hypertension and obstructive sleep apnea," Sleep Med Rev, vol. 6, pp. 157-173 Peyron, € . , Earaco, J., Rogers, W. et al. 2000, "A mutation in a case of early onset narcolepsy and a generalized absence of hypoerectin peptides in human naseuleptie bra ins," Nat Mad, vol. 6, Suppl. 9, pp. 991-997 Phillips, K. D. 1999, "Physiological and pharmacological factors of insomnia in HIV disease," / Assoc Nurs AIDS Care, vol. 10, pp. 93-97 Poceta, J. S. 2002, "Sleep-related headache," Curt Treat Options Neurol, vol. 4, pp. 121-128 Porkka-Heiskancn, T., Strecket, R. E., Thakkar, M., et al. 1997, "Adenosine: A mediator of the sleep-inducing effects of prolonged wakefulness," Science, vol. 276, pp. 1265-1267 Provini, F., Plazzi, G-, Tinuper, P., et al. 1999, "Nocturnal frontal lobe epilepsy. A clinical and polygraphs overview of 100 consecutive cases," Brain, vol. 122, pp. 1017-1031 Rao, V. & Rollings, P. 2002, "Sleep disturbances following traumatic brain injury," Curr Treat Options Neurol, vol. 4, pp. 77-87 Rechtschalfcn, A. &
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G protein-coupled receptors that regulate feeding behavior," Cell, vol. 92, p. 697 Sateia, M., Doghnamji, K,, Hauri, P. J. et al. 2002, "Evaluation of chronic insomnia," Sleep, vol. 23, pp. 243-308 Schcffer, I. E., Bhatia, K. P., Lopes-Cendes, 1., et al. 1995, "Autosomal dominant nocturnal frontal lobe epilepsy—A distinctive clinical disorder," Brain, vol. 118, pp. 61-73 Scheneck, C. H., & Mahowald, M. M. 2003, "REM sleep behavior disorder," in Sleep and Movement Disorders, eds S. Chokroverty, W. Hening, & A, Walters, Butterworth/ Heinemann-Elsevier Science, Philadelphia, pp. 286-299 Shahar, E., Whitney, C. \V., Redlinc, S., et al. 2001, "Sleep disordered breathing and cerebrovascular disease: Cross-sectional results of the Sleep Heart Health Study," Am J Respir Crit Care Med, vol. 163, pp. 19-25 Sher, A E. 2002, "Upper airway surgery for obstructive sleep apnea," Sleep Med Rev, vol. 6, pp. 195-212 Siegel, J. M. 2003, "The narcoleptic borderland (editorial)," Sleep Med, vol. 4, pp. 3-4 Siegel, J. M, 1999, "Narcolepsy: A key role for hypocretins (orexins)," Cell, vol. 98, pp. 409-412 Sinton, C. M. & McCarley, R. W. 2000, "Neu roan atomic a I and ncurophysiological aspects of sleep: Basic science and clinical relevance," Semin Clin Neuropsychiatry, vol. 5, pp. 6-19 Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. 1992, "Preliminary report: EEG arousals: scoring rules and examples," Sleep, vol, 15, pp. 173-184 Smith, M. T, Perlis, M. 1.., Park, A., et al. 2002, "Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia," Am J Psychiatry, vol. 159, pp. 5-1 I Smits, M. G. Sc Nagtegaal, J. E. 2000, "Post-traumatic delayed sleep phase syndrome," Neurology, vol. 55, pp. 902-903 Stacdt, J., Stoppe, G., Kogler, A., et al. 1995, "Nocturnal myoclonus syndrome (periodic movements in sleep) related to central dopamine D 2 -receptor alteration," Eur Arch Psychiatry Clin Neurosci vol. 245, pp. 8-10 Steriade, M. 1999, "Neurophysiologies mechanisms of non-rapid eye movement (resting) sleep," in Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, ed S. Chokroverty, Buttcrworth-Heinemann, Boston, pp. 51 -62 Syed, B. H., Rye, D. B., & Singh, G. 2003, "REM sleep behavior disorder .iiul SI, A I iM.icli.nio |OM-;I|I disease!,"
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vol. 60, p. 148 Tan, E.-K. & Jankovic, j. 2000, "Treating severe bruxism with botulinum toxin," j Am Dent Assoc, vol. 131, pp. 211-216 Terzano, M. C., Parrino, I.., Smeriari, A., et al. 2002, "Atlas, rules and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep," Sleep Med, vol. 3, pp. 187-199 Thannickal, T. C, Moore, R. Y., Nienhuis, 11., et al. 2000, "Reduced number of hypocretin neurons in human narcolepsy," Neuron, vol. 27, pp. 469-474 Thatcher, G. W. & Maisel, R. H. 2003, "The long-term evaluation of tracheostomy in the management of severe obstructive sleep apnea," I aryngoscope, vol. 1 13, pp. 201-204 The International Restless Legs Syndrome Study Group. 2003, "Validation of the International Restless Legs Syndrome StudyGroup rating scale for restless legs syndrome," Sleep Med, vol. 4, pp. 121-132 Trenkwalder, C, Walters, A. $., Henning, W. A., et al. 1999, "Positron emission tomographic studies in restless legs syndrome," Mov Disord vol. 14, pp. 141-145 Trenkwalder, C, 6c Winkelmann, J, 2003, "Pathophysiology of the restless legs syndrome," in Sleep and Movement Disorders,
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eds S. Chokrovcrty, W. Hening, & A, Walters, Butterworth/ Heinemann-Elsevier Science, Philadelphia, pp. 322-332 Turjanski, N., Lees, A. J., & Brooks, D. J. 1999, "Striatal dopaminergic function in restless legs syndrome: F-dopa and C-raclopndc PET studies," Neurology, vol. 52, pp. 932-937 US Xyrem Multicenter Study Group. 2003, "A 12-month, openlabel, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy," Sleep, vol. 26, pp. 31-35 Walsh, J. K. St Schweitzer, P. K. 1999, "Ten-year trends in the pharmacological treatment of insomnia," Sleep, vol. 22, pp. 371-375 Walsh, J. K., Vogel, G. W., Scharf, M., et al. 2000, "A five week polysomnography assessment of zaleplon 10 mg for the treatment of primary insomnia," Sleep Med, vol. 1, pp. 41-49
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Chapter 75 Headache and Other Craniofacial Pain Christopher J. Boes, David J. Capobianco, F. Michael Cutrer, David W. Dodick, Eric J. Eross, and Jerry W. Swanson Pain Transmission and Modulation as Related to Headache C lasiifii .11 ion Headache Attributed to Nonvascular, Noninfectious Intracranial Disorders Tumors Arachnoid Cysts Abnormalities of Cerebrospinal Fluid Circulation Transient Syndrome of Headache with Neurological Deficits and Cerebrospinal Fluid Lymphocytosis I k-.!,l.i.Jn- Attribured to Infection Headache Attributed to Cranial or Cervical Vascular Disorders
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Headache Caused by Disorder of the Cranium, Neck, Eyes, Ears, Nose, Sinuses, Teeth, Mouth, or Other Facial or Cranial Structures Headaches and the Cervical Spine Other Primary Headaches \ii;.y-iiiHCluster Headache and Other Trigeminal Autonomic Cephalalgias Tndomethadn-Responsive Headache Syndromes Other Types of Headache and Facial Pain Headache in Children and Adolescents
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Headache is one of humanity's most common afflictions. It has been estimated that one person in three experiences severe headaches at sonic stage of life. Most people with a mild recurrent or isolated headache do not consult a physician, and therefore the true prevalence is unknown. The lifetime prevalence for any type of headache as estimated from population-based studies is more than 90% for men and 95% for women. A survey of a sample of 20,000 households in the United States revealed a prevalence rate of migraine of 18.2% in females and a 6.5% rate among males, resulting in an estimated 27.9 million migraineurs in the United States. Approximately 6 0 % of patients with migraine experience 2 or more attacks per month, and more than 7 5 % of migraineurs report severe or extremely severe pain during attacks. More than 90% of patients report an impaired ability to function during migraine attacks, and 5 3 % report severe disability requiring bedrest. Approximately 3 1 % of patients with migraine missed at least one day from work or school in the preceding 3 months due to migraine (Lipton et al. 2001). Indirect costs of migraine related to decteased productivity and lost days of work have been calculated to be $13 billion per year; it has been estimated that there are the equivalent of 112 million bedridden days per year due to migraine (Hu et al. 1999). Indeed, the World Health Organisation declared migraine to be among the most disabling medical conditions experienced worldwide.
PAIN TRANSMISSION AND MODULATION AS RELATED TO HEADACHE An understanding of the pathophysiology of headache must first start with a knowledge of which intracranial structures are pain sensitive. Ray and Wolfe reported on the painsensitive structures in the head and mapped the pattern of pain referral based on the structure simulated from intracranial surgery performed during local anesthesia in the 1930s. The intracranial pain-sensitive structures include the arteries of the circle of Willis and the first few centimeters of their medium-sized branches, meningeal (dural) arteries, large veins and dural venous sinuses, and portions of the dura near blood vessels. Pain-sensitive structures that are external to the skull cavity include the external carotid artery and its branches, scalp and neck muscles, skin and cutaneous nerves, cervical nerves and nerve roots, mucosa of sinuses, and teeth. Pain from these structures is carried largely by cranial nerves V, VII, IX, and X. Inflammation, traction, compression, malignant infiltration, and other disturbances of pain-sensitive structures lead to headache. Superficial structures tend to refer pain locally, whereas deeper-seated lesions may refer pain imprecisely to a distant part. A purulent maxillary sinus, for example, causes pain over the involved sinus, whereas within the cranial vault, nociceptive signals reach the central nervous system (CNS) largely by way of the first division of the trigeminal nerve, and therefore an occipital 2055
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lobe rumor may refer pain to the frontal head region. Infra tentorial lesions tend to refer pain posteriorly because this compartment is innervated by the second and third cervical nerve roots, which also supply the back of the head. This can change when posterior lesions or cervical spine pathological conditions produce frontal headache, which may occur because the caudal portion of the trigeminal nucleus extends down as far as the dorsal horn at the C3 level. Impulses arriving from C2-C3 converge on neurons within the trigeminal nucleus and may refer pain to the somatic distribution of cranial nerve VI.
migraine and other primary headache disorders is expected to free future research and clinical publications from the confusing and often poorly defined terminology of earlier work. Until the actual pathogenesis of primary headache syndromes is determined, it will not be possible to develop a unitary classification of head pain.
Afferent pain impulses into the trigeminal nucleus are modified and modulated by descending facilitatory and inhibitory influences from critical brainstem structures, including the periaqueductal gray, rostral ventromedial medulla, locus ccrulcus, and dorsal raphe nuclei. Opioids diminish the perception of pain by activating the inhibitory systems, whereas fear, anxiety, and overuse of analgesics may activate the facilitatory systems thereby aggravating the pain.
Intracranial lesions that occupy space, often referred to as mass lesions, produce head pain by traction on or compression of pain-sensitive structures. The nature, location, and temporal profile of headache produced by an intracranial mass depend on main [actor-., IIIJ-.KIIIH; tinlocation of the lesion, its rate of growth, its effect on the cerebrospinal fluid (CSF) pathways, and any associated cerebral edema. The intracranial mass lesion may be neoplastic, inflammatory, or cystic. Each type can result in either localized or generalized head pain. The type of headache is characteristic i>( raised iiitracraniaI pressure (sec later) but is not diagnostic of a particular underlying disease. Intracranial and nil r.iparcrk liyni,;' hematomas ate akn mass lesions and are responsible for traction headaches, but they are classified under vascular disorders causing headache.
CLASSIFICATION In 198H, the I leadache Classification Committee of the International Headache Society introduced a detailed classification of headaches, which was revised in 2004. The 14 main headache types are shown in Table 75.1. bach In.\i J ulu- type ;•. furl her dclincd ;ind subclassified according to criteria agreed to by several international subcommittees. Careful definition of the many types of Tabic 75.1:
Classification of headache
The Primary Headaches 1. Migraine 2. Tension-type headache 3. Cluster headache and other trigeminal-autonomic cephalalgias 4. Other primary headache disorders The Secondary Headaches 5. Headache attribured to head and/or neck trauma 6. Headache attributed to cranial and/or cervical vascular disorder 7. Headache attributed to nonvascular, noninfectious intracranial disorder 8. Headache attributed to a substance or its withdrawal 9. Headache attributed to infection 10. Headache attributed to disturbance of homeostasis 11. Headache or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures 12. Headache attributed to psychiatric disorder 13. Cranial neuralgias and central causes of facial pain 14. Other headache, cranial neuralgia, central or primary facial pain Source; Reprinted with permission from the International Headache Society Second Headache Classification Committee 2004. "The International Headache Classification, 2nd ed," Cephalalgia, vol. 24, suppl. 1, pp. 1-195.
Headache Attributed to Nonvascular, Noninfectious Intracranial Disorders
Tumors Approximately 5 0 % of patients with brain rumors report headaches; in one third to one half of these patients headache is considered the primary complaint. The headache can be generalized, but in approximately one third of patients, it overlies the tumor and is referred to the scalp near the lesion. Rapidly growing tumors are more likely to produce headache than are indolent lesions, but slowly enlarging lesions can eventually produce pain by compromising the ventricular system or exerting direct pressure on a pain-sensitive structure, such as the trigeminal nerve. When the CSF circulation is partially obstructed, headache often becomes generalized and worse in the occipitonuchal area. This type of headache, which is a manifestation of raised intracranial pressure, is often worse on awakening, is aggravated by coughing and straining, and is often associated with nausea and vomiting. In children particularly, the vomiting may be precipitate and without nausea. This can lead to projectile vomiting because it occurs without warning. Projectile vomiting rarely occurs in adults. Large parenchymal tumors and small tumors that interfere with the CSF pathways can be associated with periodic increases in inrracranial pressure. Monitoring reveals periods of increased pressure (called the plateau waves of Lundberg), the beginning of which may be associated with increasing severity of headache and the peak of which may
HEADACHE AND OTHER CRANIOFACIAL PAIN
be associated with vomiting or other ictal events, such as decreased consciousness or a change in respiration. Supratentorial masses generally produce frontal or temporal head pain because of the trigeminal nerve supply to the anterior and middle cranial fossae. The superior surface of the tentorium cerebelli is supplied by the meningeal branches of the first division of the trigeminal cranial nerve, so an occipital lesion can cause pain referred to the fronto-orbital tegion. Mass lesions of the posterior fossa generally cause occipitonuchal pain because the meningeal nerve supply is largely through the upper cervical nerves, which also supply the occipital and cervical dermatomes. Some sensory innervation of the posterior fossa is also carried via cranial nerves VII, IX, and X, and therefore pain referral can be more widespread. Posterior fossa tumors result in headache earlier than their supratentorial counterparts because the greater likelihood of compromise of the ventricular system leads to rapidly developing hydrocephalus and raised intracranial pressure (Forsyth and Posner 1993). Pituitary tumors and tumors around the optic chiasm commonly cause a frontotcmporal headache, but they can also cause referred pain near the vertex. However, patients with tumors of the sellar and parasellar regions do not often present with headache as the initial symptom because the visual and endocrine symptoms are typically noted first (Edmeads 1997). Tumors growing in the ventricular system are rare, but they can present dramatically. The classic presentation of a colloid cyst of the third ventricle is a sudden headache of great severity, rapidly accompanied by nausea and vomiting and possibly by loss of consciousness. Intraventricular meningiomas, choroid plexus papillomas, and other intraventricular tumors can present in this manner if they suddenly obstruct the ventricular outflow pathways. A positional change may precipitate such an event; similarly, adoption of a different posture may rapidly relieve the headache and other symptoms. Colloid cysts of the third ventricle generally lead to slowly enlarging hydrocephalus that may result in a generalized, rather constant headache, superimposed on which may be episodes of catastrophic increases in headache. Obstruction of the egress of CSE from the ventricular system rapidly leads to increased intracranial pressure, which can exceed the capillary perfusion pressure of the brain and lead to loss of consciousness due to cerebral ischemia. Headaches that have a rapid onset and are associated with loss of consciousness, amaurosis, or vomiting are serious and should lead the examinet to consider conditions such as subarachnoid hemorrhage, brain tumor, or other mass lesions. Headache, especially in the occipital region, that is precipitated by sudden Valsalva maneuvers (e.g., coughing, sneezing, ot lifting) or exertion should be taken seriously, A posterior fossa lesion, such as a cerebellar tumor or Chiari malformation, can lead to this clinical picture. In most patients with cough or exertional headache, however, no serious lesion is found.
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Infiltrating tumors, such as gliomas, can reach considerable size without causing pain because they may not deform or stretch the pain-sensitive vessels and nerves. Such lesions are more likely to present as focal neurological deficits or with seizures than with headache. Sudden worsening of the neurological state due to hemorrhage into the tumor mass may present with sudden headache. The headache may initially appear in the part of the skull overlying the tumor and then become generalized if intracranial pressure rises. Infarction of a tumor can cause edema and swelling that result in a similar dramatic onset of head pain and neurological deficit. Tumors that are intracranial but extraparenchymal, such as meningioma, acoustic neuroma, pinealoma, and craniopharyngioma, can all produce headaches, but, as with the parenchymal lesions, there are no specific headache patterns. The headaches can be near the lesion, referred to a more distant site in the cranium, or generalized when intracranial pressure increases. Meningiomas and meningeal sarcomas can invade the skull and can even cause a mass externally by direct tumor spread or by overlying hyperostosis. Such tumors arc often associated with localized head pain. Meningeal carcinomatosis (carcinomatous meningitis) produces a headache in most subjects, but the associated cranial nerve involvement and other neurological symptoms are generally more striking. The headache associated with other intracranial mass lesions, such as cerebral abscess and intracranial granuloma, is no more specific than that due to a cerebral neoplasm. In summary, the following features should serve as warnings that a patient's headaches may not be of benign origin and raise the possibility of an intracranial mass lesion (Purdy 2001): 1. Subacute and progressive in nature of headache 2. New onset in adult life (>40 years of age) 3. Change in headache pattern, such as incteascd intensity of pain, increased incidence of attacks, development of new features, or decreased response to treatment 4. Association with any of the following: nausea or vomiting not explained by migraine or systemic illness; nocturnal occurrence or morning awakening; precipitation or worsening by changes in posture or Valsalva maneuver; confusion, seizures, or weakness 5. Abnormalities on neurological examination
Arachnoid Cysts Cystic spaces bounded by arachnoid membranes found with computed tomography (CT) or magnetic resonance imaging MR I scans IIUMIH-tin investigation ol headaches are rarely responsible for head pain. Uncommonly, an arachnoid cyst has a one-way valvelike structure in its wall, so that arterially induced pulsations of the CSF gradually pressurize
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NEUROLOGICAL DISEASES
the cyst and cause it to enlarge. Compression of cranial nerves, such as the trigeminal nerve, or distortion of the midline structures causes headaches that may be either generalized or localized. Serial CT or MRI scans reveal the cyst to be increasing in size, and this finding should lead to operative intervention. Enlargement of normal subarachnoid spaces such as the cisterna magna and cisterna ambiens is not a cause for headache and should not lead to shunting or other surgical approaches.
Abnormalities of Cerebrospinal Fluid Circulation Whether raised intracranial pressure, in the absence of a shift of intracranial structures, results in headache is uncertain. The rate at which the intracranial pressure is increased and the duration of the increase are probably factors that determine whether pain is produced. Obstruction of the Cerebrospinal ¥luid Pathways Lesions that prevent free egress of CSF from the ventricular system result in obstructive hydrocephalus. If this occurs before closure of the cranial sutures, enlargement of the skull occurs, usually without producing headache. Ventricular obstruction after closure of the sutures leads to raised intracranial pressure and often to headache. The pain is often worse on awakening, occipital in distribution, and associated with neck stiffness. Vomiting, blurred vision, and transient obscuration of vision due to papilledema may follow as well as failing vision due to optic atrophy. Rapidly developing obstruction due to a posterior fossa mass lesion or a ball-valve tumor, such as a third ventricular colloid cyst, can lead to a rapidly increasing headache followed by vomiting, impaired consciousness, and iniTi'.isinj.'. nourological deterioration. S'.nwly developing hydrocephalus may result in massively dilated ventricles and may be associated with little or no headache. Congenital obstruction of the foramina of l.usehk and Magendie—the Dandy-Walker syndrome—can lead to ballooning of the fourth ventricle and deformity of the cerebellum, Minor degrees of this malformation can remain asymptomatic until later in life and then present with obstructive hydrocephalus and headache. Similarly, the Chiari malformation in its various forms can obstruct the free circulation of CSF and lead to hydrocephalus and headache (Taylor and Larkins 2002). This malformation can result in an occipital-suboecipiral headache that is worsened or even initiated by Valsalva's maneuver during lifting, straining, or coughing. Thus, the Chiari malformation is one ol the causes of an exertional 01 Valsalva-induced headache. In communicating hydrocephalus, there is free communication between the ventricular system and the subarachnoid space bill Mime impairment of CSI; circulation or absorption. Obstruction in the basal cisterns or at the
arachnoid granulations may follow subarachnoid hemorrhage and meningitis. Venous sinus occlusion can impair absorption of C5F. Headache may be a prominent symptom of both obstructive and communicating hydrocephalus, except in the case of normal pressure hydrocephalus, which is generally painless (see Chapter 65).
Low Cerebrospinal Fluid Pressure Headache The headache of lowered CSF pressure characteristically develops with the patient in the upright position and is rapidly relieved by recumbency. It most commonly occurs after a lumbar puncture, especially when this is performed as part of myelography. Loss of CSF volume, due in part to the removal of some CSF for diagnostic purposes and in part to later leakage through the hole in the arachnoid and dural layers, results in a traction headache. The brain normally floats in the intracranial CSF, loss of which allows the brain to sink and thereby exert traction on structures such as bridging veins and sensory nerves. Recumbency removes the effect of gravity, and the traction headache is relieved. The headache that occurs after a spinal tap usually resolves in a few days if the patient remains in bed with good hydration. Occasionally, the syndrome persists for days, weeks, or even months. Relict i.in usually be obtained by the application of a blood patch, in which 10-20 mL of the patient's own blood is injected into the epidural space close to the site of the original spinal tap. This technique prevents further leakage of CSF by exerting increased pressure in the epidural space and by coagulation of the blood, thereby relieving the headache in a few hours. The injection of blood is associated with a small risk of cauda equina compression or subarachnoid hemorrhage, but this is unlikely if the blood volume is small and the blood is injected gently. An identical syndrome of headache due to low CSF prcssute can occur when there is a leak of fluid through the cribriform plate, through the petrous bones, or through any basal skull defect. CSF rhinorrhea and especially CSF otorrhea may not be obvious to the patient, whose complaint may be postoperative or post-traumatic headache. Leakage of CSF from the skull can occur spontaneously when inttacranial pressure is raised or a tumor erodes through the base of the skull. This occurs most often around the cribriform plate region, where the bone is especially thin. The CSF leak can be identified by radioisotope cisternography. Leakage of CSF through the nasal sinuses can be detected by placing numbered cotton pledgets in the nose next to the various ostia of the sinuses. Contamination of the pledgets by radioactivity enables the sinus, through which the fluid is leaking, to be identified. CSF otorrhea is not easy to identify if the fluid is draining down the eustachian tube when the eardrum is intact. Scanning with a gamma camera after instillation of a radioactive tracer by lumbar puncture may allow the leak
HEADACHE AND OTHER CRANIOFACIAL PAIN to be identified. Treatment is usually surgical repair of the bony and meningeal defect, A similar low CSF pressure headache can occur when a tear develops in the spinal theca. This is usually in the midthoracic region and may result from lifting or coughing or, at times, spontaneously. It can also occur with a crush injury to the chest or abdomen and in patients with overdrawing CSF shunts. When it occurs without a significant history of trauma, it can be overlooked as a cause of daily headache. The history of a headache rapidly responding to recumbency should lead one to suspect the condition. However, in some patients whose headaches are longstanding, a persistent headache may be noted and the postural feature of the headache may become less prominent, Nausea or emesis, neck pain, dizziness, horizontal diplopia, changes in hearing, photophobia, upper limb paresthesias, vision blurring, and dysgeusia may also occur, particularly when the headache first develops. The diagnosis first requires a clinical index of suspicion followed by an MRI scan with gadolinium. MRI has become an invaluable diagnostic tool in this syndrome, with the cardinal features being diffuse pachymeningeal thickening with gadolinium enhancement, subdural collections of fluid, and evidence of brain descent (Figures 75,1 through 75.3). This evidence includes cerebellar tonsillar descent (resembling a Chiari type I malformation); reduction in size or effaccment of the prcpontine, perichiasmatic, and subarachnoid cisterns; inferior displacement of the optic chiasm; and descent of the iter (the opening of the aqueduct of Sylvius as seen on a midsagittal MRI scan). If the clinical and MRI findings are typical, determination of the CSF opening pressure may not be necessary. Measurement or the opening pressure is warranted in patients with normal MRI scans. However, in only 5 0 % of patients is the CSF pressure less than 40 mm H 2 0 . Because the opening pressure may be normal, the term CSF volume depletion identifies best the core of the problem in this disorder (Mokri 2000). These patients may have a variable pleocytosis with up to 40 or more mononuclear cells per ram 1 and a mild-tomodest increase in CSF protein (Mokri 1999). In patients with the typical clinical and radiographic features of low CSF pressure headache, management may be conservative with bed rest and hydration for 1-2 weeks. If this is either not practical or not effective, options include empirical treatment with a blood patch or further studies to identify the site of the CSF leak. In patients with spontaneous leaks, the leak is often at the level of the thoracic spine or the cervicothoracic junction. Myelography with a CT scan of the spine is more sensitive than radioisotope cisternography or an MRI scan of the spine, but the latter procedures may serve as guides for obtaining multiple CT images at the appropriate levels. Most leaks are stopped with either conservative therapy or blood patches. Although an epidural blood patch is effective in the majority of patients, most requite more than one blood patch (Mokri 1999), and some require as many as four
2059
to six blood patches (Mokri 2001). For resistant leaks, surgical intervention with repair of the dural tear may be necessary. Even after a protracted duration, surgical repair of the causative dural tear can be quite effective (Schievink et al. 1998), Idiopathic
Intracranial
Hypertension
Headache, transient visual obscuration, pulsatile tinnitus, and diplopia are the most common presenting symptoms of idiopathic intracranial hypertension (pseudotumor cerebri). The headache is rather nonspecific but tends to be worse on awakening and to be aggravated by activity. The blurring and obscuring of vision arc direct results of raised intracranial pressure leading to papilledema. Once it has been determined by MRI scans that there is no intracranial mass, obstruction of the ventricular system, or thrombosis of a dural venous sinus, the high CSF pressure can be confirmed by lumbar puncture manometry. Removal of CSF to achieve a normal closing pressure relieves the headache and temporarily prevents visual obscuration. Long-term management of idiopathic intracranial hypertension is discussed in Chapter 65.
Transient Syndrome of Headache with Neurological Deficits and Cerebrospinal Fluid Lymphocytosis There is a transient syndrome characterized by recurrent episodes of headache accompanied by reversible neurological deficits and CSF pleocytosis, originally termed migrainous syndrome with CSF pleocytosis (Bartlcson ct al, 1981). Several reports of this syndrome used various terms, including headache with neurological deficits and CSF lymphocytosis (Berg and Williams 1995) and pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis (Gomez-Aranda et al. 1997). This self-limited syndrome consists of one to several episodes of variable neurological deficits accompanied by moderatc-tosevere headache and sometimes fever. Each episode lasts hours, with total duration of the syndrome being from 1-70 days. CSF abnormalities have included a lymphocytic pleocytosis varying from l() to more tha:i ,'UQ CL-lls/inm \ elevation of CSF protein, and in some patients, elevated opening pressure, MRI and CT scans are invariably normal, but an electroencephalogram often shows focal or diffuse slowing. Results of microbiological studies have been negative. The etiology of the syndrome is unclear, although it has been speculated to be due to an immune response to a viral infection. No treatment has been shown to alter the self-limited course of this disorder. In contrast to this syndrome, Mollaret's meningitis is characterized by recurrent episodes of aseptic meningitis with fever (see Chapters 59B and 79). The episodes are separated by months to years and are typically not accompanied by focal neurological symptoms. Classically, the CSF shows a
2060
NEUROLOGICAI. DISEASES
FIGURE 75.1 Coronal Tl-weighted magnetic resonance images with gadolinium in a patient with an overdrawing cerebrospinal fluid shunt and low-pressure headache demonstrate diffuse pachymeningeal thickening and enhancement (A) with resolution after shunt revision and resolution of headaches (B). Patient developed recurrent symptoms and imaging abnormalities after shunt revision (C) followed by resolution after another shunt revision (D). (Reprinted with permission from Mokri, B., Picpgras, D. G., &C Miller, G. M. 1997, "Syndrome of orthostatic headaches and diffuse pachvmeningeal gadolinium enhancement," Maya Clin Proc, vol. 72, pp. 400-413.)
pleocytosis and in the first 24 hours, neutrophils predominate, and large "endothelial cells" are present; these have been shown to represent monocytes.
Headache Attributed to Infection Inflammation of any pain-sensitive structures in the cranial caviry can produce headache. Meningitis and
meningoencephalitis both have headache as a major symptom. The eharactetistics of the head pain depend on whether the infection is acute or chronic. Acute meningitis produces a severe headache with neck stiffness and other signs of meningism, including photophobia and irritability. Pain is often tetro-orhital and worsened by moving the eyes. Chronic meningitis due to fungal or tuberculous infection can also lead to headache that may be severe and unrelenting. The headache of intracranial infection is nonspecific but
HEADACHF. AND OTHER CRANIOFACIAL PAIN
2061
FIGURE 75.2 Sagittal and coronal Tl-weighted magnetic resonance images with gadolinium of a patient with spontaneous low cerebrospinal fluid (CSF)-p res sure headaches demonstrate subdural fluid collections and p achy meningeal enhancement {top row) with loculation and progression of subdural fluid collections (middle row). Bottom row demonstrates resolution of the fluid collections and meningeal enhancement after correction of the CSF leak and headache resolution. (Reprinted with permission from Mokri, B., Piepgras, D. G., & Miller, G. M. 1997, "Syndrome of orthostatic headaches and diffuse pachymeningeal gadolinium enhancement," Mayo Clin Proc, vol. 72, pp. 400-413.) tinist be considered in the differential diagnosis, especially in patients with a compromised immune system. The diagnosis can be confirmed only by examination of the CSF. The chronic granulomatous meningitis of sarcoid may require biopsy of the basal meninges to confirm the diagnosis. Meningitis is discussed further in Chapter 59.
Sinusitis, mastoiditis, epidural or intraparcnchymal abscess formation, and osteomyelitis of the skull can all cause focal and generalized headache. The diagnosis is usually suspected from the associated symptoms and signs. After craniotomy, increasing pain and swelling in the operative site may be due to osteomyelitis of the bone flap. Plain
1W.1
NEUROLOGICAL DISEASES
FIGURE 75.3 Sagittal Tl-weighted magnetic resonance images (MRIs) demonstrate cerebellar tonsillar descent and crowding of the posterior fossa in a patient witli spontaneous low-pressure headaches. After symptomatic resolution, the MR] scan of the posterior fossa returns to normal. (Reprinted with permission from Mokri, B., Piepgras, D. G., & Miller, G. M. 1997, "Syndrome of orrhosniric headaches and diffuse pachymeningeal gadolinium enhancement," Mayo Clin Proc, vol. 72, pp. 400-413.)
skull roentgenograms reveal the typical mottled appearance of the infected bone. Removal of the flap is necessary. Mollaret's meningitis is tate, recurrent, and sterile (see Chapters 59B and 79). The CSF cellular response includes large epithelioid cells i Molhret's a lis). The pathogenesis is unknown but may be related to the herpes simplex virus (Jensenius et al. 1998). The condition may recur every few days or every few weeks for months or years. Headache, signs of meningism, and low-grade fever accompany each attack. Treatment is mainly symptomatic.
Headache Attributed to Cranial or Cervical Vascular Disorders Aneurysms and Arteriovenous Thunderclap Headache
Malformations and
Intracranial aneurysms are rarely responsible for headache unless the) rupture. K apid enlargement i .11: aneurysm may produce local pain by pressure on a cranial nerve, especially the oculomotor nerve, or on other pain-sensitive structures. This is most common with aneurysms of the internal carotid and posterior communicating arteries. Enlargement of an aneurysm may occur shortly before rupture, and the local pain is therefore an important clinical sign. Cerebral aneurysms are not a cause of recurrent
migraine-like headaches, even when the headache attacks are confined to one side. The prevalence of migraine in patients with subarachnoid hemorrhage due to a ruptured aneurysm is similar to the prevalence of migraine in the general population. Parenchymal arteriovenous malformations (AVMs) rarely cause pain before rupture. Very large lesions can be associated with ipsilateral or bilateral throbbing cephalalgia, but they rarely cause a migraine-like syndrome. Large AVMs can usually be suspected by the presence of a cranial bruit or of the classic triad of migraine, seizures, and focal neurological deficits. The prevalence of headache in patients harboring AVMs is probably no higher than that in the general population. The myth has developed that headaches of a migrainous type, if consistently on one side of the head, could be due to an aneurysm or an AVM. In the past, this belief led to many unnecessary arteriograms. The worry expressed by patients and physicians that a recurrent headache might be due to an aneurysm or AVM is now usually easily resolved by obtaining a cranial MRl scan or m.igneric resonance angiogram (MRA). Any aneurysm or AVM responsible tor a recurrent or persistent headache has a very high probability of being seen. Roth aneurysms and AVMs can bleed in a way that produces a less than catastrophic subarachnoid hemorrhage. These small warning leaks can result in one or more sentinel
HtADACHE AND OTHER CRANIOFACIAL PAIN
2063
headaches. 1'acli may be relatively mild Mid short-lived. They usually have a sudden, but not very dramatic, onset. Identification of the sentinel headache is important but is vety difficult. Patients who do not usually have headaches should be examined whenever they report new onset of headaches or even a single episode if it was described as "the worst headache I've ever had" or if it was associated with neck stiffness or pain, transient neurological symptoms (e.g., extraocular nerve palsy), or fever. Patients in whom there is any suspicion of a sentinel bleeding episode or who describe a recent thunderclap headache should be examined with CT scanning to detect blood in the subarachnoid cisterns. If the scan is normal, the continuing suspicion of a warning bleeding episode should lead to an examination of the CSF. If the CSF is blood-stained or xanthochromic or if, despite the absence of positive findings on the lumbar puncture, there is still a suspicion of a sentinel hemorrhage, an MR A or cerebral angiogram may be advisable.
studies of patients with normal neurological, CT, and CSF examinations, indicates that a symptomatic intracranial aneurysm will be rarely found in such patients. The issue of which patients need additional investigations in this setting depends on the clinical suspicion of an underlying disorder (Dodick 2002). Several follow-up studies of patients with thunderclap headache and negative evaluations for subarachnoid hemorrhage and other underlying disorders have elucidated the often benign natural history of this peculiar headache disorder. Slivka and Philbrook (1995) reported four patients with thunderclap headache without subarachnoid hemorrhage, in three of whom angiography revealed diffuse segmental iir.iaccivlual .irieri.i! vasoconstriction. Resolution of the vasospasm was seen in the one patient in whom angiography was repeated. V/c have seen two similar patients, and through this collective experience, a characteristic profile has begun to emerge (Table 75.2).
The term thunderclap headache describes a severe headache of instantaneous onset (within seconds)—abrupt and without warning like a "clap of thunder." A patient with a sudden, severe headache must be evaluated on an emergency basis for evidence of a subarachnoid hemorrhage as outlined above. Other conditions can present with thunderclap headache including cerebral venous sinus thrombosis, cervicocephalic arterial dissection, pituitary apoplexy, acute hypertensive crisis, and spontaneous intracranial hypotension (Dodick 2002). These entities are associated with significant neurological morbidity and may not be easily seen on the initial CT image, thus undctscoring the need for MRI in this group if results of the initial workup are negative,
Subarachnoid
The question as to whether an unruptured cerebral aneurysm can cause a thunderclap headache has been debated. The weight of evidence, based on several prospective
Tabic 75.2:
Hemorrhage
Rupture of an intracranial aneurysm or AVM results in a subarachnoid hemorrhage, with or without extension into the parenchyma of the brain. The headache of a subarachnoid hemorrhage is characteristically explosive in onset and of overwhelming intensity. Subjects who survive may relate that they thought they had been hit on the head. The headache rapidly generalizes and may quickly be accompanied by neck and back pain. Loss of consciousness may rapidly supervene, but many patients remain alert enough to complain of the excruciating headache. The patient is often vomiting, which aggtavates the head pain. Intraventricular blood, the distortion of the midline structures, and the heavy contamination of the basal cisterns by blood can each contribute to the rapid development of hydrocephalus, which worsens the headache.
Diagnostic criteria for thunderclap headache
Idiopathic thunderclap headache Very severe pain intensity Hyperacute onset of pain (
ulriil ilii's an o f f e n d i n g
foodstuff, but in our experience, dietary precipitation of migraine is uncommon. Other headache authorities disagree. In some migraineurs attacks are precipitated by strong odors, especially of the perfume or aromatic type. Avoiding the use of strong-smelling soaps, shampoos,
perfumes, and other items (e.g., fabric softeners and aftershave lotions! can be helpful for some individuals. Kveryone is under stress at some time as part of living. People with migraine are not under more stress than any other group of the population, although their responses to stress may differ on the basis of personality and the effectiveness of their defense mechanisms. Many people react to stress by mechanisms that increase the blood pressure, increase the production of gastric acid, or produce symptoms of increased gastrointestinal motility. Others develop various dermatological conditions. The migraincur seems to react with the cerebral and cranial circulations by mechanisms that arc far more complex than this statement would imply. Helping the patient deal with or avoid stress is difficult. It may be helpful to use a minor tranquilizer or sedative if the response to stress is overwhelming and if the source of the stress is temporary. Long-term stress management requires the help of a psychologist or other appropriately trained professional. Many techniques are used, including biofeedback, relaxation training, and hypnosis. There is evidence that biofeedback, relaxation training, and cognitive behavioral training are useful (Campbell et al. 2000) Pharmacotherapy. Medical therapy can be administered prophylactically to prevent attacks of migraine or symptomatically to relieve the pain, nausea, and vomiting of an attack. Prophylactic therapy is needed when the frequency or duration of attacks or the dread of attacks seriously interferes with the patient's lifestyle. Other indications for prophylaxis include the occurrence of severe or prolonged neurological symptoms or a lack or response to symptomatic treatment. In general, a prophylactic program should be considered if attacks occur as often as 1 day per week. Symptomatic Treatment. Symptomatic treatment should usually be started as early in the development of an attack as possible. If an aura is recognized, patients should take most medications during it rather than waiting for the pain to begin. One exception is the subcutaneous form of sumatriptan, which is less effective if taken before the onset of the headache phase. It must be recalled, though, that once the attack is fully developed, otal preparations are almost always less effective because of decreased gastrointestinal motility and poor absorption. If vomiting develops, oral preparations are no longer appropriate. For many patients, a simple oral analgesic, such as aspirin, acetaminophen, naproxen, or ibuprofen, or an analgesic combination with caffeine may be effective. Caffeine aids absorption, helps to induce vasoconstriction, and may reduce the firing of serotonergic brainstem neurons. However, the use of caffeine-containing combination analgesics more than 2 days per week may lead to increased incidence of headaches. The addition of 10 mg of metoclopramide by mouth may be helpful with any simple analgesic regimen. The patient should rest in a dark, quiet
HEADACHE AND OTHF.R CRANIOFACIAL I'AIN
room with an ice pack on the head, which provides the best situation for the analgesic to relieve the pain. If sleep occurs, the patient often awakens headache free. In some countries, walk-in headache clinics provide a patient with a simple analgesic, an antinausea agent, and a place to sleep for a few hours. In North America, both patients and physicians have come to expect a quick fix; thus, stronger and stronger analgesics and other drugs have been given to those with a headache. Drug addiction is a major problem in some patients who are treated this way. Induction of sleep, control of nausea, simple analgesics, and other nonnarcotic agents should be more widely used. Although increasingly less available, and supplanted in some cases by newer agents, ergot preparations remain important in the symptomatic treatment of migraine. The actions of ergotamine tartrate and other ergot preparations are complex. They are both vasoconstrictors and vasodilators, depending on the dose and the resting tone of the target vessels. Internal and external carotid vessels are believed to read differentl) to therapeutic doses ol these preparations. The external carotid vessels are constricted by ergot preparations. There is no convincing evidence that the internal carotid vessels are similarly affected. The ergot preparations probably exert their effects on migraine via agonist activity at 5-HT receptors. The use of ergotamine tartrate in migraine necessitates intelligent administration by both patient and physician if it is to be effective and if side effects are to be minimized. Oral preparations arc far less effective than those given rectally or parcnterally. It is important to know the amount of ergotamine in the various preparations and to be familiar with the dose limits and the signs and symptoms of ergotism. Table 75.6 shows the composition and strength of some ergotamine preparations available in the United States. Evidence for the efficacy of these agents in the treatment of migraine is largely based on uncontrolled clinical observations. When available to the patient, 2 mg of ergotamine tartrate should be administered by mouth as soon as the patient recognizes the symptoms of an acute migraine attack. This dose can be combined with a simple oral analgesic-caffeine combination, and the ergot preparation can be taken again in 1 hour. Possibly a better regimen, but one that is inconvenient and unpleasant to some patients, is to administer ergotamine tartrate by rectal suppository. At the onset of the aura or pain, a 1- or 2-mg rectal suppository of ergotamine tartrate should be inserted and a simple analgesic taken orally. The etgot preparation can be given again in 60 minutes. Expeticnce in the course of several artacks can Table 75.6: Brand . Ercaf Bellersal-S Cafergot
2081
be used to determine the amount of ergotamine needed to obtain relief. With subsequent attacks, the entire dose can be taken at the onset. If nausea is troublesome, metoclopramide in doses of 10 mg orally aids absorption of the ergotamine tartrate and may prevent vomiting. For patients who are close to vomiting or who are vomiting, an antiemetic suppository, such as chlorpromazine (25-100 mg) or prochlorperazine {25 mg), can be helpful. Analgesics in rectal suppository form include aspirin and acetaminophen, either of which may provide some relief. With frequent attacks of migraine, care musr be taken to avoid the vicious cycle wherein ergotamine is used so often that the drug-induced vasoconstriction is almost continuous. If this occurs, a lew hours of abstinence from ergotamine leads to relative vasodilatation and results in a withdrawal headache. Such patients often awaken with a vascular headache, obtain relief with a further dose of ergot.inline, arid thus perpetuate the vicious cycle. A sntiil.itphenomenon can occur with caffeine in people dependent on coffee or caffeine-containing soft drinks. If more than 6 mg of ergotamine is required per week, an alternative preparation should be used. Ergotamine must be used cautiously in patients with hypertension and in those with peripheral vascular disease. It is contraindicated in patients with coronary artery disease and in women who are pregnant. Administration of ergotamine to patients in whom the aura is particularly prolonged or characterized by a major neurological deficit is also considered unwise. The fear of potentiating the vasospasm to the point of cerebral infarction may be unjustified, but the potential risk can be avoided by withholding potent vasoconstrictors. As an alternative to ergotamine in the symptomatic treatment of migraine, the sympathomimetic agent, isometheptene mucare, is useful. Ir is available in proprietary preparations combined with acetaminophen and dichloralphenazone. It has the advantage of not increasing nausea and of being well tolerated, but it may fail to give relief for severe attacks. Dihydroergotamine (DHE) has been used for Treatment of migraine since the 1940s. Its poor oral bioavailability limits its administration to the parenteral and intranasal routes (Tables 75.7 and 75.8). Patients can be readily taught to self-administer this drug by each of these routes. This medication should be considered when nausea and vomiting limit the LISL- ol" oral medications or when other medications are ineffective. Although the effect of DHE is slower than that of sumatriptan (see Table 75.8), it does have similar efficacy after 2 hours, and it is associared
Ergotamine preparations available in the United States Route of administration
F.rgot.nninc ts act at central as well as peripheral c o m p o n e n t s of the trigeminal vascular system, a n d at least p a r t of their clinical action m a y be centrally mediated. S u m a t r i p t a n can be a d m i n i s t e r e d orally, intranasally, a n d by s u b c u t a n e o u s injection (Table 7 5 . 9 ; see also T a b l e s 75.7 a n d 75.8). Given as a 6-mg s u b c u t a n e o u s injection, either
Tabic 75.9:
Headache response (%)* Drug
Table 75.H: agonists
Siihciiraneons and intranasal serotonin (5-HT)
Headache response (%)* Dose *>"£ Dihydroergotamine Subcutaneous Intranasal Sumatriptan Subcutaneous Intranasal Zolmitriptan Intranasal
fax
1 hr
2 hr
4 hr
Recurrence
of
Oral serotonin (5-HT) agonists
Almotriptan Eletriptan Frovatriptan Naratriptan
headache Rizatriptan
Dose (mg) 12.5 20.0 40.0 2.5 1.0 2.S 5.0 10.0 25 50 100 2.5
Recurrence of headache*
I hr
2 hi
4 hr
35 20
57 49 60 42 42 48 60 67-77 52 50 56 64 66
NA NA NA 61 51 67
23% 30 22 10-25% 17-28%
\-\
30-35%
to NA 19 21 30 37 NA NA NA 38 44
NA 68 7d 75 75 77
35^0%
1 2
57 46
73 47-61
85 56-70
18 14
6 20
70 55
75 M)
83 X \
55-40 35^0
Zolmitriptan
5
55
70
78
25
Note: Composite data from product information inserts and literature. * Headache response is defined as a reduction in headache severity from moderate or severe pain to mild or no pain. Recurrence of headache within 24 hours after initial headache response. NA — not available.
^Headache response is defined as a reduction of headache severity from moderate or severe pain to mild or no pain. Recurrence of headache within 24 hours after initial headache response. NA = not available,
Sumatriptan
Vii
31";,
HEADACHE AND OTHER CRANIOFACIAL PAIN
self-administered using the manufacturer's auto-injector device or by conventional subcutaneous injection, sumatriptan resulted in significant pain relief at 1- and 2-hour time points after drug administration (see Table 75.8}. For subjects who had no significant pain relief after 1 hour, administration of a second dose of 6 mg provided little further benefit. Zoimattiptan is available as an oral and intranasal preparation. There are now seven triptans available in the United States. All seem to have a beneficial effect on migraineassociated symptoms, including nausea, photophobia, and phonophobia, which also improves the patient's ability to return to notmal functioning. Table 75.9 provides a comparison of the currently available oral triptans. Side effects of sumatriptan by injection include local reaction at the injection sitcv usually of mild-to-moderate severity, and a transient tingling or flushed sensation that may be localized or generalized. A more unpleasant sense of heaviness or pressure in the neck or chest has also been described in a small percentage of recipients. It rarely lasts more than a few minutes and is generally not associated with electrocardiogram changes or other evidence of myocardial ischemia. However, because sumatriptan has been shown to produce a minor reduction in coronary artery diameter, it should be used with caution in patients who have significant risk factors for coronary artery disease and should not be given to patients with any history suggestive of coronary insufficiency. It is also contraindicated in patients with untreated hypertension or peripheral vascular disease and in those using ergot preparations. It should not be given to women during pregnancy or lactation or to patients with hemiplegic or basilar migraine. The potential side effects of all the oral triptans are quite similar. They consist of tingling, flushing, and a feeling of fullness in the head neck or chest. In general, both the indications and contraindications for these newer 5-HTj agonists are the same as those for sumatriptan. They have not been shown to he safe when administered within 24 hours of ergot preparations or other members of the triptan class. At this time, there is no evidence to allow accurate prediction of which of these agents will be most effective in a given patient. A few practical guidelines can be given based on the clinical situation and knowledge about available agents. If severe nausea or vomiting occurs early in an attack, the parenteral or intranasal routes should be used. I-'or individuals whose headaches peak rapidly, almotriptan, rizatriptan, and zolmitriptan should be considered, given their early response rates. Some patients may prefer nasal or injectable routes (sumatriptan, DHE, and zolmittiptan). For patients with benign but intolerable side effects from this group of medications, naratriptan, almotriptan, or frovatriptan should be considered, given their favorable side effect profiles. Finally, i! [.here is recurrence of headache after initial relief, DHE, frovatriptan, or naratriptan should be considered. However, it must
2083
be remembered that after administration of a triptan, the use of another triptan or any ergotamine derivative within the next 24 hours is contraindicated. If one agent is used and fails, it seems reasonable, barring major side effects, to try another agent in the class. There is evidence that some of these agents have a lower oral bioavailability when taken during acute migraine attacks than when taken intetictally. Accordingly, it is logical to consider combining these with metoclopramide to improve gastric emptying. Furthermore, experience suggests that coadministration with a nonsteroidal antiinflammatory drug (NSAID) might be helpful, especially in individuals whose headache responded only partially or who tend to have a headache tceurrence after initial relief (Peroutka 1998). Symptomatic treatment of migraine with typical aura is essentially the same as that desctibed previously, although subcutaneous sumatriptan is not effective if taken during the aura phase. Modification of the aura is rarely possible or needed. For many patients, an attack of migraine becomes a harrowing experience. After a variable period, they go to an emergency room or physician's office expecting relief. These patients pose a difficult problem tor the physician. The simplest treatment and generally what the patient wishes or demands is injection of a combination of a opioid, most often meperidine (75-100 mg), and an agent for nausea, such as cblorpromazinc (25-50 mg), promethazine hydrochloride (12.5-25.0 mg), or prochlorperazine (5-10 mg). This is an effective treatment and one that can be used if the physician is sure the patient genuinely has a headache of major proportions. Unfortunately, the complaint of headache is all too easy to simulate as a drugseeking behavior. The decision to treat with an opioid must be made in each case on the basis of the patient's behavior, the physician's knowledge of the previous history from emergency room records, and the local knowledge of the nursing and emergency room staff. Unfortunately, many patients with headache who report to emergency rooms are given less than adequate relief for fear of indulging drug-seeking behavior. To avoid using opioids, one can use neuroleptic agents acutely, with or without DHE. DHF, 0.5-1.0 mg, with metoclopramide, 10 mg by intravenous injection, is an effective treatment for acute headache and provides an alternative to the use of an opioid. Similarly, prochlorperazine, 10 mg intravenously over 3-4 minutes alone or combined with DHF, can be effective. Sumatriptan, 6 mg subeutaneously, may provide relief of both the headache and the associated symptoms. Some evidence points to the possibility of magnesium deficiency having a role in the pathogenesis of migraine, and intravenous infusion of 1 g of magnesium sulfate results in rapid relief of headache pain in patients with low serum ionized magnesium levels (Bigal et al. 2002). Alternatively, chlorpromazinc, 5 mg injected intravenously every 10 minutes to a maximum of 25 mg,
2084
NEUROLOGICAL DISKASF.S
is also an effective agent when used acutely. The latter agent often produces hypotension, and patients should first receive a bolus of 250-500 mL of 5% dextrose in one-half normal saline. (Dehydrated patients should always receive appropriate intravenous hydration.) Some patients develop acute extrapyramidal symptoms after treatment with neuroleptic agents. These can be treated with parenteral diphenhydramine, 25-50 mg. The neuroleptic agents do produce sedation, and patients should be advised not to operate a motor vehicle after treatment. Injectable ketorolac, 60 mg given intramuscularly, is another alternative to the narcotic or sedative agents. The use of this NSAID in elderly patients, those who are dehydrated, or those having any history of renal insufficiency should be avoided. A single dose of dexamethasonc combined with other parenteral antimigraine agents has been used for the emergency room treatment of attacks of intractable migraine. When a migraine lias lasted for many days with little or no relief, the term status migrainosus has been used. Dehydration, tiredness due to lack of sleep, and continued pain may necessitate admission to a hospital to terminate the attack. Fluid replacement, correction of electrolyte imbalance, and suppression of vomiting with metoL-lopi-.iniide. chlorpi'oina/ine, or prochlorperazine generally result in improvement. DHE combined with an antiemetic initially, given intravenous!) every S hours, may aborl migraine status. It is effective, but increased nausea and vomiting may be a reason to switch to an alternative regimen. Corticosteroids, such as dexamethasone or prednisolone, can be administered. A dose of prednisolone of 20 mg every 6 hours initially, followed by a rapidly tapering dose over 2-3 days, may help abort status migrainosus. It is best to avoid narcotic and benzodiazepine agents when treating status migrainosus. Prophylactic Treatment. When the attacks of migraine occur weekly or several times a month or when they occur less often but arc very prolonged and debilitating, a preventive program is appropriate. Attacks of migraine that occur in a predictable pattern can also respond to prophylactic medication. For example, menstrual migraine can be treated in this way (see Prophylactic Menstrual Migraine Therapy, later in this chapter). jS-Adrenergic Blockers /J-Adrenergic antagonists are widely used for the prophylaxis of vascular headaches (Silberstein 2000). Propranolol is effective in 55-93% of patients. These figures do not mean that the migraine attacks stopped but that the patients with responding headaches reported at least a 5 0 % reduction in the frequency and severity of their attacks. In other studies, more than 5 0 % of patients reported having a favorable response to a placebo. Propranolol should be administered in doses of 80-240 mg per day and, if tolerated, should be given a trial of
2 to 3 months. Compliance is increased with the use of a long-acting form of propranolol that can be given once daily. Side effects are not usually severe. Lethargy or depression may occur and may be a reason for discontinuation of the medication. Hypotension, bradycardia, impotence, insomnia, and nightmares can all occur. As with all ^-adrenergic blocking agents, administration of propranolol should be discontinued slowly to avoid cardiac complications. It is contraindicated in people with a history of asthma and should be used with caution in patients using insulin or oral hypoglycemic agents because it may mask the adrenergic symptoms of hypoglycemia. The benefit of propranolol in migraine may be separate from its action as a /J-adrencrgic blocking agent, but its exact mechanism of action is unknown. Almost all the available ^-adrenergic blocking agents have been tested for their potential use in migraine. Timolol, nadolol, atenolol, and metoprolol have each been shown to have approximately the same benefit in migraine as propranolol. A n tidep ressa n ts Amitriptyline and other tricyclic antidepressants can be helpful in migraine prophylaxis (Silberstein 2000), just as they are useful in the prevention of muscle contraction icnsitei! headaches. The benefit seems to lie independent of their antidepressant action. Blockade of noradrenaline uptake at catecholamine terminals and inhibition of serotonin reuptake may be related, but the action of antidepressants in migraine is unclear at present. Used in doses of 10-150 mg at night, amitriptyline, imipramine, desipramine, or nortriptyline may all provide some reduction in attacks of migraine, although evidence of efficacy in clinical trials is available only for amitriptyline. Side effects can be rather troublesome. Morning drowsiness, dryness of the mouth, weight gain, tachycardia, and constipation are common. The anticholinergic side effects may decrease with time. If tolerated, the tricyclic agents should be given a trial of at least 3 months after a therapeutic dose is reached. The optimal dose for migraine prophylaxis must be determined by titration to the effective or maximum tolerated dose within the therapeutic range (usually 40-150 mg). The efficacy of newer antidepressants of the selective serotonin reuptake inhibitor type, such as fluoxetine and sertraline, has not been consistently demonstrated in clinical trials, and these drugs have a relatively limited role in the prophylaxis of migraine. Headache is a common side effect of several drugs in this class of antidepressants. Use of the monoamine oxidase inhibitor (MAOI) phenelzine for migraine prophylaxis is based on the agent's inhibiting the breakdown of serotonin, which would thereby continue to act as a constrictor of cranial vessels. Unfortunately, the dietary restrictions that must be carefully followed if a hypertensive crisis is to be avoided limit
HEADACHE AND OTHER CRANIOFACIAL PAIN
the widespread use of these inhibitors for prevention of migraine, h'or patients with particularly severe and intractable attacks, the MAOIs should be considered. The patient must be given a list of a mine-containing foodstuffs to he avoided, such as strong cheese, red wine, beer, yeast products, cream, broad beans, fermented foods, yogurt, and many others. Dangerous drug interactions can occur with preparations such as sympathomimetic agents, L-dopa, central anticholinergics, tricyclic antidepressants, and opioids, especially meperidine. Side effects of MAOIs include hypotension as well as hypertension, agitation, hallucinations, retention of urine, and inhibition of ejaculation, Calcium-Channel
Blockers
The calcium-channel antagonists prevent spasm of arteries by inhibiting contraction of smooth muscle. Although the relevant mechanism by which they affect migraine is not known, their use in migraine was originally based on their ability to prevent vasoconstriction and on their other actions, including prevention of platelet aggregation and alterations in release and re-uptake of serotonin. Several clinical trials have indicated some benefit for verapamil, nimodipine, and tlimari/.inc in preventing recurrent migraine. Nifedipine seems to cause a generalized headache as a side effect and has little to add to migraine prophylaxis. Verapamil in doses of 80-160 mg three times a day reduces the incidence of migraine with aura, but it is not as useful in migraine without aura. Experience with diltiazem is too limited to permit an assessment of its value at this time. Anticonvulsants Over the past several years, anticpileptic drugs have been the fastest expanding class of drugs in the prophylactic arsenal for migraine. Although the mechanism by which the drugs act in migraine prevention is not known, they are all modulators of the y-aminobutyric acid system. In the early 1990s sodium valproate was shown in several blinded, placebo-controlled studies to have a beneficial effect in the prophylactic treatment of migraine (Silberstein 2000). Fifty percent of patients showed a response with a 5 0 % or better reduction in migraine incidence. Valproic acid is usually given in the form of divalproex sodium and is generally effective at a range of 500-1750 mg per day taken in divided doses. Side effects include sedation, dizziness, increased appetite, increased bleeding time, increased fragility of hair, and an asymptomatic increase in liver function test values. Valproate should not be used in women who are at risk of becoming pregnant because it is associated with an increased risk of neural tube defects in the infants of women taking it during the first trimester. Gabapentin has been shown to be effective in the reduction of migraine incidence (Mathew ct al. 2001), It also has beneficial effects in somatic pain and
2085
may be a good choice if a patient has neck pain, back pain, or painful peripheral neuropathy as well as migraine. It appears to be relatively well tolerated although dizziness and sedation may limit its use in some patients. The therapeutic dose range for gabapentin is 600-2400 mg per day. Topiramatc is the most recent addition to the antimigraine armamentarium. Its efficacy for migraine has been demonstrated in several small blinded series (Storey et al. 2001). Topiramate has effects not only on y-aminobutyric acid but also on non-NMDA glutamate and carbonic anhydrase activity. It may have prominent sedating and cognitive side effects, making a slow gradual titration of the drug (15 mg per week initially) to the therapeutic range of 70-200 mg per day the most successful strategy. Other side effects include paresthesia and weight loss, the latter making topiramate a particularly attractive choice for many patients. It is also associated with a mildly increased risk nl kidney stones. Serotonergic
Agents
Methysergidc may be an effective prophylactic agent for all types of vascular headache. At this time, though, its manufacturer has ceased its production in the United States, and whether it will reappear is uncertain. Historically it has been a very useful agent despite its potential for producing serious complications, such as retroperitoneal, pulmonary, and heart valve fibrosis, which seriously limit its use as a long-term prophylactic agent. It should be reserved for the most intractable migraine and should be given for periods of only 6 months at a time. Between such courses, methysergide should be discontinued for 4 weeks. A clinical examination, urinalysis, and serum creatinine determination may be undertaken to detect any evidence of the fibrotic complications. Some authorities also advise obtaining a chest roentgenogram, scrum creatinine level, and an abdominal CT or MRI scan. If there are no signs of side effects, treatment with the drug can be restarted and continued for another 6 months. The incidence of fibrotic complications is low, perhaps 1 in 1000 patients. If fibrosis does develop, it may resolve if methyscrgide is immediately and permanently withdrawn, but this is not always the case. Whenever methysergidc is prescribed, it must be started very slowly. A fraction of a 2-mg tablet is the initial dose, followed by a gradual increase ovet 7-10 days to the minimal effective dose, generally in the range of 6-8 mg in three or four divided doses per day. Rapid introduction of the drug leads to nausea, abdominal cramps, pain in the legs (possibly due to venospasm), hallucinations, and agitation. Methysergide is a derivative of lysergic acid *" diethylamide. It can act as a serotonin antagonist peripherally and as a serotonin agonist centrally, but its mode of action in vascular headaches is incompletely understood. Cyproheptadine is also a peripheral serotonin antagonist. It also has weak antibradykiuin activity and prevents platelet aggregation. In adults, it has a minor role in the
2086
NEUROLOGICAL DISEASES
prevention of migraine, but it is more effective in children. At all ages, it causes drowsiness and may cause significant weight gain. Other Prophylactic Agents Riboflavin administered orally in a dose of 400 mg per day has been shown to be effective in migraine prophylaxis in a prospective, randomized, controlled study that enrolled a relatively small number of subjects. The effect on the frequency of attacks was not statistically significant until the third month of the trial (Schocncn et al. 199S). There are minimal side effects associated with this treatment. Oral magnesium supplementation has also been shown in double-blinded, placebo-controlled, randomized studies to be effective in migraine prophylaxis. Oral magnesium supplementation with 600 mg of a chelated or slow-release preparation is recommended. Magnesium-induced diarrhea and gastric irritation are the most common side effects (Mauskop and Altura 1998). Aspirin, 325 mg taken every other day for the prevention of cardiovascular disease, reduces the incidence of migraine slightly. The NSAIDs have been tried for migraine prophyl.iM-,, wiili some bcnchl. 1 hoy arc, however, helpful for providing analgesia during the acute attack. Botulinum toxin A injection in the treatment of migraine is supported by an increasing body of anecdotal evidence from small MTICS .iiul n conirulled •.iin.U ^i I bets: cm ci al. 2000b). The treatment may exert its effect by reducing the release of proinflammatory and vasodilating neuropeptides from nociceptive terminals. Botulinum toxin blocks the release of glutamate from nociceptive terminals and therefore may reduce or inhibit the development of peripheral and central trigeminal sensitization. Doses of up to 100 units ate injected in muscles of the forehead, as well as temporalis, splemus capitis, and trapezius. The effect, when it occurs, appears within 7-10 days and persists for up to 3 months. Side effects are minimal when lateral forehead injection is avoided. For patients who do not tolerate or do not comply with daily drug usage or who may prefer an injectable agent rather than chronic oral therapy, botulinum toxin may be a viable option. Hormones and Migraine Migraine occurs equally in both sexes before puberty, but it becomes three times more common in women after menarehe. Approximately 2 5 % of women have migraine during their reproductive yeats. The changing hormonal environment throughout a woman's life cycle, including menarehe, menstruation, oral contraceptive LLSC, pregnancy, menopause, and hormonal replacement therapy (HRT), can have a profound effect on the course of migraine. Menstrual Migraine. Migraine attacks are associated with menses in one of three ways. The attacks may occur
exclusively during menstruation and at no other time during the cycle. This association is referred to as true menstrual migraine (TMM), and it has recently been proposed that TMM be defined as attacks that occur between days —2 and +3 of the menstrual cycle (MacGregor 1996). The incidence of T M M according to this definition is approximately 7%. Mote commonly, migraine attacks occur throughout the cycle but increase in frequency or intensity at the time of menstruation. This association occurs in up to 6 0 % of female migraineurs. Finally, premenstrual migraine can occur between days —7 and —3 before menstruation as part of premenstrual syndrome or late-luteal phase dysphoric disorder. This disorder is characterized by a cluster of symptoms in the luteal phase, including depression, irritability, fatigue, appetite changes, bloating, backache, breast tenderness, and nausea. These different relationships between migraine and the menstrual cycle can reliably be determined by reviewing headache diaries, and their distinction is important because pathophysiology may differ as would the therapeutic approach. Numerous mechanisms have been proposed to explain the pathogenesis of menstrual migraine. There is abundant clinical and experimental evidence to support the theory that estrogen withdrawal before menstruation is a trigger tor migraine in some women. Estrogen withdrawal may modulate hypothalamic /t-endorphin, dopamine, ^-adrenergic, and serotonin receptors. This complex relationship causes significant downstream effects, such as a reduction in central opioid tone, dopamine receptor hypersensitivity, increased trigeminal mechanorcceptor receptor fields, and increased cerebrovascular reactivity to serotonin, These changes, which occur during the luteal phase of the cycle, may be germane to the pathogenesis of menstrua] migraine, Several lines of investigation have implicated both prostaglandins and melatonin in the pathogenesis of menstrual migraine. Prostaglandins and melatonin are important mediators of nociception and analgesia, respectively, in the CNS. The concenttation of prostaglandin F 2 and nocturnal melatonin secretion increase and decrease, respectively, during menstruation in female migraineurs. These observations are the basis for the clinical use of NSAIDs and melatonin for the prophylaxis of mensttual migraine. Management of Menstrual Migraine, A direct link between menstruation and headache attacks must be established by asking the patient to keep a diary card of migraine attacks and menstrual periods for at least 3 consecutive months. The nature of this relationship determines subsequent therapy. For example, for patients who have both menstrual and nonmenstrual attacks (menstrua I-associated migraine), a standard prophylactic medication might be used throughout the cycle rather than the perimenstrual use of a prophylactic agent. The goals of therapy should be clearly outlined in addition to the
HF.ADAQ IE AND OTHER CRANIOFACIAL PAIN dosages, benefits, a n d side effect profile of each recommended medication. A headache d i a n should ideally be started by the patient in an effort to identify other n o n h o r m o n a l triggers. Biofeedback a n d relaxation t h e r a p y can be helpful in selected patients a n d should be used whenever possible. Lifestyle factors, such as regular meals, sufficient sleep, and regular aerobic exercise, are i m p o r t a n t items to emphasize. These simple efforts c a n h a v e a significant i m p a c t o n t h e patient's h e a d a c h e b u r d e n a n d may limit the incidence of attacks t h a t require p h a r m a c o logical intervention. Acute Menstrual Migraine Therapy. T h e goal of acute menstrual migraine t h e r a p y is to decrease the severity a n d d u r a t i o n of pain as well as the associated s y m p t o m s of an individual migraine attack, including n a u s e a , vomiting, p h o t o p h o b i a , and p h o n o p h o b i a . Some w o m e n m a y control attacks of m e n s t r u a l migraine quite a d e q u a t e l y w i t h abortive therapy only (Figure 75.fi). T h e acute m a n a g e m e n t of m e n s t r u a l migraine does n o t differ from the treatment of migraine unassociated with m e n s t r u a t i o n . Mild attacks (which a r e relatively rare) can h r m a n a g e d with a c e t a m i n o p h e n o r N S A I D s . M o d e r a t c to-severe attacks can be treated by using an oral t r i p t a n .
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If there is significant nausea and vomiting, h o w e v e r , an alternate route of a d m i n i s t r a t i o n is necessary. In this setting, parenteral t h e r a p y with s u m a t r i p t a n , D H E , k e t o r o l a c , or a neuroleptic, such as p r o c h l o r p e r a z i n e , is a p p r o p r i a t e . Alternatively, both s u m a t r i p t a n a n d D H E a r e available in a nasal formulation a n d can he helpful in patients with significant gastrointestinal upset. T h e combination of an antiemetic with a n y of these m e d i c a t i o n s may n o t only alleviate nausea a n d vomiting b u t m a y also potentiate the efficacy of these c o m p o u n d s . Prophylactic Menstrual Migraine Therapy. Prophylaxis m a y either be perimenstrual (cyclic) or c o n t i n u o u s (noncyclic) (Table 7 5 . 1 0 ) . M a n y of the regimens suggested for perimenstrual migraine prophylaxis depend on regular m e n s t r u a t i o n . Perimenstrual p r o p h y l a x i s c o m m e n c e s a few days before the period is expected and is c o n t i n u e d until t h e end of m e n s t r u a t i o n . In w o m e n w h o s e cycles are difficult to predict, c o n t i n u o u s p r o p h y l a x i s with s t a n d a r d migraine p r o p h y l a c t i c agents, such as tricyclic antidepressants a n d beta blockers, can be quite effective if taken continuously. N S A I D s arc considered to be a first-line agent for b o t h acute a n d p r o p h y l a c t i c t h e r a p y in patients with either
FIGURE 75.6 Algorithm for acute treatment of menstrual migraine. (ASA = acerylsalicylic acid: 1)1 II-. • dihydroergotamine; NSAID = nonsteroidal antiinflammatory drug.)
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NEUROLOGICAL DISEASES
Table 75.10;
Nonhormonal prophylaxis for menstrual migraine
Cyclic (perimenstrual) days —3 through +3 Nonsteroidal anti-inflammatory drugs Naproxen sodium 5.50 nig hid Mefenamic acid 250 mg tid Ketoprofen IS mg tid Triptans and ergots Sumatriptan 25 mg tid Narairiptan 1.0 mg tid or 2.5 mg bid Frovatriptan 2.5 mg once daily Zolmitriptan 2.5 mg bid Ergotamine tartrate + caffeine (Wigraine) 1 mg qhs or bid Dihydroergotamuie 0.5-1.0 mg (SC, 1M, or intranasal) bid Noncyclic (throughout cycle) Tricyclic antidepressants Nortriptyline or amitriptyline 10-150 mg qhs Beta blocker Propranolol or nadolol 40-240 mg daily Calcium-channel blocker Verapamil 240-480 mg daily Anticonvulsant Divalproex 250-500 mg bid Dopamine agonists Bromocriprine 2.5-5.0 mg tid Oilier
Magnesium 360-600 mg daily
menstrua I-associated migraine or TMM when the timing of menstruation is predictable. Different classes of NSAlDs should be tried because response may vary in a given individual. Ergot derivatives in the form of ergotamine tartrate, etgonovine maleate, and DHE can also be effective when used as a symptomatic or prophylactic drug around the time of menstruation. Concerns about habituation or rebound headaches are minimal given the limited duration of treatment when used drugs are used perimenstrually. For those with T M M , attacks can also be prevented by stabilizing estrogen levels during the late luteal phase of the cycle. Estrogen levels can be stabilized by maintaining high levels with estrogen supplements or by maintaining low levels that result from a natural or medically induced menopause (Table 75.11). Estradiol implants, percutaneous estradiol gel, and estrogen patches produce reasonably stable levels of estrogen and rhcit use can be an effective preventive strategy. If periods are less predictable, suppression of the ovulatory cycle with high, static estrogen levels can be accomplished
Table 75.11:
Hormonal prophylaxis for menstrual migraine
Static high-maintenance levels Transdermal estradiol (1 x 100 ug days —3/—1/+2) Combined oral contraceptive or transdermal patch !.i 4 mosl Percuraneous esrradiol (1.5 mg daily days —3 ro +6) Static low-maintenance levels Danazol 200-600 mg/day Tamoxifen 5-15 mg/day (days 7-14 luteal cycle) Goserclin (treatment limited to 6 mo)
with either a low-dose combined estrogen-progestin oral contraceptive pill taken continuously for 3-4 months or with two 100-ug patches replaced every 3 days in combination with cyclic progestogens. Treatments that suppress the cycle by reducing estrogen levels (danazol), inducing a medical menopause (goserclin [Zoladexj), or modifying the effect of estrogen (tamoxifen) have also been anecdotally reported to be successful in the treatment of resistant menstrual migraine. They are not commonly used in clinical practice, howevct, because the menopausal side effects of these medications can be unpleasant. Theit use should be reserved for patients with recalcitrant migraine. Progesterone atone is ineffective in the treatment of menstrual migraine. Bromocriptine, a dopamine (D2) receptor agonist, may decrease perimenstrual symptoms of breast engorgement, irritability, and headache when administered during the luteal phase of the cycle. Efficacy is enhanced, however, when the medication is used continuously throughout the cycle rather than perimenstrually (Herzog 1997). The use of magnesium for the acute and prophylactic treatment of migraine and menstrual migraine has received considerable attention over the past few years. Low levels of systemic magnesium have been found in women with menstrual migraine, and MRS studies have demonstrated reduced lewis 1 mlI.KVIIUI.U magnesium in the cerebral cortex of migrameurs. Low levels of intracellular magnesium may lead to neuronal hypei excitability and spontaneous depolarization, which may be the central process by which a migraine attack is initiated. This has led some investigators to study the effect of magnesium on both the acute and prophylactic management of menstrual migraine (Mauskop and Altura 1998). Some physicians still advocate the use of hysterectomy and oophorectomy in women with intractable PMS and menstrua] migraine whose headaches tespond to medical ovariectomy. There ;iu- no loiigicrni tulUm -up ur controlled studies to conclusively substantiate this position. Because no study has been placebo controlled, the positive results seen in some studies may reflect the daily postoperative use of estrogen. Although two thirds of women who have physiological menopause experience migraine relief, the opposite effect may occur with surgical menopause with bilateral oophorectomy. A retrospective study of 1300 women also demonstrated the unfavorable effects of surgical menopause on migraine (Granclla ct al. 1993). Therefore, until convincing evidence demonstrates otherwise, hysterectomy with or without oophorectomy is not currently recommended for women with menstrual migraine. Oral Contraception in Female Migraineurs. Migraine prevalence is highest in women during their reproductive years, the very population who use oral contraceptive therapy. Oral contraceptives have a variable effect on migraine. Migtainc may begin dc novo after a woman starts taking oral contraceptives, pre-existing migraine may
HEADACHE AND OTHER CRANIOFACIAL L'AIN worsen in severity or frequency, or the characteristics of the migraine attack may change. For example, aura symptoms may develop in a woman who for years may have had migraine without aura. On the other hand, migraine attacks may lessen after an oral contraceptive is started, particularly in women whose migraine attacks had a very close relationship to menstruation. In the majority of women, however, the pattern of migraine does not change appreciably alter ney a/irt raking .111 oral conrau'prive, particularly with the lower doses of estrogen and progestin now found in most oral contraceptives. The concern ahout the use of synthetic estrogen in women with migraine pertains to the increased risk of ischemic stroke in this population, relative to age-matched women without migraine. There is now convincing evidence that female migraineurs have a greater risk of experiencing ischemic stroke. Tzourio and colleagues (19951 found migraine to be strongly associated with the risk of ischemic stroke in young women (odds ratio 3.5), and this association was independent of other vascular risk factors. The risk of ischemic stroke was particularly increased in women with migraine who were using oral contraceptives (odds ratio 13.9), were heavy smokers (odds ratio 10.2}, or who had migraine with aura (odds ratio 6.2). It has been estimated that the incidence of ischemic stroke in young women with migraine with aura who use oral contraceptives is 28 and 78 per 100,000 women aged 25-34 and 35-44, respectively. This is in contrast to the incidence of ischemic stroke of approximately 4 and 11 per 100,000 women in the general population in the same respective age groups. Although the relative risk of ischemic stroke is increased in this group, it is important to hear in mind that the absolute risks are still small. The International Headache Society Task Force developed evidence-based recommendations for the use of oral contraceptives and hormone replacement therapy in migraineurs (Bousser et al. 2000). When prescribing combination oral contraceptives (COCs) in women with migraine, their recommendations were the following: • Identify and evaluate risk factors. • Diagnose migraine type, particularly the presence of aura. • Recommend that women with migraine should stop smoking before starting COCs. • Treat other conditions, such as hypertension and hyperlipidemia. • Consider non-ethinylestradiol methods in women who are at increased risk of ischemic stroke, particularly in those who have multiple risk factors. Some of these contraceptives are as or more effective in preventing pregnancy than COCs and include progestogcn-only hormonal contraception. Observational studies suggest that progestogen-only hormonal contraceptive use is not associated with an increased risk of ischemic stroke, although quantifiable data are limited.
2089
• High-dose COCs (>50 pg cthinylestradiol), particularly those containing first-generation progestogens, are no longer recommended for routine use. • Low-dose formulations (M- uv.v, hi- :i sign ol caudal midline nuclear involve ment of the t h i r d C N . Silverman, Lui, a n d Galetta (1995) provide a comprehensive teview of brainstem s y n d r o m e s and crossed paralysis. (See also C h a p t e r 22 for a discussion of brainstem s y n d r o m e s affecting the third C N . )
Aneurysmal Involvement of the O c u l o m o t o r N e r v e After the fascicles of the o c u l o m o t o r nerve exit t h e brainstem, they fuse in the interpeduncular fossa. Any Table 76.1:
Syndrome Benedict's (1889)
e x t r a - a x i a l m a s s in this s u b a r a c h n o i d area could involve o n e or b o t h o c u l o m o t o r nerves. A n e u r y s m s of b o t h t h e posterior c o m m u n i c a t i n g a r t e r y a n d the basilar bifurcation m a y p r o d u c e internal o p h t h a l m o p l e g i a , with a dilated a n d relatively fixed pupil as its initial manifestation. O c u l o m o t o r dysfunction is also relatively c o m m o n as a c o m p l i c a t i o n of surgery on a basilar bifurcation a n e u r y s m . T h e palsy is likely d u e to retraction of the nerve d u r i n g surgery. W h e n it occurs in isolation, the prognosis for recovery is g o o d , with resolution o c c u r r i n g over several m o n t h s . O n t h e o t h e r h a n d , w h e n the third C N dysfunction is a c c o m p a n i e d by a hemiparesis, recovery is often incomplete. In the past the d i c t u m t h a t compressive third nerve etiologies invariably p r o d u c e pupillary paralysis and microscopic vascular etiologies spare the pupil h a s been widely believed. H o w e v e r , because of t h e ftequency of o v e r l a p p i n g factors such as aging and vascular risk factors, this clinical guideline is less reliable in p l o t t i n g a c o u r s e of action ( T r o b e 1998). Raised i n t t a c t a n i a l pressure, from w h a t e v e r cause, may p r o d u c e t r a n s t e n t o r i a l uncal h e r n i a t i o n with extrinsic c o m p r e s s i o n of t h e third CN on t h e m a r g i n of t h e t e n t o r i u m . Because of t h e peripheral location of the pupilloconstrjctot fibers, or theit vulnerability to c o m p r e s sion, a unilateral pupillary e n l a r g e m e n t on the side of the lesion may be the earliest sign of increased intracranial pressure ( H u t c h i n s o n ' s pupil).
Terminology for midbrain syndromes Milter and Newman (Walsh and Hoyt)
CLisrr
I
Oculomotor palsy
Oculomotor palsy
Oculomotor palsy
Oculomotor palsy
Contra la [era 1 chorea, tremor, ballismus, or aril cms is LS: rhird nF, RN
Contralateral ataxia and intention tremor
>
Contralateral hemiparesis
LS: third nF, RN
LS: third nF, RN, CP
Contralateral involuntary movements or tremor LS: third nF, CP, SN?, RN? Oculomotor palsy Contralateral ataxia asynergy, dysdiadocliokinesia
Claude's (1912) Oculomotor palsy Contralateral asyncrgia, ataxia, dysmctria, dysdiadocliokinesia LS: third nF, RN, BC Nothnagel's Oculomotor palsy (1879) Ipsilateral ataxia LS: third nF, BC
Not mentioned
i-ifii-
•
;
'ii
Original description
/ • • '
Oculomotor palsy l .13111 i. L :. t H i : 11
.U.IM.I,
and slow rubral tremor
Not mentioned
LS: third nF, RN Oculomotor palsy with vertical gaze palsy LS: third nF and ?
±Trochlear palsy, iscnsory loss LS: third nF, RN, SCP (ifourth nerve, ML, MLF) Bilateral oculomotor palsies of varying degree and usually as) mmetrical ±Nysragmus Gait ataxia LS: superior and inferior colliculi
BC = brachium conjunctivum; CP = cerebral peduncle; LS = lesion site; ML = medial lemniscus; MLF = medial longitudinal fasciculus; RN = red nucleus; SCP = superior cerebellar peduncle; SN — substantia nigra; third nF = third cranial nerve fascicle. Source: Used with permission from Liu, L C. T., Crenner, C. W., Logigian, E. L., et al. 1992, "Midbrain syndromes of Benedikt, Claude and Nothnagel: Setting the record straight," Neurology, vol. 42, pp. 1820-1822.
CRANIAL NEUROPATHIES
2109
Trauma
Superior Orbital Fissure and Orbit
The third CN in the subarachnoid space can be injured in head trauma. Even minor head trauma may produce a third nerve palsy as the initial sign of parasellar or clival tumor, presumably because the oculomotor nerves are already stretched over the rumor or are partially encased and fixed by the tumor and hence vulnerable to sudden mechanical stress. A third nerve palsy triggered by mild head injury should prompt investigation for a basal tumor.
The third CN passes through the superior orbital fissure in its passage from the cavernous sinus into the orbit. It is often difficult to distinguish lesions of CN III in the orbit from those of the superior orbital fissure and those in the proximal orbit. Coexisting optic nerve dysfunction suggests orbital involvement. Involvement of maxillary division facial sensation suggests that the lesion extends at least as far back as the midcavcrnous sinus. Although the superior :irbiral :issi;re ma\ be bivolved ir almost an\ or the conditions mentioned previously, the Tolosa-Hunt syndrome merits special comment. Usually appearing in the fourth through sixth decades of life, this syndrome manifests over several weeks as a steady, boring, unilateral orbital pain. Palsies of the third, fourth, or sixth CNs, in any combination, are possible. Optic nerve involvement is unusual. Although first-division trigeminal sensory involvement may occur, involvement of the maxillary division is uncommon. Both sexes are affected equally, and spontaneous remissions are reported. The entity is diagnosed by exclusion of other space-occupying lesions in the area of the superior orbiral fissure and its contiguous parts. Corticosteroid responsiveness is the rule. Pathological examination reveals nonspecific inflammatory granulation tissue filling the cavernous sinus.
Cavernous Sinus Syndromes As the third CN enters the cavernous sinus, it courses forward in the upper aspects of the lateral sinus wall, above the trochlear and trigeminal nerves. In this location, it is prone to compromise by a variety of pathological processes that may simultaneously compromise other cavernous sinus structures, t impression A\\d dysfunction of the third, fourth, or sixth CNs in the cavernous sinus may be i..iu^J by .1 i-:i!'!>;id arury enlarged by diswiinn, bin tinmore likely cause of ocular motor palsies in spontaneous carotid dissection is interruption of the nutrient arteries supplying the nerves. Thrombophlebitis of the cavernous sinus is a potentially life-threatening condition secondary to contiguous infection in the surrounding sinuses, eye, or nose. Involvement of the third CN, along with any other CNs or vascular structures traversing this cavity, can result in a clinical picture of a sick and septic patient with headache, with varying degrees of ophthalmoplegia, chemosis, and proptosis. If the condition is untreated, the initial unilateral picture may become bilateral via spread through the circular sinus. In the immunosuppressed or poorly controlled diabetic in acidosis, mucormycosis must be considered in the diffetential diagnosis. This fungal infection, caused by either Rhizopus or Mucor species, often produces nasal turbinate necrosis and a serosanguineous nasal discharge. Surgical debridement of the area and intravenous amphotericin B may save the patient from otherwise certain death. Other fungal infections, such as Aspergillus, may produce similar manifestations. Aneurysms of the carorid artery in the cavernous sinus, as well as primary and metastatic neoplasia, are important causes of third or sixth nerve dysfunction. A coexisting involvement of both parasympathetic and sympathetic pupillary function suggests localization to this area. Infarction of the third CN in the cavernous sinus involves the central cote of the nerve, sparing peripheral pupilloconstrictor fibers, producing a characteristic painful pupilsparing palsy of CN III. In the past, this was offered as a reliable sign of noncompressive disease that obviated the need for invasive studies, such as angiography. Vascular versus compressive etiologies can often be predicted from how the iridoplcgia and ophthalmoplegia evolve during the first 7 days of the illness.
Distal Branch Syndromes As the oculomotor nerve enters the orbit, it subdivides into superior and inferior branches. The former, passing lateral to the optic nerve, supplies the superior rectus and levator palpcbrae superioris muscle. The inferior branch, the larger of the two, supplies the inferior and medial rectus muscles and inferior oblique muscle. A twig of nerve passing to the inferior oblique also supplies, through the short ciliary nerves, the sphincter of the pupil and ciliary body. Selective paralysis of these terminal branches has multiple causes, including orbital trauma, but may be idiopathic. Isolated superior branch oculomotor palsies produce a characteristic picture of unilateral ptosis, with weakness of the superior rectus and preserved pupillary, medial, and inferior rectus muscle function. The cause is often idiopathic and presumed in lv viral, bin internal carotid artery aneurysms, located either in the intracavernous portion or on the posterior communicating artery, may damage nerve fibers in the oculomotor nerve before division into its terminal superior and inferior branches. Myasthenia gravis may occasionally cause a similar picture.
Aberrant Regeneration Phenomena Aberrant regeneration phenomena are oculomotor synkinesias that encompass a variety of signs, the most classic of
211(1
NKKIIOI.OCICAI. D1SFASF.S
which is lid retraction on adduction or depression (pseudoGraefe's sign) of the ipsilatcral eye.
In a child, fourth nerve palsy prompts consideration of congenital origin, with head trauma being the second most common cause.
TROCHLEAR NERVE Neuroanatomy
TRIGEMINAL NERVE Neuroanatomy
The trochlear nerve, or fourth CN, is unique among the CNs m several ways. It originates from cells beneath the inferior colliculus just above the medial longitudinal fasciculus and caudal to the third CN complex. It is the only CN to exit on the dorsal aspect of the brainstem and is [lie only CN thai is completely crossed. Thus fibers from the right fourth CN nucleus cross in the anterior medullary velum to reach the left orbit, and vice versa. It is also the smallest of the CNs to the extraocular muscles and has only approximately 2100 axons as compared with the oculomotor nerve, which has 15,000, and the abducens nerve, which has 3500. The fourth CN travels forward in the lateral wall of the cavernous sinus beneath the third CN and above the trigeminal nerve to reach the orbit and ultimately the superior oblique muscle.
The trigeminal nerve, or fifth CN, is a mixed motor and sensory nerve. The larger lateral portion of the fifth CN transmits sensation from sharply defined cutaneous fields on the face, oral cavity, and nasal passages. The smaller motor branch provides motor function to the muscles of mastication and travels with the third division. The ophthalmic, maxillary, and mandibular nerves enter the cranial cavity through the superior orbital fissure, foramen rotundum, and foramen ovale, respectively, to unite in the gasserian (semilunar) ganglion situated on the cerebral surface of the petrous bone. Atrophy and fatty replacement of muscle mass can be visualized with magnetic resonance imaging (MRI) when the mandibular division of CN V has undergone motor denervation (Russo, Smoker, and Weissman 1997).
Congenital Versus Acquired Palsies
Trigeminal Sensory Neuropathy
The diplopia in traumatic fourth nerve palsies usually subsides in less than 1 year. When trauma is excluded, a small number of patients are found with congenital fourth nerve palsies. Im.ie.e rilnne, vr>inbiiH\l with vertical diplopia occurs only in acquired cases of recent onset, not in congenital fourth nerve paralysis.
Trigeminal sensory neuropathy presents with sensory disturbance in one or more divisions of the nerve. Patients with a benign form have no associated neurological defects and have preservation of the corneal reflex. The paresthesias may resolve completely in a matter of months, with only a small percentage of patients developing other conditions, such as trigeminal neuralgia. Sinister etiologies include infiltrating neoplasms or vasculitis. In this population, patients usually have other neurological signs associated with the facial numbness. If intraoral sensation is impaired sufficiently, there may be difficulty in chewing and swallowing. Perineural spread of facial skin cancer and nasopharyngeal carcinoma may occur months or years after excision of the malignancy (Catalano, Sen, and Btller 1995; Su and Lui 1996).
Etiology Trauma is the most common cause of trochlear nerve palsy in adults. Twenty percent of traumatic cases are bilateral, Head impact at the time of trauma may produce disruption of the crossing fibers in the anterior medullary velum, perhaps by distention of the fourth ventricle. Transient ipsilatcral trochlear nerve paresis may occur after anterior temporal lobectomy for intractable seizures (Jacobsen, Warner, and Ruggles 1995). The etiology of a large number of palsies of CN IV remain undetermined. Vascular ischemic disease from hypertension, diabetes, and atherosclerosis accounts for approximately one fifth of eases. On very rare occasions, aneurysm in such disparate locations as the cavernous sinus and the posterior fossa may produce a fourth nerve paralysis. Myasthenia gravis must always be considered in the differential diagnosis of any ocular muscle palsy of nontraumatic origin. On rare occasions, fourth nerve palsy may follow an attack of herpes zoster ophthalmicus, but its onset may be delayed up to 4 weeks after the rash.
Trigeminal sensory neuropathy may be associated with scleroderma and other connective tissue disease. Distinguishing features of connective tissue disease are bilaterality, associated pain, and paresthesias that are not confined to individual nerve territories. Typically, the trigeminal motor pathway is spared. The site of involvement may be the cisternal portion of the nerve or gasserian ganglion, where motor and proprioceptive fibers bypass the sensory root (Forster et al. 1996). Interferon-ty, used in the treatment of a variety of malignancies, may produce intermittent or continuous sensory disturbance in the trigeminal distribution (Read, Crawford, and Pender 1995).
CKArvTIAL NEUROPATHIES In controlling the paresthesias ami neuropathic pain associated with these disorders, a literature review by McCleanc (2000) points to the effectiveness of lamotngine in these situations.
2111
third of the patients. The ophthalmic division of the trigeminal nerve is most commonly affected.
ABDUCENS NERVE Numb Ciiin and Cheek Syndromes
Neutoan atomy
Numbness of the lower lip may be the initial manifestation of metastatic disease to the lower jaw, affecting primarily the inferior alveolar nerve. Metastatic lung and breast cancers are the most common primary tumors. There are also neoplastic causes of numbness in the malar region. History of basal or squamous cell carcinomas of the face should be sought. There may he a spread of this type of tumor along regional nerves to the skull base and into the intracranial space, with meningeal involvement. As a result of mandibular bone atrophy from aging, the elderly may develop stenosis at the mental nerve foramen with paresthesias in the ipsilateral chin. A similar phenomenon has been reported with scleroderma (Fischoff and Sirois 2000).
Of all the motor nuclei of the extraocular nerves, those of the abducens nuclei lie farthest from rheir muscles of termination and originate at the lowest level in the brainstem. They lie just below the floor of the fourth ventricle, close to the midline, in the caudal pons. In contrast to the trochlear nerve, but in common with the oculomotor fibers, the abducens or sixth CN fibers have a considerable intramedullary extent. The axons course ventrally and in a somewhat caudal direction through the brainstem parenchyma to emerge at the pontomedullary junction. The nerve then makes a right-angle turn to pass upward along the face of the clivus; it turns anteriorly at Dorello's canal and passes into the medial aspect of the cavernous sinus, where it lies just beneath the internal carotid artery, The abducens nerve supplies the lateral rectus muscle.
Trigeminal Nctjralgia See Chapter 75 for a discussion of trigeminal neuralgia.
Traumatic Neuropathies Both cranial and facial trauma may affect the peripheral infraorbital and supraorbital branches of the trigeminal nerve. Cavernous sinus tumors may also involve the trigeminal nerve, but often there is associated contiguous CN involvement that localizes the site of the disease. Trigeminal nerve branch injury can rarely result from dental anesthetic injections. Lingual nerve (a branch of the mandibular division of CN V) injury may occur after surgery on the third molar and after laryngeal mask airway placement (Laxton and Kipling 1996). These patients present with complaints of paresthesias on the ipsilateral tongue surface.
Brainstem Syndromes As with the other CNs, lesions at different foci in the brainstem produce distinct syndromes. This anatomy explains the rare combinations of ipsilateral sixth nerve palsy, gaze palsy, and peripheral seventh CN weakness (Millard-Cubler syndrome) and of sixth nerve palsy and contralateral hemiplegia (Foville's syndrome). Infarction in the territory of anteroinferior cerebellar artery is probably the most common cause of these syndromes. Foville's syndrome is often combined with varying degrees of ipsilateral Horner's syndrome, facial hypesthesia, and hearing loss. A characteristic disorder, referred to as oneand-a-half syndrome, consists of preservation of abduction in only one eye, which also exhibits jerk nystagmus in the abducted position, while the other eye lies fixed in midline for all attempts at lateral movement. See Chapter 22 for a discussion of brainstem syndromes affecting the abducens nerve.
Herpes Virus Infections Viral infection with herpes simplex and herpes zoster may occur. The recurring herpes simplex mucous membrane lesions that occur throughout an individual's lifetime are associated with lifelong residence of that virus in the trigeminal ganglia. Herpes zoster, which is the result of lifelong varicella zoster virus residence in the ganglion, produces a much more fulminating infection, with disabling pain. Preherpetic neuralgia may precede the rash by several days and is followed by postherpetic neuralgia in about one
Extra-Axial Posterior Fossa Syndromes It is possible for any cerebellopontine angle tumor to cause varying combinations of trigeminal, facial, and auditory nerve dysfunction. Chordomas of the clivus may selectively involve the sixth nerve in its climb along the clivus. In the preantibiotic era, medial extension of middle ear infection or mastoiditis resulted in osteitis of the petrous pyramid and paralysis of CN VI as it approached Dorello's canal
2112
NEUROLOGICAL DISEASES
and the petroclinoid ligament (Gradenigo's syndrome). Metastatic disease to the same area or primary neoplasia, such as cholesteatoma, may produce a similar painful sixth nerve palsy. In the middle-aged to elderly adult with abducens nerve palsy and a combination of cervical [ymphadenopathy, serous otitis media, and blood-tinged nasal discharge, evaluation must exclude a nasopharyngeal carcinoma. Both unilateral and bilateral abducens paresis may occur in the syndrome of spontaneous intracranial hypotension (Berlit, Berg-Dammer, and Kuchne 1994). For a discussion of cavernous sinus syndromes, see Oculomotor Nerve, earlier in this chapter. Pathophysiology Of all the oculomotor palsies, abducens nerve paresis is the one most frequently reported and at the same time most often indeterminate in cause. In the middle-aged to elderly adult population, especially if there is a history of hypertension or diabetes, small-vessel ischemic infarction of the nerve is the most likely cause. The microscopic neuroanatomy of the abducens nerve, as well as of rhe oculomotor and trochlear nerves, reveals rhat they are penetrated by small nutrient vessels, occlusion of which produces infarction. If the sixth nerve palsy is bilateral, however, ischemia is seldom the cause, and neoplasia, demyelinating disease, subarachnoid hemorrhage, meningeal infection, and increased intracranial pressure must be considered. Unilateral or bilateral abducens weakness is also encounteted as part of Wernicke's disease in the nutritionally deprived alcoholic population. Myasthenia gravis may produce isolated weakness of ahduction, mimicking abducens nerve palsy. Abducens. Nerve Palsy in Childhood In children, abducens nerve palsies are most frequently due to neoplasia (13%) and trauma (40%). Often the neoplasm is a primary brainstem glioma, and abducens weakness may be the first sign of disease. In the newborn period, abducens nerve paresis may be a transitory and benign finding. Amblyopia may be a complication of sixth nerve paresis in children, and close monitoring to prevent this complication is warranted (Aroichane and Rcpka 1995).
FACIAL NERVE (CRANIAL NERVE VII) Neuroanatomy The facial nerve is the most complex of the CNs because of its multiple motor, sensory, and autonomic components, and its long, tortuous intracranial and extracranial course. The nerve is the motor nerve to the mimetic muscles of the face. It also contains secretory fibers to the salivary and lacrimal glands, and the mucous membranes of the oral and
nasal cavities. There are also somatic pain fibers from the external auditory canal and a small strip between the mastoid and the pinna, as well as taste fibers from the ipsilateral two thirds of the tongue. The facial nerve has two principal roots. Seventy percent of the nerve fibers arise from motor neurons of the facial nucleus; thirty percent are mixed sensory and autonomic fibers, forming the nervus intermedius of Wrisberg. The facial motor nucleus is located in the ventrolateral portion of the caudal pons. Its fibers coutse from the dorsal aspect of the nucleus to the medial side of the sixth CN nucleus, at which point they curve laterally around the dorsal surface of the sixth CN nucleus, forming the facial colliculus in tlu- t'liior ni tlu- fourth uiiii:.lf. The fibers then pursue a ventrolateral course through the pontine tegmentum to exit from the lower body of the pons between the olive and restiform body. Fibers for voluntary and reflexive facial movements are anatomically separate rostral to the lowei pons (Urban et al. 1998). The sensory root of the facial nerve (the nervus intermedius) is a combination of sensory and parasympathetic nerve fibers that include special visceral afferent fibers arising from the bipolar neurons within the geniculate ganglion, which supply taste fibers to the anterior two thirds of the tongue by way of the chorda tympani. The centra) portions of these branches traverse the nervus intermedins and terminate in the nucleus solitarius. Visceral efferent fillers arisir.s', fruir. the superior salivatorv nuclei course in the nervus intermedius and travel with the greater superficial petrosal nerve to the synapse in the sphenopalatine ganglion, yielding postganglionic fibers to the lacrimal and palatine glands. Still other preganglionic efferents continue in the chorda tympani to the submandibular glands. After leaving the pons, the motor and sensory roots of the facial nerve course through the cerebellopontine angle cistern for approximately 24 mm before entering the internal auditory canal. Within the canal, CN VII occupies a position anterior and superior to CN VIII. From the internal auditory canal to the stylomastoid foramen, CN VII traverses a torruous course of approximately 33 mm. The facial nerve is the longest and most complex of the CNs (Figure 76.1), consisting of six segments: intracranial, internal auditory canal, labyrinthine or petrous, tympanic, mastoid, and intraparotid. The labyrinthine, tympanic, and mastoid segments are in the fallopian canal. After the facial nerve (with the nervus intermedius) leaves the internal auditory canal, it begins its long course through the fallopian canal, beginning with the labyrinthine segment, which is approximately 3—4 mm long. The nerve enters the fallopian canal at the petrous bone and runs at a right angle to the petrous pyramid. The geniculate ganglion is included in this segment, giving rise to the greater superficial petrosal nerve. This is the narrowest portion of the fallopian canal, and the nerve occupies up to 8 0 % of
CRANIA], NEUROPATHIES
2113
HCiURI- 7h. I J In, schematic ol the facial nerve shows the- major subdivision- .nu! ILUMI.IU-. die |nioci]ial functions thai mighi he impaired at the level of a lesion and distal to it. For example, a lesion at the level of the geniculate might produce impaired taste and glandular secretions, as well as hyperaeusis (in addition to facial paralysis). the available diameter. In addition, the labyrinthine portion is the only segment without anastomosing atterial arcades, making it vulnerable to ischemia and compression. The labyrinth and tympanic segments of the fallopian canal form an acute angle of approximately 75 degrees, predisposing the nerve to vascular lesions and traumatic injury. I'he tympanic portion 12-13 mm) courses behind the cochlea and semicircular canal, ending with the beginning of the mastoid segment (15-20 mm) that continues along the anterior wall of the mastoid process. It is the longest segment of the nerve and has two major branches. The first branch goes to the stapedius muscle. The second branch is the chorda tympani, the terminal branch ol the ncrvus intermedins. This branch courses anteriorly and superiorly over the incus and under the malleolus, crossing the tympanic cavity to exit the temporal bone through the petrotympanic fissure, joining the lingual nerve to innervate the submandibular and sublingual glands. The chorda tympani also contains the taste fibers from the anterior two thirds of the tongue. CN VII ends its course in the fallopian canal by exiting through the stylomastoid foramen, giving off several branches, which include an inferior branch to the posterior belly of the digastric and stylohyoid muscles. The main
trunk of the facial nerve entets the parotid gland, dividing into upper and lower parts. The upper division gives rise to frontal, zygomatic, and buccal branches; the lower trunk gives rise to the mandibular and cervical branches. Approximately 17 paired muscles of facial expression are innervated by these various branches. An upper group of muscles raises the eyebrows, moves the forehead, and is involved in frowning. An intermediate group is involved in closing the eyelids and wrinkling the nose, and an inferior group is involved in smiling, laughing, whistling, wrinkling the chin, and raising the upper lip. The only facial muscle that is not innervated by CN VII is the levator palpebra superioris, which is innervated by the oculomotor nerve. Supranuclear lesions produce a different pattern of facial paralysis than do infranuclear and nuclear lesions (Table 76.2). The traditional explanation is that the lower face has primarily a contralateral innervation, whereas the upper face has both ipsilateral and contralateral innervation. However, a contributing factot is that the conical representation of the upper face is in the anterior cingulate gytus, and not the motot cortex (Morecraft et al. 2001). There is a disparity between emotional facial mimetic expression and voluntary facial movement that is best
2114 N F.UROI.OGICAL DISEASES Table 76.2:
Clinical differential features of upper motor neuron versus lower motor neuron facial weakness
Upper motor neuron lesions
Lower motor neuron lesions
Unilateral paresis of voluntary movements of lower face with sparing of the frontalis muscle Facial muscle weakness less apparent with emotional than with voluntary action Preservation or accentuation of facial reflexes Preserved taste, anterior two thirds of tongue Normal lacrimarion
Unilateral paresis of all mimetic muscles, including the frontalis muscle Degree of facial weakness similar with emotional and voluntary movements Suppression of facial reflexes Possible impairment of taste Possible abnormality of lacrimation
is explained by different pathways subserving these functions {Holstege 2002).
lateral orbital skin between the thumb and index finger and tapping the thumb with a reflex hammer. A similar bilateral blink response is present. The afferent impulses, howevet, atisc from stretch receptors in the muscle. Clinical Evaluation Anothct stretch reflex is the orbicularis oris reflex, elicited by percussing the uppet lip and producing elevation al of the lip and angle of the mouth. Like most othet myotatic The symptoms of facial nerve disease depend on several r, responses, these reflexes are diminished or abolished by factors, including size of lesion, severity of the disordet, re segmental dysfunction and preserved or heightened with acuteness of onset, and whether the lesion or lesions are a- bilateral corticobulbar lesions. bilateral or unilateral. A sudden severe unilateral infranuclear paralysis, as seen in Bell's palsy, produces (in in Bell's phenomenon is a true associated movement. With addition to an obvious cosmetic embarrassment) significant it attempted closure of the eyes against resistance, the globes dysarthria, pooling of saliva, drooling, and decreased sd move up and out. This normal movement can be observed tearing; it also allows food to collect between the gum and id with the incomplete eyelid closure in Bell's palsy. the cheek as a tesult of buccinator weakness. Depending on >n The stapedial reflex is particularly helpful in diagnosis. the size of the lesion, there may also be perversion of taste te Stapedius muscle contraction, activated by strong acoustic and hyperacusis. On the other hand, a moderate degtcc of af stimuli, pulls the stapes out of the round window, attenuatweakness of the lower face, as seen with a unilateral al ing intense sound waves. Reduction ot absence of this reflex corticobulbar lesion, may produce few complaints relative te results in hyperacusis or phono phobia. It can be quantified to the face, particularly if attention is distracted by >y by measuring acoustic impedance (see Chaptet 41) but can ipsilateral limb weakness or if language dysfunction is is be tested at the bedside using the stethoscope loudness present because of a dominant hemisphere lesion. Bilateral al imbalance test. A stethoscope is placed in the patient's ears, corticobulbar disease, as with multiple lacunae, is much :h and a gently vibrating tuning fork is placed on the bell. With more devastating to speech and swallowing functions. s. notmal hearing, the perception of sound is symmetrical. Unilatetal facial weakness of slow evolution, as seen with :h With greater activation, the sound laterali7.es to the side of a pontine glioma, may go unnoticed by a patient, although ;h the facial paresis (in some cases) because the attenuating it is obvious to the examinet. This is consistent with the ie effect of the stapedius muscle is reduced or absent. general clinical observation that objective neutological al The sensory functions of CN VII are not easily tested, arc deficits more apparent to the examiner than to the patient "it rather cumbersome, and are not always reliable. Testing are usually of gradual evolution. taste sensation is desctibed in Chapter 20. ig With any facial paresis, it must first be determined Facial reflexes may aid in establishing or localizing s, whether the lesion is affecting the upper motor neuron or lesions of the facial nerve. Some arc true myotatic reflexes, :>f the lower motor neuron. In most instances, it is obvious, and others represent associated movements. A variety of but when it is less clear, cettain critical observations can stimuli, such as noise, sudden light, and pain, can elicit a blink reflex that uncovers unilatetal facial weakness. usually settle the issue. The bilateral orbicularis oculi (blink or glabellar) reflex is is Upper motor neuron disorders with unilateral facial elicited by tapping over the supraorbital ridge or root of the ie paresis affect the voluntary movements of the lower face nose. It should be elicited by holding a hand over the top of if with relative sparing of the orbicularis oculi, frontalis, and the forehead, to avoid a visual blink response. With early, y, corrugator supercilii muscles. There are certain circummild, or resolving unilateral facial paresis, the ipsilateral a] stances in which this rule is violated: glabellar reflex is diminished. The afferent pathway is via the first division of CN V, with a rapid unilateral al During recovery from Bell's palsy, if the upper facial monosynaptic component and a delayed bilatetal polyfgroups recover before the lower groups, and if synaptic component. A variation of this reflex is the ie recovery is incomplete, as may occasionally occur in orbicularis oculi stretch teflex, elicited by gtasping the ie incomplete acute lesions
CRANIAL NEUROPATHIES
If nuclear lesions are restricted to the caudal portions of the nucleus, as in polio, and at some stages of motor neuron disease If an extracranial lesion involves only the lower division of the facial nerve, as sometimes happens after radical neck dissection or with parotid tumors In upper motor neuron lesions, there is preservation of the blink and stapedial reflexes; lacrimal and taste sensibilities also remain unimpaired. This may also be true for lower motor neuron lesions. If reflex functions are involved, however, this is strong evidence that the lesion is not upper motor neuron. In lower motor neuron lesions, the degree of weakness is the same with voluntary and emotional movements. With upper motot neuron involvement, particularly of the prefrontal cortex, the face is relatively symmetrical, with a normal emotional smile, and the movement of the involved side may actually be exaggerated, despite the unilateral weakness on voluntary contraction. The latter observation is probably the only one that consistently separates upper motor neuron from lower motor neuron lesions. A large number of congenital and acquired disease states may damage the facial nerve anywhere along its course, from its brainstem nuclear origin to its peripheral terminations in the face.
Congenital Disorders Congenital disotders of the facial nerve must be distinguished from traumatic damage to the facial nerve as a result of birth injury. Difficult forceps delivery, periauricular ecchymosis, hemotympanum, and swelling often provide clues to a traumatic cause, but many patients seem to have an uncomplicated birth history, In contrast to infants with traumatic facial paralysis, newborns with congenital disorders of facial palsy have a poor prognosis for improvement in facial nerve function. Clues pointing to a congenital cause may be other birth defect stigmata, especially microtia and external auditory canal atresia. Congenital malformations elsewhere in the body, such as limb deformity or hypoplasia of the pectoral muscle, also suggest a congenital cause for the facial palsy. There are a number of well-recognized syndromes of congenital facial palsy, including cardiofacial syndrome and Mobius' syndrome. Cardiofacial syndrome comprises facial asymmetry when crying but not at rest and may result from isolated weakness of the depressor anguli oris and depressor labii inferioris muscles of the lower lip. It does not interfere with smiling or sucking and does not result in drooling, but it may be associated with congenital heart defects and other anomalies. Mobius' syndrome consists of a spectrum of abnormalities; most cases occur on a sporadic or familial basis.
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The mutation in one large family with dominantly inherited Mobius' syndrome was mapped to the long arm of chromosome 3. The most consistent features arc congenital paresis of CNs VII and V1I1 with variable orofacial and limb malformation. Necropsy has shown defects ranging from hypoplasia to agenesis of the respective CN nuclei.
Toxins Peripheral facial paralysis may occur in thalidomide embryopathy. Medical and occupational exposure to the antiseptic solution chlorocreso), used in electrode paste and various dcrmatological skin ctcams, may produce transient facial paralysis. Ingestion of the antifreeze component ethylene glycol, eithet in a suicide attempt or for inebriation, may also cause bilateral peripheral facial weakness, either permanent ot temporary.
Traumatic Facial Palsy A peripheral facial paralysis occurring in the context of head trauma should always raise the possibility of basilar skull fracture. Basilar temporal bone fractures are generally categorized as eithet longitudinal (extending medially along the bony external canal) or transverse (crossing the long axis of the pettous pyramid). Both types of fracture may be accompanied by facial nerve palsy. Transient facial palsy may oivur 1:1 up in ?.(.)% or patients undergoing sphenoidal electrode insertion for prolonged video electroencephalographic monitoring. The mechanism is likely related to the effect of local anesthesia on the peripheral branches of the facial nerve.
Pregnancy Cohen et al. (2000) reviewed the occutrcncc of Bell's palsy in pregnancy. They concluded that (1) women of reproductive age are affected two to four times more often than men of the same age, (2) pregnant women are affected three times more often than nonpregnant patients, and (3) most cases occur in the third trimester or in the puerperium. The authors concluded neonatal outcome is unaffected, recovery is good, and treatment of the palsy with corticosteroids is conttoversial. In women developing Bell's palsy while pregnant, there is an increased risk of hypertensive disorders of pregnancy such as preeclampsia (Shmorgun, Chan, and Ray 2002)
Bilateral Facial Palsy Bilateral simultaneous peripheral facial weakness can be part of the clinical spectrum in several syndromes.
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NEUROLOGICAL DISEASES
Best known is the facial diplegia of varying intensity that accompanies the Guillain-Barre syndrome. Bilateral facial weakness in the presence of aseptic meningitis or with a slightly erythematous indurated face resembling painless cellulitis should raise the possibility of Lyme disease. The conjunction of Lyme aseptic meningitis and facial weakness is sometimes referred to as Banmuarth's syndrome. Recurrent bilateral facial palsy is also sometimes seen in sarcoidosis and at the time of seroconversion in human immunodeficiency virus infection. Keane (1994) provided an authoritative review on the topic of bilateral facial palsy. In his extensive series, 22 of the 44 patients reported had self-limited causes, including Bell's palsy and Guillain-Barre syndrome. Schattner et al. (2001) revisited the topic adding acute lymphoblastic leukemia to the differential diagnosis. Tumor involvement of the facial nerve itself is not common, but it remains an important consideration in the differential diagnosis, particularly with slowly progressive (over many days to several weeks) peripheral facia! weakness. Metastatic invasion of the temporal bone is the most common type. Breast, lung, and prostate are the most common primary tumors. Direct extension of regional tumors and primary schwannomas of the facial nerve also occur. In all these cases, the onset and course are slow and progressive. Parotid gland cysts and tumors, both benign and malignant, may involve terminal branches of the facial nerve that produce varying degrees of peripheral weakness. Obtaining a history of facial skin cancer in a patient presenting with a partial facial palsy or facial paresthesia is important because perineural spread of tumor can present long after "complete" excision of a skin malignancy (Catalano, Sen, and Biller 1995).
Bell's Palsy The appearance of a severe, unilateral, intranuclear facial palsy is one of the most distinctive in clinical medicine. The most common cause of an acute, acquired, nontraumatic lesion is Bell's palsy, in which there is a flaccid paresis of all mimetic muscles on the involved side. In a severe case, the affected side is smooth and the brow droops, but the palpebral fissure is widened. The angle of the mouth is depressed, and the cheek balloons on expitation. The lid remains open (lagophthalmos), and on attempted closure, the globe turns up and out (Bell's phenomenon). The lower lid is everted with excessive tearing (epiphora). Facial movements arc paralyzed to voluntary and involuntary contractions, and various facial reflexes are lost. Traditional teaching posits discrete anatomical localization along the various segments of CN VII in Bell's palsy based on the test results of taste, the stapedial reflex, lacrimation, and mandibular deviation. Although there may be some validity to these observations in early lesions, the localization is much less precise in practice. As a general rule, proximal
lesions at or before the geniculate ganglion may affect taste and lacrimation, as well as the stapedial reflex, whereas those distal to the geniculate ganglion produce only muscle weakness. The incidence of Bell's palsy in the general population is approximately 20 cases per 100,000, with a peak incidence in the third decade. The typical patient complains of an acute onset of facial palsy, which may evolve over 24-48 hours, often accompanied by retroauncular pain. This disorder affects males and females of all ages and is believed to be of viral origin (most often herpes simplex). It often begins with pain in or behind the ipsilatcral car, suggesting an ear infection. Unilateral weakness invariably follows within several days and usually achieves maximal paralysis within 48-72 hours. Patients may report tingling paresthesias on the involved side of the face early in the course, but this symptom is seldom prominent. Impairment of taste and hyperacusis (due to weakness of the stapedius muscle) is present in many cases. The oral phase of swallowing was found to be disturbed in 7 9 % of patients with Bell's palsy (Scc-il, Aydogdu, and Ertekin 2002) due primarily to weakness of the orbicularis oris and buccinator muscles, resulting in the accumulation of food in the mouth. MRI shows contrast enhancement of the involved nerve (Sartoretti-Schcfer ct al. 1998). Eighty to eighty-five percent of patients recover completely within 3 months of onset. Incomplete paralysis at the onset is perhaps the most favorable prognostic sign. Electrophysiological demonstration of lack of excitability of the facial nerve to electrical stimulation and electromyographic evidence of denervation of the involved facial muscles after 2 - 3 weeks establish severe axon loss. This implies a more prolonged and probably incomplete recovery, with risk of aberrant regeneration of the facial nerve fibers. Har-El and McPhee (2000) have successfully employed transcranial magnetic stimulation in the laboratory to determine the integrity of the facia! nerve immediately after trauma, bypassing the time limitations imposed by wallerian degeneration. The prognosis is less favorable in the syndrome of facial nerve palsy with geniculate herpes (Ramsay Hunt syndrome), which involves pain and vesicles in the external auditory canal or soft palate. Scvcdia-Cayabyab and Spaeey (2002) have documented recurring Bell's palsy secondary to herpes zoster infection; acyclovir treatment produced cessation of the episodes. This report adds herpes zoster to the differential diagnosis of recurrent Bell's palsy along with sarcoid and Lyme disease. Recurrent Bell's palsy may be associated with a deeply furrowed tongue (lingua plicata) and recurrent facial edema in Melkersson's syndrome; the prognosis is initially good, but permanent paralysis may eventually result after many recurrences. Aberrant regeneration may have several variations, rhe most prominent being involuntary tearing of the eye on the involved side when eating ("crocodile tears") or synkinesis of the facial musculature when chewing. This often takes the form of a jaw-winking phenomenon, wherein the lid
CRANIAL NEUROPATHIES
closes on the involved side when the jaw opens (MarinAmat syndrome). The onset of Bell's palsy in an elderly person should prompt the physician to consider the possibility of diabetes or hypertension before the administration of prednisone, which is an often prescribed but controversial treatment.
Infections Infection of the central nervous system by Borrelia burgdorferi (Lyme meningitis) is an increasingly recognized cause of peripheral nerve weakness in endemic areas. Leprosy also affects the facial nerve (see Chapter 59A).
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Clinical Features Isolated lesions of the glossopharyngeal nerve are extremely uncommon. Almost invariably, involvement of this nerve occurs in conjunction with that of the vagus, accessory, and hypoglossal nerves. Isolated paralysis of the glossopharyngeal nerve produces slight and usually transient difficulty in swallowing, due to involvement of the stylopharyngeus muscle, and temporary decrease in parotid gland secretions. Peripheral dysfunction of the nerve may be due to blunt neck trauma, such as nonfatal suicidal hanging, diseases of the middle ear, and pharyngeal abscesses.
Glossopharyngeal Neuralgia Hemifacial Spasm In hemifacial spasm, there are recurring episodes of involuntary unilateral spasms of the facial musculature invariably beginning about the lateral canthus of the eye on the involved side and gradually spreading downward, over many months to several years to involve the remainder of the facial musculature. Although mass lesions such as meningioma are rarely encountered as the etiology, Janetta has documented the common cause to be neurovasculature compression from a redundant vascular loop. Hypertension appears to be a predisposing factor if the hemifacial spasm occurs on the left but not the right side of the face (DeFazio ct al. 2000).
COCHLEAR-VESTIBULAR NERVE (CRANIAL NERVE Vm) See Chapters 18, 19, and 4 1 .
GLOSSOPHARYNGEAL NERVE (CRANIAL NERVE DC) Neuroanatomy Fibers of the glossopharyngeal nerve, or CN IX, originate from several nuclear complexes (tractus solitarius [gustatory nucleus], nucleus ambiguus, and inferior salivatory nucleus) in the brainstem. They pass outward as several distinct subsets of fibers, to emerge from the medulla between the inferior olive and the inferior cerebellar peduncle, caudal to the seventh CN and rostral to the U'lidi (:N. UN IX exits the skull through the jugular foramen along with CN X and CN XI and comes to lie between the internal jugular vein and the internal carotid artery (Remley and Latchaw 1993). It ultimately reaches the lateral wall of the pharynx by tracking along the inferior border of the srylopharyngeus muscle.
See Chapter 75.
VAGUS NERVE (CRANIAL NERVE X) Neuroanatomy The vagus nerve is the longest of all the CNs. In many respects, its origins and functions are similar to those of the glossopharyngeal nerve. The motor fibers of the vagus arise from the nucleus ambiguus and the dorsal motor nucleus of the vagus. The sensory portions have cell bodies of origin in the jugular and nodose ganglia. Exiting the skull through the jugular foramen, the vagus travels within the carotid sheath between the internal jugular vein and the carotid artery, giving off pharyngeal branches and superior and inferior (recurrent) laryngeal nerves (Remley and Latchaw 1993), Spontaneous dissection of the internal carotid artery may present with an isolated vagal neuropathy (Moussouttas a n d T u h n m 1998).
Brainstem Lesions Supranuclear involvement of the vagus nerve is significant only when it is bilateral, producing a pseudobulbar-type syndrome with dysphagia and dysarthria. Nuclear involvement of the vagus nerve may be encountered as part of motor neuron disease in patients with progressive bulbar palsy. Poliomyelitis and primary brainstem neoplasms may also produce dysfunction at a nuclear level. (See Chapter 22 for a fuller discussion of brainstem lesions affecting the vagus nerve.) Vascular lesions within the medulla may involve the vagus nerve. Wallenberg's syndrome is the most common presentation, with the acute onset ni v.r.;'.ul:i -> (lineup), vertigo, and ataxia. On examination, an ipsilateral Horner's syndrome, crossed (ipsilateral face and contralateral body) loss of pain and temperature sensation,
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NEUROLOGICAL DISEASES
ipsilateral cerebellar tremor, and weakness of the ipsilateral oral pharynx constitute the clinical picture.
Systemic Disorders Vagal nerve dysfunction with vocal cord paresis is sometimes the initial manifestation of multiple system atrophy (see Chapters 77 and 83). The recurrent laryngeal branches of the vagus nerve may be damaged as a result of primary thoracic disease, the left more often than the right because it is longer. Of clinical value in localizing lesion sites in vagal disease is that the pharyngeal branches depart the vagus high in the neck; therefore the absence of sensory changes in the pharynx suggests that the lesion is below this level. Tumors of the mediastinum and lung are the most common causes of an isolated vocal cord palsy. Cytomegalovirus infection of the laryngeal nerves with hoarseness may occur in patients with acquired immunodeficiency syndrome.
Sl'INAL ACCESSORY NERVE (CRANIAL NERVE XI) Neuroanatomy The spinal accessory nerve is entirely motor in function and composed of two portions: a smaller cranial part ("accessory" to the vagus) and the larger spinal portion (arising from the upper five cervical cord segments). The cranial portion, with the vagus and glossopharyngeal nerves, supplies the musculature of the pharynx and larynx, whereas the spinal portion innervates the sternocleidomastoid and upper portions of the trapezius musculature. The spinal portion emerges as a series of rootlets between the dentate ligament and the dorsal horns of rhe spinal cord. Merging, they ascend and pass through the foramen magnum. Here they join the accessory rootlet originating from the nucleus ambiguus in the caudal medulla oblongata. These fused components then pass through the jugular foramen with CN TX and CN X. After exiting the skull, a branch travels with the vagus, and the spinal accessory nerve proper continues, supplying the sternocleidomastoid and trapezius muscles (Figure 76.2). The principal action of the sternocleidomastoid draws the occiput toward the side of the contraction, rotating the face to the opposite side. Contracting together, the sternocleidomastoid muscles flex the cervical spine. The upper trapezius retracts the head and elevates, retracts, and rotates the scapula; it also elevates the abducted arm above the horizontal. With bilateral contraction, the head draws back and the face up. The trapezius is also innervated by branches of the cervical plexus. The supranuclear innervation is complex. Corticobulhar fibers to the trapezius are principally crossed, but fibers destined for the sternocleidomastoid terminate predominantly in the ipsilateral nuclei (De Toledo and Dow 1998),
FIGURE 76.2 Course and distribution of the spinal accessory nerve. (Reprinted with permission from House, E. L. &: Pansky, R. 1967, A Functional Approach to Neuroanatomy, 2nd ed, McGraw-Hill, New York.)
Although the spinal accessory nerve is regarded as purely a motor nerve, the symptoms of its dysfunction are both motor and sensory, the latter being predominantly pam. In acute lesions, traumatic or inflammatory, the pain is steady, severe, and localized to the neck and top of the shoulder. Pain, however, may be delayed until the patient starts to use the arm. Paresthesias arc common and often diffuse, taking the form of pins and needles, coldness, and throbbing sensations. When the sternocleidomastoid muscle is involved unilaterally, there is loss of bulk, which is best demonstrated by turning the chin against resistance (Figure 76.3). The findings with a unilateral lesion include an obvious drooping of the affected shoulder. With the arms hanging loosely at the sides, the fingertips touch the thigh at a lower level on the affected side. Winging of the scapula is due to paresis of the middle trapezius muscle, whereas loss of abduction more than 90 degrees is due to weakness of the upper trapezius. Winging due to trapezius palsy is more prominent with abduction of the arm; the superior angle of the scapula moves farther from the midline (Figure 76,4), Wirh a long thoracic nerve lesion, the winging is increased with forward flexion of the arm. Evaluating supranuclear lesions may be confusing because of the ipsilateral innervation of the sternocleidomastoid muscle. In hemispheric lesions, the weakness of the sternocleidomastoid is on the same side as the lesion (De Toledo and Dow 1998). If this is not recognized, the signs
CRANIAL NEUROPATHIES
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FIGURE 76.4 Spinal accessory lesion on attempted abduction of the left arm, demonstrating scapular winging.
1'IGURE 76.3 (A) Normal left sternocleidomastoid muscle with forceful thrust of chin to the right. Note the prominent left sternocleidomastoid muscle. (B) The same maneuver as that shown in A, but to the left, showing loss of bulk of the right sternocleidomastoid muscle.
may indicate that the patient with a left hemiparesis has a right accessory nerve lesion and therefore a lower brainstem problem rather than a more rostral lesion. Cortical, capsular, and high brainstem lesions affecting the corticobulbar fibers may result in decreased strength on turning the head away from the side of the lesion. Dissociated weakness may also cause confusion when the sternocleidomastoid muscle is involved and the trapezius is not.
Etiology and Management The most common cause of eleventh nerve palsies are iatrogenic, secondary to nerve injury during surgery involving the posterior triangle, particularly lymph node biopsies. The symptoms are often delayed for 1-2 weeks, followed by pain and weakness. If hiss ol function is complete or the extent of the lesion is unknown, exploration with reanastomosis of the nerve is probably the best approach. Electrodiagnosis with nerve conduction studies
and needle examination done after the third week postinjury may assist in determining whether the lesion is partial or complete. Traumatic lesions other than those with iatrogenic causes include shoulder injuries, bites, stretching of the nerve, and radiation. Supranuclear involvement, as from stroke, usually causes only modest dysfunction of CN XI, manifested by contralateral drooping of the shoulder and weakness of the upper portions of the trapezius muscle, as well as weakness of head turning away from the side of the hemispheric lesion. Nuclear involvement of CN XI occurs in motor neuron disease, syringobulbia, and syringomyelia and is associated with muscle paresis, atrophy, and fasciculations, A large group of named syndromes (Table 76.3) occurs with involvement of this nerve and other medullary structures. Isolated peripheral involvement is uncommon and, as with central involvement, is usually attended by evidence of involvement of other structures. Causes include internal jugulai \ cm C.UIIHII.IILOII. biting injures n> the neck, shoulder dislocation, unsuccessful attempts at suicidal hanging, and radical neck dissection. Selective trapezius involvement has occurred in patients undergoing carotid endartcrectomy; traction on the sternocleidomastoid muscle during surgery may produce stretch injury to the branch to die trapezius. In myotonic dystrophy, atrophy of the sternocleidomastoid muscle, simulating selective spinal accessory nerve involvement, is prominent. A benign self-limited isolated paralysis of the eleventh CN may be analogous to other types of spontaneous and restricted neuropathies, such as Bell's palsy or long thoracic nerve palsy. An abrupt onset of sharp pain localized to the posterior sternocleidomastoid region is followed by resolution of the pain and the typical features of an accessory nerve lesion, with winging of the scapula and drooping of the affected shoulder. Matz and Barbara (1996) and London, London, and Kay (1996) provide excellent reviews of the diagnosis and treatment of iatrogenic spinal accessory nerve injury.
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Table 76.3:
Syndromes of the upper, middle, and lower cranial nerves
Syndromes
Cranial nerve involvement
Clinical abnormalities
Weber's
III
Benedikt's
III
Tolosa-Hunt
Varying combinations of III, IV, V (ophthalmic or maxillary) and VI VI and Vll
Oculomotor palsy with contralateral hemiplegia due to pyramidal tract involvement at the base of the midbrain Oculomotor palsy with contralateral corticospinal signs, tremor, and cerebellar ataxia due to involvement of the red nucleus and the corticospinal tract Multiple designated cranial nerve palsies with cavernous sinus lesions; coexisting optic nerve dysfunction suggests a distal cavernous sinus, superior orbital fissure locus
Millard-Gubler and Fovilie's Verntt's (jugular foramen) Schmidt's
IX, X, and XI
Tapia's
X and XII
Jackson's
X, XI, and XII
Collet-Sicard
IX, X, XI, and XII
Villaret's
IX, X, XI, XII, and cervical sympathetic
X and XI
Combinations of ahducens and peripheral facial palsies and contralateral hemiplegia from pontine lesion; sometimes a gaze palsy to the side of a lesion (Foville's) Loss of taste at the posterior one third of tongue; paralysis of the VC, palate, and pharynx; paralysis of trapezius plus SCM Paralysis oi the -. • H IL p.il.iK', pli.ir yu\. ,nnl MIVIU; i ----- i I. i L . i .il u i/akncss of the trapezius and SCM Paralysis of the pharynx and larynx; paralysis and atrophy of die tongue Patesis of the palate, pharynx, and larynx; paresis of the trapezius and SCM; paresis and atrophy of the tongue Anesthesia of the palate; paresis of the VC and palate; weakness of the trapezius and SCM; paresis and atrophy of the tongue; hemianesthesia of the pharynx and larynx Same as Collet-Sicard, plus Horner's syndrome
Note: Unless otherwise noted, the clinical abnormality is ipsilateral to the involved nerve or nerves. SCM = sternocleidomastoid; VC = vocal cord.
HYPOGLOSSAL NERVE (CRANIAL NERVE XII) Neuroanatomy A purely motor nerve, the hypoglossal nerve (CN XII) supplies innervation to the extrinsic and intrinsic muscles of the tongue. Arising from the hypoglossal nucleus beneath the floor of the fourth ventricle in the caudal medulla, it courses ventrally through the brainstem to exit between the pyramidal tract and the olivary eminence. The rootlets coalesce and pass through the hypoglossal canal to exit the skull. The nerve travels briefly with the ninth, tenth, and eleventh CNs before it separates at approximately the mastoid level and passes on to the tongue musculature (Figure 76.5). A lesion of the hypoglossal nerve causes ipsilateral weakness and wasting of the tongue, which deviates to the weak side when protruded.
Clinical Syndromes Isolated involvement is rare but occasionally occurs in the context of inadvertent nerve trauma incurred at the time of carotid endarterectomy because of the proximity of CN XII to the carotid bifurcation; the dysfunction is usually temporary.
The review by Keane (1996) of 100 cases of twelfth nerve palsy provides an overview of common etiologies for dysfunction in CN XII. Tumors, predominantly malignant, produced nearly one half of the palsies (49 cases). Gunshot wounds made trauma the second most common cause (12 cases), and stroke (6 cases) the third. Aneurysms or dissection of the carotid artery may selectively compress the twelfth CN (Lemmerling et al. 1996). Primary bony disease and malformations affecting the base of the skull (as seen with platyhasia and Pager's disease) may produce mechanical damage to the nerve. Giuffrida et al. (2000) emphasized that after appropriate exclusionary studies, a transient twelfth nerve palsy can be encountered that is analogous to the more common and invariably benign seventh nerve Bell's palsy. Keane (2000) also reviewed his extensive experience with combined twelfth and sixth nerve palsies. He confirmed the observation made in 1947 by Godtfrcdsen that combined dysfunction of these two CNs (Godtfredsen's syndrome) suggests the presence of an aggressive tumor. In Kcane's experience, a metastatic lesion to the clivus was the most common etiology, followed by nasopharyngeal carcinoma that was infiltrating posteriorly. Vertebrobasilar vascular disease may produce an ipsilateral hypoglossal paralysis (medial medullary syndrome) (see Chapter 22). In medial medullary syndrome, as a result of occlusion of cither the vertebral arterv or the anterior
CRANIAL NEUROPATHIES
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FIGURE 76.5 Origin, course, and distribution of the hypoglossal nerve. (Reprinted with permission from Mouse, E. L. & Pansky, B. 1967, A Functional Approach to Neuroanatomy, 2nd ed, McGraw-Hill, New York.)
spinal artery high in the neck, there is ipsilateral paralysis of the tongue (nucleus or root fibers), with a contralateral corticospinal tract lesion causing paresis of the arm and leg. The syndrome also involves diminished proprioceptive and tactile sense caused by medial lemniscus involvement. Motor neuron disease and poliomyelitis may involve the hypoglossal nuclei, causing progressive tongue atrophy with fasciculations.
JUGULAR FORAMEN SYNDROME This section covers the lower CN syndromes when they are affected as a group.
Neuroanatomy The jugular foramen is located between the lateral portion of the occipital bone and the petrous portion of the temporal hone. It is a canal coursing anteriorly, inferiorly, and laterally in an intracranial-to-extracranial projection. Two compartments of the foramen are recognized. The anteromedial compartment (the pan nervosa) contains the inferior petrosal sinus and the glossopharyngeal nerve. The pars venosa contains the vagus and accessory nerves, as well as a portion of the jugular bulb. There are many variations on this theme, and there is no agreement on position of the nerves in the jugular foramen or on the constancy of the separation of these compartments. After exiting the cranial base, CN IX is anterolateral and CN XI medial and next to the carotid sheath. CN X runs deeper between the internal jugular vein and internal carotid artery (Lustig and Jacklcr 1996). Upon leaving the jugular foramen, the three CNs enter the posterior retropharyngeal space, along with CN XII. This space is bordered posteriorly by the cervical spine, medially by the pharynx, anteriorly by the parotid gland and muscles attached to the styloid
process, and superiorly by the base of the skull and the jugular foramen. The space contains the last four CNs, the internal jugular vein, the carotid artery, and the cervical sympathetic nerves. After exiting this space, the nerves separate and follow their individual courses.
Clinical Features and Etiology The most common causes of the jugular foramen and allied syndromes are primary and metastatic tumors, vascular lesions, trauma, inflammatory, and iatrogenic lesions. The most common primary tumors are schwannomas, glomus tumors, and meningiomas. Schwannomas constitute approximately 2 5 % of all tumors in the head and neck, but schwannomas of nerves IX, X, and XI, in the absence of neurofibromatosis, arc decidedly rare, constituting approximately 3% of all intracranial schwannomas. A neuroirnaging review of the appearance of schwannomas of the jugular foramen (Eldevjk, Gabrielson, and Jacobsen 2000) emphasized a characteristic picture with a sharply demarcated, contrast-enhancing lesion enlarging the jugular foramen with rounded bony borders and a sclerotic rim. Schwannomas are more common in women, with the average age at diagnosis in the fourth decade. The symptoms generally manifest when the tumor is large and are determined by both origin and size of the tumor. Most cases present with hearing loss and dizziness indistinguishable from acoustic neuroma. Other presentations are the jugular foramen syndrome or a neck mass. The clinical signs indicate dysfunction of CNs IX, X, and XI in 80%, hearing loss in 70%, and facial palsy in 2 5 % . Contemporary diagnosis of these tumors involves both computed tomographic scan and MR], Glomus jugulare tumor is a highly vascular tumor that may involve the glossopharyngeal nerve, as well as the other nerves (vagus and accessory) traversing the jugular foramen, and can enlarge sufficiently to damage the facial
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and hypoglossal nerves. T h e patient usually presents with pulsatile tinnitus followed by conductive hearing loss, Because the t u m o r partially or completely occludes t h e intravascular p o r t i o n of the jugular vein, the patient m a y also present with increased intracranial pressure. O t h e r s y m p t o m s e n c o m p a s s a s p e c t r u m of nonspecific dizziness, he.ill lehe, .nil c.iMehe. Otolo:'jcal e v i m i n . i n o r ~omerimes reveals the pulsating d a r k red lesion behind the e a r d r u m . Biopsy of these t u m o r s is contraindicated because of their hypervascularity. T r e a t m e n t often consists of initial r a d i o therapy, followed if necessary by surgical removal of the t u m o r en bloc with the jugular bulb. The most c o m m o n neoplastic causes of jugular foramen s y n d r o m e are either p r i m a r y n a s o p h a r y n g e a l t u m o r s t h a t spread locally to the cranial base or distant metastases from breast, Ling, prostate, and K m p h tissue. Villarer's s y n d r o m e consists of unilateral lesions of the last four C N s (IX-XII) and I lorner's s y n d r o m e (see T a b i c 763). T h e s y n d r o m e results from lesions occupying the posterior retropharyngeal space, such as parotid t u m o r s , enlarged l y m p h n o d e s , nasopharyngeal carcinomas, pharyngeal abscesses, carotid artery a n e u r y s m s , g i a n t cell arteritis, and penetrating w o u n d t r a u m a (Tiliket et al. 1996).
REFERENCES \ ii ii, I I.I m n:, VI. cv Repk,; . M. \. 1 ' ' ' ' y "On:-, •.-:n- !•: -,i\[li in • vv palsy or paresis in young children," J Pediatr Ophthalmol Strabismus, vol. .32, pp. 152-156 Berlir, P., Berg-Dammer, E., Sc Kuehne, D. 1994, "Abducens nerve palsy in spontaneous intracranial hypotension," Neurology, vol. 44, p, 1552 Catalano, P. J., Sen, C, & Biller, H. F. 1995, "Cranial neuropathy secondary to perineural spread of cutaneous malignancies," Am j Otol, vol. 16, pp. 772-777 Cohen, Y„ Lavie. O., Granovskj-Grisaur, S., ct al. 2000, "Bell's palsy complicating pregnancy: A review," Obstet Gynecol Surf, vol. 55, pp. 184-188 De Toledo, J. C. & Dow, R. 1998, "Srornomasroid function during hemispheric suppression by Amytal: Insights into the inputs to the spinal accessory nerve nucleus," Mov Disord, vol. 13, pp. 809-812 DeFazio, G., Berardelli, A., Abburu/zese, G., et al. 2000, "Primary hemifacial spasm and arterial hypertension: A multi center casecontrol study," Neurology, vol, 54, pp. 1198-1200 Eldevik, O. P., Gabrielson, O., Sc Jacohsen, I-".. A, 2000, "imaging findings in schwannomas of the jugular foramen," AjNR Am ] Neuroradiol, vol. 2 1 , pp. 1139-1144 Fischoff, D. K. & Sirois, D. 2000, "Painful Trigeminal neuroparhy caused by severe mandibular resorption and nerve compression in a patient with systemic sclerosis," Oral Surg Oral Med Oral Pathol Oral Radiol Endod, vol. 90, pp. 456-459 Forster, C, Brandt, T, Hund, E., et al. 1996, "Trigeminal sensory neuropathy in connective rissue disease: Evidence for the sire of rhc lesion," Neurology', vol. 46, pp. 270-271 Giuffrida, S., LoBartolo, M. L., Nicoletti, A., et al. 2000, "Isolated, unilateral, reversible palsy of the hypoglossal nerve," l.ur j Neurol, vol, 7, pp. 347-349
Har-FI, G. Sc McPhce, J. R. 2000, "Transcranial magnetic stimulation in acute facial nerve injury," Laryngoscope, vol, 110, pp. 1105-1111 Holstegc, G. 2002, "Emotional innervation of facial musculature," Mov Disord, vol. 17, suppl. 2, pp. S12-S16 Jacobsen, D. M., Warner, J. J., & Ruggles, K. H. 1995, "Transient trochlear nerve palsies following anterior temporal lobectomy for epilepsy," Neurology, vol. 45, pp. 1465-1468 Keane, J. R. 1994, "Bilareral seventh nerve palsy: Analysis of 43 cases and review of the lirerature," Neurology, vol. 44, pp. 1198-1202 Keane, J. R. 1996, "Twelfth nerve palsy. Analysis of 100 cases," Arch Neurol, vol. 53, pp. 561-566 Keane, J. R. 2000, "Combined Vlth and Xllth cranial nerve palsies: A clival syndrome," Neurology, vol. 54, pp. 1540-1541 Laxton, C. II, & Kipling, R. 1996, "Lingual nerve paralysis following rhc use of the laryngeal mask airway," Anesthesia, vol. 561, pp. 869-870 Lemmerling, M., Crevitis, L., Defreyne, L., et al. 1996, "Traumatic dissection of the internal carotid artery as an unusual cause of hypoglossal nerve dysfunction," Clin Neurol Neurosurg, vol. 98, pp. 52-54 London, J„ London, N. J., & Kay, S. P. 1996, "Iatrogenic accessory nerve injury," Ann R Coll Surg Engl, vol. 78, pp. 146-150 Lustig, L. R. &C Jackler, R. K. 1996, "The variable relationship between the lower cranial nerves and jugular foramen rumors: implications for neural preservation," Am j Otol, vol. 17, suppl. 4, pp. 658-668 Markinovic, S. He Gibo, H. 1994, "The neurovascular relationships and the blood supply of the oculomotor nerve: The microsurgical anatomy of its cisternal segment," Surg Neurol, vol. 42, pp. 505-516 Matz, P. E. & Barbaro, N. M. 1996, "Diagnosis and treatment of iatrogenic spinal accessory nerve injury," Am Surg, vol. 62, pp. 682-685 McClcane, G. J. 2000, "Lamotrigine in the management of neuropathic pain: A review of the literature," Clin ] Pain, vol. 16, pp. 321-326 Morecraft, R. J., Louie, J. L., Herrick, J. L., & Stilwell-Morecraft, K. S. 2001, "Corrical innervation of the facial nucleus in the non-human primate: A new interpretarion of the effects of stroke and related subtotal brain trauma on the muscles of facial expression," llrain, vol. 124, pp. 176-208 Moussouttas, M. £c Tuhrim, S. 1998, "Sponraneous inrernal carotid artery dissection with isolated vagus nerve deficit," Neurology, vol. 5 1 , pp. 317-318 Read, S, J., Crawford, D. H. F., & Pender, M. P. 1995, "Trigeminal sensory neuropathy induced by interferon alpha therapy," Aust N Z / Med, vol. 25, p. 54 Remley, K. B. & Latchaw, R. E. 1993, "Imaging of cranial nerves IX, X and XL Functional anatomy and pathology," Neuroimagmg Clin North Am, vol, 3, pp. 171-192 Russo, C. P., Smoker, W. R., & Weissman, j. L. 1997, " M R appearance of trigeminal and hypoglossal motor denervation," AJNR AmJNeuraradiol, vol. 18, pp. 1375-1383 Sartorerti-Schefer, S., Kollias, S., Wichmann, W., & Valavanis, A. 1998, "T2-wcighted three-dimensional fast spin-echo MR in inflammarory peripheral facial nerve palsy," AjNR Am j Neuroradiol, vol. 19, pp. 491 -495 Schartner, A., Koz.ack, N., Sandler, A., et al. 2001, "Facial diplegia as the presenting manifesration of acure lymphoblastic leukemia," Mt Sinai J of Med, vol. 68, pp. 406-409
CKANlAl NEUROPATHIES Secil, Y., Aydogdu, I., & Ertekin, C, 2002, "Peripheral facial palsy and dysfunction of the oropharynx,' 1 / Neurol Neuromrg Psychiatry, vol. 72, pp. 391-393 Sevedia-Cayabyab, S. & Spacey, S. D. 2002, Can j Neurol Sci, vol. 29, suppl. 1, pp. S58-S59 Shmorgun, D., Chan, W. S., & Ray, J. G. 2002, "Association between Bell's palsy and pregnancy and preeclampsia," Q } Med, vol. 95, pp. 359-362 Sicenica, T., Venkata Balaji, G., Klein, A., ct al. 2000, "Villaret's syndrome in a man with prostate carcinoma," Am J Med, vol. 108, suppl. 6, pp. 516-517 Silverman, I. E., Lui, G. T., & Galetta, S. L. 1995, "The crossed paralyses. The original brain-stem syndromes of Miller-Gubler,
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Foville, Weber and Raymond-Cestan," Arch Neurol, vol. 52, pp. 635-638 Su, C. Y. & Lui, C. C. 1996, "Perineural invasion of the trigeminal nerve in patients with nasopharyngeal carcinoma," Cancer, vol. 78, pp. 2063-2069 Tiliket, C, Pctitot, P., Arpin, D., et al. 1996, "Clinical and radiological aspects of Villaret's syndrome," Clin Neurol Neurosurg, vol. 98, suppl. 2, pp. 194-196 Trobe, J. D. 1998, "Managing oculomotor nerve palsy," Arch Ophthalmol, vol. 116, pp. 723-727 Urban, P. P., Wicht, S., Marx, J., et al. 1 998, "Isolated voluntary facial paresis due to pontine ischemia," Neurology, vol. 50, pp. 1859-1862
Chapter 77 Movement Disorders Kathleen M. Shannon Movement Disorders and the Basal Ganglia Basal Ganglia Anatomy Functional Organization of the Basal Ganglia and
Other Pathways Biochemistry Neurodegeneration and "Toxic Proteins" Parkinsonian Syndromes Parkinson's Disease (Idiopathic Parkinson's Disease, Paralysis Agitans) Genetic Parkinsonisms Dementia with Lewy Bodies Multiple System Atrophy Progressive Supranuclear Palsy Cortieobasal Degeneration Frontotemporal Degeneration with Parkinsonism Linked to Chromosome 17 Bilateral SrriatopalJidodentate Calcification (Fahr's Disease) Parkinsonism-Pementia Complex of Guam Guadeloupean Parkinsonism Vascular Parkinsonism (Lower Half Parkinsonism) Postencephalitic Parkinsonism Drug-Induced Parkinsonism Toxin-Induced Parkinsonism Tremor Physiological Tremor Kssential Tremor Dystonic Tremor Primary Writing Tremor Orthostatic Tremor Neuropathic Tremor Cerebellar Tremor Fragile X Premutation Palatal Tremor Chorea Huntington's Disease Dentatorubral-Pallidoluysian Atrophy (Haw River Syndrome)
2125 2126
2126 2 I 29 2130 2131 2131 2139 2140 2140 2141 2142 2142 2143 2143 2143 2143 2143 2144 '111 2144 2144 2144 2146 2146 2147 2147 2147 2147 2147 2148 2148
Neuroaeanthocytosis and the Mcl.eod Syndrome Benign Hereditary Chorea Sydenham's Chorea Ballismus (Hemiballismus, Hemichorea) Senile Chorea Tardive Dyskinesia Dystonia Childhood-Onset Generalized Primary Dystonia Adult-Onset Primary Focal and Segmental Dystonia X-Linked Dystonia-Parkinson ism (DYT3; Lubag's Syndrome) Dopa-Responsive Dystonia (DYT5) Myoclonus Dystonia (DYT11) Rapid-Onset Dystonia Parkinsonism (DYT12) Wilson's Disease (Hepatolenticular Degeneration) Post-Traumatic Dystonia Tardive Dystonia Paroxysmal Kinesigcnic Dyskinesia (DYT10) Paroxysmal Nonkinesigenic Dyskinesia (DYT8) Secondary Paroxysmal Dyskinesia Tics Tourette's Syndrome Adult-Onset Tics Postinfectious Autoimmune Ncuropsychiatric Disorders Associated with Streptococcal Exposure Myoclonus Essential Myoclonus Hereditary Geniospasm (Chin Tremor) Posthypoxic Myoclonus (Lance-Adams Syndrome) Startle and Hyperekplexia Spinal Myoclonus and Propriospinal Myoclonus Toxin- and Drug-Induced Myoclonus Miscellaneous Movement Disorders Hemifacial Spasm Painful Legs-Moving Toes Syndrome Stiff Person Syndrome Psychogenic Movement Disorders
2152 2153 2153 2153 2154 2154 2155 2155 2156 2157 2158 2158 2158 2159 2160 2160 2160 2161 2161 2161 2161 2162 2162 2162 2162 2162 2163 2Id3 2163 2164 2164 2164 2165 2165 2165
2152
M O V E M E N T D I S O R D E R S A N D T H E BASAL GANGLIA Neurologists often equate m o v e m e n t disorders with disease or dysfunction of the basal ganglia, a n d no c h a p t e r on inn: emcnl disorders would be complete without .: dis cussion of basal ganglia a n a t o m y , physiology, a n d p a t h o physiology. T h e implied connection is a n a t u r a l one. In some m o v e m e n t disorders, such a s p a r k i n s o n i s m , c h o r e a , a n d ballism, the link to the basal ganglia is s u p p o r t e d by climcopathological, biochemical, functional n e u r o i m a g i n g ,
a n d electrophysiological d a t a , w h e r e a s in o t h e r m o v e m e n t d i s o r d e r s , such as t r e m o r , d y s t o n i a , a n d tics, dysfunction of the basal ganglia is implied b u t n o t p r o v e n . Clinicopathologica! studies relate' [he ^ g n s ol P.irkinson's disease (PD) to deficient d o p a m i n e r g i c n e u r o t r a n s m i s s i o n in t h e striatum c o n s e q u e n t to the d e a t h of d o p a m i n e r g i c n e u r o n s in the substantia nigra p a r s c o m p a c t a (SNc). Choreic m o v e m e n t s in H u n t i n g t o n ' s disease ( H D ) a r e linked to the d e a t h of m e d i u m spiny n e u r o n s in the c a u d a t e and p u t a m e n . I Icmiballism is typically associated with structural lesions in t h e c o n t r a l a t e r a l s u b t h a l a m i c nucleus (STN) or its afferent 2125
2nd
NFUROLOCICAI
IMSFASIS
or efferent connections. Changes in basal ganglia neurotransmission are well described in many movement disorders, and deepening understanding of basal ganglia neurotransmission has yielded promising symptomatic therapies in many such conditions. Functional ncuroimaging studies with specific radiopharmaceutical agents demonstrate abnormal function of basal ganglia structures, and intraoperative electrophysiology studies demonstrate abnormalities in neuronal firing rates and patterns in the STN and globus pallidus (GP) in parkinsonism and chorea. Animal models, including the l-methyl-4-phenyl-1,2,3,6-tetrahydropyridinc (MPTP) model of PD, excitotoxic and transgenic models of HD, and the STN lesion model of hemiballismus (HIS) confirm the central role of disordered basal ganglia function in these conditions. In other movement disorders, such as dystonia, the link with basal ganglia function is more complex. For example, although secondary dystonias may result from structural lesions in the contralateral putamen, other sites of pathology include the thalamus, rostral brainstem, and cerebellum. Functional ncuroimaging studies in patients with dystonia show abnormal activation of the lenticular nucleus, but also the cortex, brainstem, and cerebellum. In other movement disorders, such as essential tremor (ET), stiff person syndrome (SPS), and hemifacial spasm, we now know the dysfunction lies outside of the basal ganglia, often in the brainstem, cerebellum, spinal cord, or even in the peripheral nervous system.
Basal Ganglia Anatomy There is no clear consensus on which structures should be included in the basal ganglia. For the purposes of this discussion, we consider those structures in the striatopallidal circuits involved in modulation of the thalamocortical projection—the caudate nucleus, the putamen, the external segment of the GP (GPe), and the internal segment of the GP {GPi). In addition, we consider related structures, the two divisions of the SN (the pars compacta [SNc] and the pars reticulata [SNrP, and the STN. The caudate nucleus is a curved structute that traverses the deep hemisphere at the lateral edge of each lateral ventricle. Its diameter is largest at its head, tapering to a small tail. It is continuous with the putamen at the head and tail. The caudate and putamen together arc called the striatum, and they form the major target for projections from the cerebral cortex and the SN. The putamen and the GP together form a wedge-shaped structure called the lenticular nucleus. The GP is divided into two parts, the GPe and the GPL The GPi is structurally and functionally homologous with the SNr. The SNr and SNc extend the length of the midbrain ventral to the red nucleus and dorsal to the cerebral peduncles. The STN is a small lens-shaped structure at the border of the brainstem and cerebrum. The basal ganglia and its relation to the thalamus and overlying cortex are illustrated in Figure 77.1.
Area
Area 6
FIGURE 77.1 Schematic tint wing of the interconnections between the basal ganglia and its afferent and efferent connections. C, P — caudate putamen; GPI = lateral (external) globus pallidus; GPm = medial (internal) globus pallidus; Sth = subthalamic nucleus; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata; SC = superior eolliculus; T = thalamus; VA = ventral anterior; VL = ventrolateral; CM = centromedian nucleus of the thalamus.
Functional Organization of the Basal Ganglia and Other Pathways Afferent projections to the striatum arise from all areas of the cerebral cortex, the intralaminar nuclei of the thalamus, mesencephalic SN, and ftom the locus ceruleus and raphe nuclei. There is also a projection from the cerebral cortex to the STN. The major efferent projections are from the GPi and SNr to the thalamus and brainstem nuclei such as the pedunculopontine nucleus. The GPi and SNr project to ventral anterior and ventrolateral thalamic nuclei. The GPi also projects to the centromedian thalamic nuclei and the SNr projects to the mcdiodorsai thalamic nuclei and superior eolliculus. The ventral anterior and ventrolateral thalamic nuclei then project to the motor and premotor cortex. Throughout, these projections are somatotopically organized (Yelnik 2002). The basal ganglia has dense internuclear connections exemplified by the box and line circuit diagrams that have become entrenched in the literature. Five parallel and separate closed circuits through the basal ganglia have been proposed. These are the motor, oculomotor, dorsolateral prefrontal, lateral orbitofrontal, and limbic loops. It is now
MOVEMENT DISORDERS Table 77.1:
Divisions of the striatum
Division
Origin of striatal afferents
Sensorimotor
Motor cortex
Associative
I iinlii.
2127
Fronral cortex Parietal cortex Temporal cortex Occipital cortex Hippocampus Amygdala Cingulate cortex Temporal cortex Orbitofrontal cortex
Striatal nucleus ! ' : i - . 1111. -::
Dorsal caudate
Ventral striatum
generally agreed t h a t these loops form three major divisions, sensorimotor, associative, and limbic, t h a t are related to motor, cognitive, and emotional functions, respectively (Table 77.1), T h e functions of t h e sensorimotor s t r i a t u m are subserved mainly by the p u t a m e n , which derives its afferent cortical inputs from both m o t o r cortices. Sensorimotor p a t h w a y s a r c somatotopically organized and the p a t h w a y ultimately t e r m i n a t e s in t h e p r e m o t o r and primary m o t o r cortices and the s u p p l e m e n t a r y m o t o r area. Cognitive functions a r e m a n a g e d by t h e associative striatum. In this p a t h w a y , the dorsal c a u d a t e nucleus receives afferent i n p u t from the h o m o l a t e r a l frontal, parietal, t e m p o r a l , a n d occipital cortices. Projections from this p a t h w a y ultimately terminate in t h e prefrontal cortex. T h e limbic striatum subserves emotional a n d motivational functions. Its input derives from the cingulate, temporal, and orbitofrontal cortices, the h i p p o c a m p u s , a n d the a m y g d a l a . It comprises mainly the ventral s t r i a t u m with ultimate projections to the anterior cingulate and medial orbitofrontal cortices (Yclnik 2 0 0 2 ) . W h e t h e r these divisions are interconnected or organized in parallel remains a topic of debate.
Termination of basal ganglia efferents
Function
I *11 • i:: i t o r 11 :• U ' \
Movcmnii
Primary motor cortex Supplementary motor area Prefrontal cortex
Cognition
Anterior dngukue Medial orbitofrontal
Emotion Motivation
In t h e indirect pathway, excitatory a x o n s from the cerebral c o r t e x synapse o n p u t a m i n a l n e u r o n s . T h e s e n e u r o n s send inhibitory projections to the G P e . T h e GPc sends an inhibitory projection to the S T N . T h e net effect of these projections is disinhibition of the S T N . T h e S T N in t u r n h a s an excitatory projection to the GPi (see Figure 7 7 . 2 C ) . Activity in the indirect p a t h w a y t h u s excites the GPi/SNr, which in t u r n inhibits the t h a l a m o c o r t i c a l p a t h w a y .
Within each basal ganglia circuit lies an additional level of complexity. Each circuit contains t w o p a t h w a y s by w h i c h striatal activity is translated into pallidal o u t p u t . These t w o p a t h w a y s , n a m e d the direct a n d indirect p a t h w a y s , depending on w h e t h e r striatal outflow connects directly with the GPi or first traverses the GPe and S T N . T h e direct and indirect p a t h w a y s have opposite effects on outflow n e u r o n s of t h e GPi and SNr. A closer look at the m o t o r circuit illustrates this principle (Figure 7 7 . 2 A ) . In the m o t o r direct path way, excitatory n e u r o n s from the cerebral cortex synapse on p u t a m i n a l n e u r o n s , w h i c h in turn scud inhibitory projections to the GPi and its h o m o l o g u e , t h e SNr. T h e GPi/SNr sends an inhibitory outflow to the t h a l a m u s (Figure 77.2B). Activity in t h e direct p a t h w a y disinhibits the t h a l a m u s , facilitating t h e excitatory thalamocortical p a t h w a y and e n h a n c i n g activity in its target, t h e m o t o r cortices. T h u s the direct p a t h w a y constitutes p a r t of an excitatory cortical-cortical circuit t h a t likely functions to m a i n t a i n o n g o i n g m o t o r activity.
FIGURE 77.2 Schematic drawing of the internuclear connections of the basal ganglia, including (A) direcr and indirect pathways and depicting (B) the direcr pathway. (See Figure 77.3 for a depiction of the indirect pathway.) Excitatory pathways in solid lines, inhibitory pathways in dotted lines. MC = motor cortex; SMA = supplementary motor area; PMC = premotor cortex; GPe = external segment of the globus pallidus; SN = substantia nigra; STN = subthalamic nucleus; GPi = internal segment of the globus pallidus; VA/VL = ventral anterior/vcntrolateral thalamic nuclei; glu = glutamate; GARA = y-amiuobutyric acid; D^ = dopamine D2 receptor; Dt — dopamine D] receptor. Continued
F1CURE 77.2, cont'd.
Thus the net effect of increased activity in the indirect pathway is cortical inhibition. The striatum also receives robust afferent input from the SNc. This projection from the SNc, an important modifier of striatal activity, facilitates activity in the direct pathway and inhibits activity in the indirect pathway, thus promoting cortical excitation through both pathways (see Figure 77.2A). Disorders ol the basal ganglia result in prominent motoi dysfunction, though not generally in frank weakness. The absence of direct primary or secondary sensory input and the lack of a major descending pathway below the level of the brainstem suggest that the basal ganglia moderates rather than controls movement. In the simplest sense, the direct and indirect pathways have opposite effects on the cerebral cortex. The direct pathway is important in initiation and maintenance of movement and the indirect pathway helps with suppression of extraneous movement. From this model of basal ganglia connectivity, hypotheses about the motor function of the basal ganglia have been proposed. One hypothesis is that the relative activities of the direct and indirect pathways serve to balance the facilitation and inhibition of the same population of thalamocortical neurons, thus controlling the scale ol movement. A second hypothesis proposes that direct pathway-mediated facilitation and indirect pathwaymediated inhibition of different populations of thalamocortical neurons serve to focus movement in an organization reminiscent of center-surround inhibition. These hypotheses relate activity in the direct and indirect pathways mainly to rates of firing in the STN and GPi. Thus death of neurons in the SNc decreases activity in the direct pathway and increases activity in the indirect pathway. These changes cause an increased rate of tiring of subthalamic and GPi neurons with excessive inhibition of thalamocortical pathways and produce the behavioral manifestations of bradykinesia in PD (Figure 77.3A). On the other hand, selective loss of indirect pathway neurons, as in HD, interferes with supptession of involuntary movements. Choreic involuntary movements arc the usual result (see Figure 77.3B). Direct electrophysiological recordings of the STN and GP during stereotactic functional neurosurgical procedures confirm that the GPi and STN arc overly active
B Huntington's disease
FIGURE 77.3 Schematic drawing of the functional activities in the direct and indirect pathways in Parkinson's disease and Huntington's disease. (A) Reduced dopaminergic facilitation of the direct pathway and inhibition of the indirect pathway due to death [jf
d l i p . l i n i l u T;.'.il
!\-llN>ll*-
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ilKTV.'l-.I'll
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inhibition of thalamocortical pathways, producing bradykinesia. (B) Loss of striatal neurons leads to reduced activity in the indirect pathway, causing reduced inhibition thalamocortical pathways with the production of excessive or involuntary movements.
in patients with PD. The activity of these nuclei returns toward normal with effective pharmacotherapy, and chorea is associated with lower firing rates of neurons in these nuclei. Unfortunately, this model does not completely explain some important features of movement disorders. For example, bradykinesia and chorea coexist in HD and in treated PD. Thalamic lesions that might be expected to wotsen parkinsonism by reducing excitatory thalamocortical activity do not do so. Pallidal lesions that might be expected to worsen chorea by decreasing inhibition of thalamocortical pathways instead are dramatically effective at reducing chorea. The model is even more problematic when applied to dystonia. It has been suggested that in dystonia, there is overactivity of both the direct and indirect pathways. Yet, intraoperative recordings in dystonia have shown low rates and abnormal patterns of neuronal firing in the GPi. A simple change in firing rate of the STN or GPi is thus insufficient to explain the underlying physiology of dystonia. It is likely that disordered patterns and synchrony of pallidal firing as well as changes in sensorimotor
MOVEMENT DISORDERS
integration and the control of spinal and brainstem reflexes are important. These factors are under investigation, but current models remain useful for understanding the rationale of pharmacological and ablative surgical procedures for certain movement disorders. Although much of the emphasis has been on GPi and SNr effercnts to the thalamocortical system, there is growing evidence that descending pathways, particularly to the zona incerta and pedimculopontine nucleus, are important in movement disorders. The pedunculopontine nucleus appears to play a role in the genesis of akinesia. A number of other pathways also seem particularly relevant to myoclonus, including a corticolemni seal thalamocortical circuit and a spinobulbar-spinal circuit that primarily involves the spinoreticular tracts, nucleus reticularis gigantocellularis of the medullary reticular formation, and the reticulospinal tracts. The Guillain-Mollart triangle is a network connecting the red nucleus, dentate nucleus, and inferior olive, which has been implicated in palatal tremor (formerly known .is j-.djtdi mytn limns), [he propnospinal pathways and segmental spinospinal loops are important in the genesis of propriospinal and spinal segmental myoclonus, respectively.
Biochemistry Our understanding of basal ganglia pharmacology is growing rapidly. Along with this growth is an expanding spectrum of practical applications for pathology, neuroimaging, and therapeutics. For example, catecholamine and amino acid neurotransmitters coexist with peptides. This co-localization may allow histopathological differentiation among medium spiny striatal projection neurons that secrete K-aminobutyric acid (GABAergic), further elucidating the specific nature and progress of striatal neu rode generation. Neuroimaging technology has been aided by the development of radiopharmaceutical ligands with such discrete targets as the dopamine transporter on the presynaptic dopamine neuron and subpopulations of dopamine receptors on the postsynaptic neuron. The pharmaceutical industry is searching for ways to provide better targeted and more physiological stimulation of neurotransmitter receptors and is expanding its investigations from the primary targets themselves to approaches that may modify responsiveness of the primary targets. The major neurotransmitters of the basal ganglia arc outlined in Table 77.2 (see also Figure 77.2). Most excitatory synapses of the basal ganglia and its connections, including those from the cerebral cortex to the striatum, the STN to the Gl'i, and the thalamocortical projections, use glutamate. Projections from the striatum to the GPe and Gl'i and from the GPe to the STN and from the GPi to the thalamus arc inhibitory and employ GABA. Medium spiny GABAergic neurons in the direct pathway colocalize substance P and dynorphin. GABAergic neurons in the
Table 77.2:
2129
Pharmacology of the basal ganglia
fathway Striatal affcrents Cerebral cortex -> striatum Cerebral cortex —* STN Lotus ecruleus —• striatum Locus ceruleus —* SN Raphe nuclei -> striatum Raphe nuclei -*• SN Thalamus -* striatum SNc -» striatum
Transmitter Glutamate Glutamate Norepinephrine Norepinephrine Scroronin Serotonin Acetylcholine? Clutamate? Dopamine, choleeystokinin
Intrinsic connections GABA, acetylcholine, Striatal interneurons M ill l.l [ O S I , 11,11, Striatum -*• GPi Striatum -» SNr neuropeptide Y, nitric acid, Striatum —> GPe calretinin Globus pallidus externa -» STN GABA, substance P GABA, dynorphin, substance P Subthalamic nucleus ->• GPi, SNr, GPe GABA, enkephalin CABA, glutamate Striatal effercnts GPi — thalamus GABA SNpr —* thalamus CABA
CABA = y-aminobutyric acid; GPe = external segment of the globus pallidus; CPi = internal segment of the globus pallidus; SN = substantia nigra; SNc = subsrantia nigra pars compacra; SNr = substantia nigra pars reticulata; STN = subthalamic nucleus.
indirect pathway colocalize enkephalin. Dopamine is the major neurotransmitter in the nigrostriatal dopamine system; it has excitatory or inhibitory actions depending on the properties of the stimulated receptor. Acetylcholine is found in large aspiny striatal interneurons. Norepinephrine is important in the autonomic nervous system, lateral tegmentum, and locus ceruleus. Serotonin is found in the dorsal raphe nucleus of the brainstem, the hippocampus, cerebellum, and spinal cord. For each of rhese neurotransmitters, multiple types of receptors may exist. Glutamate is active at a number of types of ligand-gatcd ion channel receptors named for their selective agonists: N-methyl-D-aspartate (NMDA); a-amino-3-hydroxy-5-methy]-4-isoxazole propionic acid (AMPA); and k a mate. The NMDA receptor has been the focus of particular attention because of its potential role in excitotoxic neuronal injury. There arc also mctaborropic glutamate receptors. There are two classes of GABA receptors, named GABA,\ and GABA^. GABAA receptors are ligand-gated chloride channels. There are many subtypes of this receptor. The GABAu receptor is a mctaborropic receptor. Five types (D[ through D5) and two families (D] and D2) of dopamine receptors have been identified. The D5 family of receptor is adenylate cyclase dependent and contains subtypes Di and D5. D] receptors reside primarily in the direct pathway, cerebral cortex, and limbic system, D^ receptors arc located primarily in the indirect pathway, cerebral cortex and limbic system,
2130
NEUROLOGICAL DISEASES
as well as the pituitary gland. There are two families of acetylcholine receptors, nicotinic and muscarinic. There are two subtypes of nicotinic and five subtypes of muscarinic receptors. Most striatal cholinergic receptors are muscarinic. In the norepinephrine system, there are two primary receptor systems, a and fi. There are 14 distinct receptor subtypes of serotonin receptors including G proteincoupled receptors in the 5-HTj, 5-HT 2 , 5-HT 4 , 5-HT 5 , 5HT 6 , and 5-HT 7 families and the 5-HT 3 type ligand-gated ion channels. Drugs targeting specific subpopulations of receptors are in use or under development for movement disorders, but there remains a knowledge deficit about the relative clinical utility of specific rcccpror agonists and antagonists,
NEURODEGENERATION AND "TOXIC PROTEINS" Many of the neutodegenerative movement disorders share the property of neuronal damage caused by the accumulation of aggregation-prone proteins that have toxic effects (Table 77.3). In order for a protein to function normally, it must be properly synthesized and folded into its normal three-dimensional structure. Nascent proteins are aided in folding by molecular chaperones. Proteins that are not properly folded arc otherwise damaged, or beyond their useful lives are degraded by the ubiquitin-dependent proteasome protein degradation system (Taylor ct al. 2002). In the ubiquitin-dependent proteasome system, proteins are first iabeled for degradation by attachment of a polyubiquitin chain (Figure 77,4). Ibis three-step process involves activation, conjugation, and ligation, steps catalyzed by three types of enzymes, E 1; E 2 , and E 3 , respectively. Polyubiquinated protein enters the 26S proteasome, a cylindrical complex of peptidases. The end products of proteasome action are protein fragments and polyubiquitin. The polyubiquitin is then degraded and recycled to the cellular ubiquitin pool, a process requiring enzymatic action by ubiquitin carboxy terminal hydrolase 1 (McNaught and Olanow 2003). Recent ultrastructural work has elucidated that many degenerative movement disorders can be linked to abnormal synthesis, folding or degradation of specific proteins or protein families. Thus, a number of akinetic-tigid disorders Tabic 77.3:
involve the alpba-synuelein or tau proteins. Certain other disorders are linked to abnormalities in pathways involving proteins with expanded polyglutaminc tracts (poh/Q). Among these disorders, clinical and pathological differences depend on the distribution of protein aggregates or in the abnormal configuration they assume when they aggregate. The synudeinopathies include PD, diffuse Lcwy body disease, and multiple system atrophy (MSA). The tauopathies include progressive supranuclear palsy (PSl'i, corticobasal degeneration (CBD), familial frontotemporal dementia with parkinsonism (FTDP), postencephalitic parkinsonism (PEP), post-traumatic parkinsonism, and amyotrophic lateral sclerosis (ALS) PD of Guam. The poiyQ disorders include HD, dentalin'iibr.d-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxias. The cascade of pathogenic events linking abnormal protein aggtegation to cell death is the subject of intense investigation. AliJituirJ'. .is>,s.\ivj.'.,iu-s arc the nn^: striking physical change in surviving cells, the actual role of the aggregate remains a mystery. Indeed, many now believe that the formation of aggregates may be a protective mechanism sequestering the wayward protein from vulnerable cell processes. Misfolded proteins may produce the most mischief as they form protofibrils. A number of mechanisms have been described. In some cases, these are specifically related to the type of protein, but in many other cases, they are nonspecific mechanisms shared by all the misfolded protein diseases. Some potential mechanisms of ncuro degeneration related to misfolded protein stress arc listed in Table 77.4. The mutant protein may be unable to perform a vital function or may interfere with the function of the wild type protein. Mutant protein, protofibrils, or aggregates might intetfere with other proteins. Interference with transcription factors may be particularly important in this regard. Mutant proteins may activate caspases or in other ways activate the apoptotic cascade. They may interfere with intracellular transport or other vital processes. They may suppress activity of the proteasome, enhancing protein aggregation. They may interfere with mitochondrial function, making cells more vulnerable to excitotoxicity. Oxidative stress may be enhanced and there may be microglial activation (Taylor et al. 2002). Despite that most of these abnormal proteins are widely expressed in neuronal and non-neuronal tissues,
Toxic proteins ;ind neurodegenerative movement disorders
Alpha-synuciein
Tan
Volyglutamine tract
Parkinson's disease Diffuse Lewi' body disease Multiple system atrophy
Four-repeat tau Progressive supranuclear palsy Corticobasal degeneration Frontotcmporal dementia with parkinsonism (chromosome 17) All six isoforms Parkinsonism dementia complex of Guam Postencephalitic parkinsonism Pronto temp oral dementia with parkinsonism (chromosome 17)
Huntington's disease Spinocerebellar ataxia (SCA-3) Denfatorulir.il p^illnJoluysian atrophy
MOVEMENT DISORDERS
2131
FIGURE 77.4 Ubiquitin-de pen dent proteasomc proteolysis. Once a protein is tagged for degradation, it is tagged with a poiyubiquitin chain, a three-step process involving first activation, then conjugation followed by ligation. The ubiquinated protein enters the 26$ protcasome, where it is degraded into protein fragments and the poiyubiquitin chain is degraded back to monomcric ubiquitin, U = ubiquitin; UCHL1 = ubiquitin catboxy-terminal hydtolase.
these diseases wreak their particular havoc within the nervous system, suggesting that nervous system cells are especially vulnerable to misfolded protein stress. Within nervous tissue itself, certain neuronal populations seem selectively vulnerable to the effects of certain aberrant proteins. This preferential degeneration of specific neuronal populations ultimately determines the phenotypc of the disorder. The key to successful neuroprotection will lie in careful reconstruction of the intracellular crime scene. Potential therapeutic interventions might include reducing translation of the aberrant protein, upregulating molecular chaperoncs, or facilitating protein ubiquination or proteasomal function. Other options include reducing oxidative stress, improving mitochondrial function, and blocking proapoptotic processes. Many of these interventions might be suitable for any of the candidate diseases, although others might be disease specific. A single intervention might produce a benefit of small magnitude and significant neuroprotection might be achieved only with a combination of treatment interventions. Animal studies hint that neuroprotective interventions early enough in the protein aggregation neurodegeneration might actually be able to
Table 77.4: Mechanisms of neurodegeneration related to misfolded protein stress Loss of protein function Interaction of the mutant protein with the wild-type protein Interaerion with other proteins including transcription factors Caspase activation Interference with mitochondrial function Oxidative stress Microglial activation
partially reverse extant neurodegenerative changes. For example, in a conditional transgenic HD model that allows the transcription of the mutant gene to be turned off, reversal of behavioral and pathological changes may be seen {Yamamoto ct ah 2000).
PARKINSONIAN SYNDROMES Parkinson's Disease (Idiopathic Parkinson's Disease, Paralysis Agitans) Although described by others before him, James Parkinson is attributed with rendering the first cogent description of PD. In his monograph, The Shaking Palsy (1817), he identified the hallmark features of the illness through descriptions of cases observed in the streets of London. Over time, the specific terms PD and idiopathic PD have come to be reserved for the clinical syndrome of asymmetrical parkinsonism, usually with rest tremor, in association with the specific pathological findings of loss of dopaminergic SN neurons with eosinophilic cytoplasmic inclusions (Lewy bodies). Dopamine deficiency in parkinsonian brain homogenates was described by Horny kiewicz in 1959, a discovery that ultimately led to highly effective pharmacotherapy with L-dopa and direct-acting dopamine agonists (DAs). Recently, a genetic form of parkinsonism that is clinically indistinguishable from PD has been linked to missense mutations in the alpha-synuclein gene. This discovery undermined the concept that PD represents a homogeneous disease but also revealed the importance of disordered protein handling in the genesis of PD. In its present context, PD is best considetcd a syndrome with genetic and environmental etiologies.
2132
NEUROLOGICAL DISEASES
Epidemiology and Clinical Features In community-based series, PD accounts for more than 80% of all parkinsonism, with a prevalence of about 360 per 100,000 and an incidence of 18 per 100,000 per year. I'D is a disease of aging, showing a gradual increase in prevalence beginning after the age of 50 years and a steep increase in prevalence after age 60 years. Disease before the age of 30 years is very rare and often suggests a hereditary form of parkinsonism. Prevalence rates in the United States are higher than those in Africa and China, but the role of race remains unclear. Within the United States, race-specific prevalence rates vary, with some studies suggesting a similar prevalence among whites and American blacks. Unfortunately, blacks make up only a small fraction of most specialty clinic populations, thus .ire under-represented in clinic-based studies and clinical trials. Typically the onset and progression of PD are gradual. The most common presentation is with rest tremor in one hand, often associated with decreased arm swing and shoulder pain. Hradykinesia and rigidity are often detectable on the symptomatic side, and midline signs such as reduced facial expression or mild contralateral bradykinesia and rigidity may already be present. The presentation may be delayed if hradykinesia is the earliest symptom, particularly when the onset is on the nondominant side. The disorder usually remains asymmetrical throughout much of its course. With progression of the illness, generalized hradykinesia may cause difficulty with arising from a chair or turning in bed. The gait and balance arc progressively affected and falls may occur. Sudden arrests in movement, also called freezing or motor blocks, soon follow, first with gait initiation, turning and traversing narrow or crowded environments, and then during walking. Bulbar functions deteriorate, impairing communication and nutrition. The Hoehn and Yahr stage, first described before effective dopaminergic treatment became available, accurately outlines the milestones in progression of the illness from mild unilateral symptoms through the endstage nonambulatory state (Table 77.5). Nonmotor symptoms are universal in PD and contribute prominently to declining quality of life. Autonomic symptoms include reduced gastrointestinal transit time
Table 77.5:
Hoehn and Yahr stage
Stage I
Unilateral involvement only, minimal or no functional
II
Bilateral or midline involvement, without impairment of balance First sign of impaired righting reflex, mild to moderate disability Fully (ic\ eloped, severe]; disabling disease; [Utiem Mill able to walk and stand unassisted Confinement to bed or wheelchair unless aided
impairment
III IV V
with postprandial bloating and constipation, urinary frequency and urgency sometimes with urge incontinence, impotence, disordered sweating, and orthostatic hypotension. Cognitive and behavioral changes are universal as well. Attention and concentration wane. Executive dysfunction with diminished working memory, planning, and organization is common. Global dementia occurs in about 3 0 % of patients, increasing in frequency with the age of the patient. Those with prominent early executive dysfunction and more severe motor signs seem particularly at risk (Levy et al. 2002). Anxiety and mood disorders are common in PD. Each is seen in as many as 4 0 % of patients with PD, with considerable overlap (Walsh and Bennett 2001). Sleep disturbance is nearly universal in PD and is multifactorial. Disordered sleep onset and maintenance lead to fragmentation of nocturnal sleep. A variety of motor movements including restless legs and periodic leg movements of sleep may be seen and many patients have rapid eye movement (REM) sleep behavior disorder (RBD) with active motor movements during REM sleep. Some patients have sleep apnea. Vivid dreams and nightmares are very common, particularly in treated patients. Sleep disorders in PD variably relate to pathological changes of the disease itself, arousals due ro immobility, comorbid primary sleep disorders, and side effects of antiparkinsonian medications. Many patients with PD are excessively sleepy during the day, sometimes with serious consequences such as unintended sleep episodes while driving. In most cases, this excessive daytime drowsiness is related to dopaminergic drugs (Ondo et al. 2001). Fatigue is a common and complex symptom of PD. The differentiation of fatigue from excessive daytime sleepiness, depression, apathy, and other conditions can be difficult, and there is not yet a useful body of literature on its assessment and treatment. PD is a clinical diagnosis, and it is not usually difficult to diagnose a patient with unilateral or asymmetrical rest tremor, hradykinesia, and rigidity. Clinicopathological studies have found that the syndrome that best reflects the typical pathological changes of PD is an asymmetrical illness with rest tremor along with rigidity or hradykinesia, and significant improvement with i.-dopa supplementation, in the absence of other diagnoses known to cause parkinsonism. The presence of this syndrome carries a positive predictive value of 9 2 % , with a sensitivity of 90%. Misdiagnosed cases generally are found to have MSA, PSP, or subcortical vascular disease. When making the diagnosis of early PD, the clinician should be aware of a number of "red flags" (Table 77.6). Cognitive impairment within the first year should raise the possibility of Alzheimer's disease, dementia with Lewy bodies (DLB), CBD, PSP, or ETDP. Symmetrical or prominent midline or bulbar signs suggest MSA or PSP. Early gait disorder with falls points to the diagnosis of PSP or to subcortical vascular disease. Dependence on a wheelchair within 5 years of onset is suggestive of PSP, MSA, or vascular parkinsonism. Early orthostatic hypotension or incontinence points to the
MOVEMENT DISORDERS
Tabic 77.6:
"Red flags" in the diagnosis of Parkinson's disease
Early or prominent dementia Symmetrical signs Bulbar dysfunction Early gait disorder Falls within the first year Wheelchair dependence within 5 years Early autonomic failure Sleep apnea Gasping respirations Apraxia Alien limb Cortical sensory loss
autonomic dysfunction of MSA. Severe sleep apnea or sighing or gasping respirations also suggest MSA. Apraxia, alien limb, or cortical sensory loss may be seen in CRD. Routine laboratory studies are not helpful in the diagnosis of PD, and their use should be directed by other clinical indications. Neuroimaging studies such as computed tomography (CT) and magnetic resonance imaging (MRI) are also not helpful in making a diagnosis of PD, because they are generally normal or show only incidental abnormalities. Sometimes, neutoimaging abnormalities can be useful in suggesting alternative diagnoses such as PSP or MSA, The radiopharmaceutical 6-[ 18 FJ-fluorodopa (F-dopa) is taken up by dopaminergic neurons in the SN and metabolized to 6-[ 1!t Fl-fluorodopaminc. Positron emission tomography (PET) scans using this radiopharmaceutical agent show reduced E-dopa uptake in dopaminergic nerve terminals in the putamen and caudate proportional to the severity of degeneration in the ipsilateral SN and symptoms in the conttalateral hemibody (Plate 77.1). Although these tests make useful contributions to PD research, they are not clinically available at this time. Single-photon emission CT* (SPECT) with radioligands that label the dopamine transportet on nerve terminals in the striatum is another research tool, and its clinical relevance is now being studied. There is no role for routine electrophysiological testing in the diagnosis of PD. Because identified genetic causes are rare, there is as yet no role for routine genetic testing in PD. Pathology The most striking pathological changes in PD occur in the SNr. The SN appears pale to the naked eye. Microscopic chanties include nciuncal loss, gliosis, and the presence of extracellular pigment. Surviving neurons may show characteristic cytoplasmic inclusions (Plate 77.11). The inclusions, called Lewy bodies, have a dense eosinophilic core and a pale halo. They contain hyperphosphorylatcd neurofilament proteins, lipids, iron, ubiquitin, and alphasynuclein (Jellinger 2002). Pigmented nuclei elsewhere in the brainstem, including the locus ceruleus, dorsal motor
2133
nucleus of the vagus, and others, may also show Lewy bodies and characteristic degenetative changes. The substantia innominata and intermediolateral cell column in the spinal cord also are affected. Patients with PD and dementia show more diffuse Lewy body pathology of comorbid Alzheimer's disease (Apaydin et al. 2002). Etiology Studies of large numbers of patients with PD have suggested that PD is a multifactorial illness with likely genetic and environmental determinants. Although strongly hereditary PD is rare, there is a tendency for familial aggregation of I'D. Twin studies suggest that hctcdity plays a relatively small role in the population at large, but the hereditary component is greater if one twin has disease onset at younger than 50 years of age (Tanner et al. 1999). Moreover, PPT studies of twins suggest that most monozygotic co-twins of patients with PD show subclinical declines in dopamine innervation, strengthening the evidence for a significant hereditary contribution irrespective of age at onset. Families whose pedigrees suggest dominant!y inherited PD are rare, making up no more than 5% of the PD population at latge. Most of these families show no identified genetic mutation. However, linkage studies have suggested genetic susceptibility factors on chromosomes 5, 6, 8, 9, 10, 16, and 17. Association studies point to genes for monoamine oxidase B (MAO-B), N-acetyltransferase-2 detoxification enzyme, tau, and glutathione transferase detoxification enzyme, but the relevance of these associations is not yet known {Tan et al. 2000). Evidence for environmental causes of PD comes primarily from two sources—the fortuitous discovery of parkinsonism in parenteral drug users exposed to the contaminant MPTP and epidemiological associations of sporadic PD or other parkinsonisms with certain lifestyle ot occupational exposures. More than two decades ago, the discovery that a handful of drug addict-, had developed ; \ C U T I i.-dup.iresponsive form of parkinsonism following parenteral administration of a meperidine analogue contaminated with the mitochondrial protoxin MPTP suggested that environmental toxins might cause PD, The discovery of MPTP-induccd parkinsonism in humans was a sentinel event in our understanding of the disease because it pointed to a class of environmental toxins that might be important in sporadic disease. Although MPTP spawned the development of reproducible models of disease in many kinds of animals, its role in human disease is limited to the cluster of cases in drug addicts and a few others. Intriguing studies have confirmed that certain pesticides such as paraquat and rotcnone can reproduce the pathology of PD in animals, but their role in human disease remains undefined (Grcenamyre et al. 1999). Epidemiological studies suggest that exposure to environmental metals or organic toxins may be associated
2134
NEUROLOGICAL DISEASES
with an increased risk of PD or an earlier age at onser of PD (Tsai et al. 2002). Case-control studies have suggested that the risk of PD is increased in persons who have worked in the agricultural industry, who have been exposed to pesticides, or who have sustained significant head injury, Exposure to welding seems to predispose to earlier onset Ldopa-rcsponsive PD, possibly as a result of manganese poisoning. On the other hand, the risk of PD seems less in those with a high dietary intake of antioxidant-rich foods, as well as caffeine drinkers and those who have smoked cigarettes (Ross and Petrovitch 2001), These epidemiological studies have failed to find a "smoking gun" in the etiopathogenesis of PD. Irrespective of genetic or environmental influences, the central feature of ncurodegeneration in PD is aggregation of alpha-synuclein. In PD, the natural tendency of alphasynuclein to aggregate is likely enhanced by genetic factors controlling the protein synthesis, secondary processing or degradation and environmental factors such as aging, oxidative stress, and toxic exposures. Misfoldcd alphasynuclein triggers mechanisms in the cell (see previous discussion) that ultimately lead to its demise. Trent meat A preclinical period lasting years to decades and a slow progression rate make PD an ideal candidate for neuroprotection. The increased understanding of disease etiopathogenesis suggests many candidate neuroprotective agents (Table 77.7). Neuroprotective trials to this point have been somewhat disappointing. Pie lirsi and larr.iM iuuro protective trial, DATATOP, randomized patients with early PD to treatment with placebo, tocopherol, selegiline (deprenyl), or both, using the time until patients needed potent symptomatic dopaminergic therapy, L-dopa, as a proxy endpoint for disease progression. The selective MAO-B inhibitor selegiline successfully delayed this endpoint, but interpretation of the study was contaminated by its mild antiparkinsonian and antidepressant properties, as Tabic 77.7: Candidate neuroprotective approaches in Parkinson's disease Mechanism
Potential neuroprotective approaches.
Oxidative stress
Antioxidants, for example, monoamine oxidase inhihitors, coenzyme Qm Coenzyme QKJ, creatine
Mitochondrial dysfunction Excitotoxicity ( i a s p a s e ;li iw.UKiii
Apoptosis Inflammation Trophin deficiency
Glutamate antagonists, for example, riluzole Caspasc inhibitors, for example, minocycline Antiapoptotic agents, for example, mixed lineage kinase inhibitors Anti-inflammatory drugs Neil rotropfi ins
well as potential effects of its amphetamine metabolites. A similar magnitude effect was shown in a latge randomized placebo-controlled study of another MAO-B inhibitor, lazabemide, but this drug is no being actively developed. A third MAO-B inhibitor, rasagiline, has been shown to have modest symptomatic benefit. Its effect on disease progression is under study. A recent randomized placebocontrolled study of three doses of coenzyme Q J 0 suggested a slowing of decline in function in the 1200-mg-per-day group. This finding warrants w litional study in a larger group of research subjects (Siiults et al. 2002). Two intriguing studies comparing the effects of carbidopa-Ldopa (CD-LD) and DAs (pramipexole and ropinirole) on decline in functional ncuroimaging markers of presynaptic dopaminergic function in early DD suggested a slower loss of dopamine neurons in patients tteated with DAs than with CD-LD (Marek ct al. 2002). Although these studies are thought provoking, they require independent confirmation using clinical measures. Symptomatic Treatment of Parkinson's Disease. Six types of medications arc available for the symptomatic treatment of PD: anticholinergics, amantadine, L-dopa, monoamine oxidase inhibitors (MAOIs), catcchol-O-methyltransferase (COMT) inhibitors, and DAs (Tabic 77.8). Anticholinergics such as trihexyphenidyl and benztropine antagonize the effects of acetylcholine at muscarinic receptors postsynaptic to striatal intcrneurons. They reduce tremor and rigidity but have no effects on bradykinesia. Toxicity relates to antagonism of acetylcholine at central receptors, causing confusion, and peripheral receptors, causing blurred vision, dry mouth, constipation, and utinary retention. Although amantadine has been available for nearly four decades
Table 77.8:
Commonly used antiparkinsonian drugs
Drug Anticholinergics Trihexyphenidyl Benztropine Bipendin Amantadine
Usual starting dose 1 0.5 1 100
mg mg mg mg
Usual daily dose
2-12 mg 0.5-6.0 mg 2-16 mg 100-300 mg
L-DOPA
(with carbidopa) Immediate release Controlled release Dopamine agonists Bromocriptine Pergolide Pramipexole Ropinirole C -alx'rgoline Catcchol-O -methyl transferase inhibitors Entacapone Toleapone
100 mg 100 mg 1.25 0.05 0.375 0.75 0.25
150-800 mg 200-1000 mg
mg mg mg mg mg
15-40 mg 2-4 mg 1.5^4.5 mg 8-24 mg 0.25^1.0 mg
200 mg with each dose 300 mg
200 mg with each dose 600 mg
MOVEMENT DISORDERS (it was originally marketed as an antiviral agenr), irs antiparkinsonian mechanisms have been poorly understood. It has been thought to stimulate release of endogenous dopamine stones, to block reuptake of dopamine from the synaptic cleft, and to have anticholinctgic properties. However, recently, it has been found to have antiglutamatergic properties and as such is the only antiparkinsonian drug that improves L-do pa-induced dyskinesia. CD-LD combines L-dopa, the immediate precursor of dopamine w h carbidopa, an aromatic acid decarboxylase inhibitor thrit prevents its peripheral metabolism, Its global antiparkinsonian efficacy is so dramatic and predictable that a positive therapeutic response is used to define the disease its*If. Advetse effects of CD-ID include nausea and von ;i ting, orthostatic hypotension, sedation, confusion, sleep disturbance, altera nous of dream phenomena, hallucinations, and dyskinesias, A number of direct-acting DAs are available including bromocriptine, pergolide, pramipexole, and ropinirole. Cabergoline is available in the United States, but it does not have Food and Drug Administration (FDA) approval for the treatment of PD and is prohibitively priced. Lisuride, piribedil, and apomorphine are not available in the United States. DAs cause side effects similar to those of L-dopa, although orthostatic hypotension, sleepiness, and hallucinations are more common or severe. DA monotherapy is associated with a very low incidence of dyskinesia. Agents that interact with the metabolism of L-dopa or dopamine are also available for the treatment of PD (Figure 77.5). Selegiline blocks MAO-B-dcpcndent dopamine degradation and has modest effects in potentiating the action of L-dopa. COMT inhibitors block peripheral degradation of peripheral levodopa (entacapone and
2135
tolcapone) and central degradation of L-dopa and dopamine (tolcapone), increasing central L-dopa and dopamine levels. Hcpatotoxicity associated with tolcapone has limited its use. Triple-combination therapy containing L-dopa, carbidopa, and entacapone became recently available for pancms with modcralcb advanced I'D, Symptomatic treatment should begin when the patient is noticing functional, occupational, or social disability related to PD symptoms. Prospective studies have suggested that about 7 0 % of patients with PD will require symptomatic therapy within 2 years of disease onset. Less potent therapies such as selegiline and amantadine may be useful for initial therapy, but CD-LD or DAs arc the choices when more potent therapy is indicated. The choice between CDLD and DA for initial therapy remains controversial. There is universal agreement that CD-LD is the most potent and best tolerated drug in the modern PD arsenal, but there are concerns that it might be toxic to dopaminergic neurons and that it promotes the development of motor fluctuations. The argument that L-dopa might be toxic to dopaminergic neurons is based on the recognition that dopamine metabolism increases oxidative stress and the observation that i.-dopa is toxic to cultures of mesencephalic neurons in vivo. There is no in vivo evidence in laboratory animals that i.-dopa accelerates disease progression, and it is difficult to reconcile the potential of dopamine toxicity with the obvious fact that the drug prolongs life in patients with PD. A 9-month study, called ELLDOPA, compared different doses of L-dopa with placebo and found no evidence of L-dopa toxicity. Clinical experience with CD-LD treatment of PD suggests that there is a progressive increase in the
FIGURE 77.5 Peripheral and central L-dopa and dopamine Meta holism. COMT = catecholO-methyl transferase; DDC = dopa decarboxylase; DOl'AC = dihydroxyphenylacetic acid; HVA = homovanillic acid; MAO = monoamine oxidase; 3-MT = 3-methyttyrosine; 3-OMD = 3-O-methyldopa.
2136
NEUROLOGICAL DISEASES
prevalence of drug-related motor fluctuations (wearing off, dyskinesia) over time that relates mainly to the seventy of the underlying PD. Wearing off results from loss of continuous receptor stimulation. Experimentation in animal models relates the development of dyskinesia to changes in striatal glutamate receptor sensitivity consequent to pulsatile stimulation of striatal dopamine receptors. Continuous dopamine receptor stimulation with L-dopa or with long-acting dopamine receptor agonists prevents or reverses this phenomenon. Two pivotal clinical trials studied whether more sustained dopamine receptor stimulation afforded by DA (pramipexole and ropinirole) therapy was less likely to induce motor fluctuations and dyskinesia than therapy with the shorter half-life agent CDLD. In both studies, the efficacy of CD-LD for the primary symptoms of PD was superior to that of DA, even though open-label supplementation with CD-LD was allowed during the study. CD-LD was better tolerated than DA, which caused more edema, sleepiness, and hallucinations than CD-LD (Table 77.9). In both studies, the risk of development of dyskinesia or motor fluctuations was substantially reduced in the DA monotherapy group and even in subjects who ended the study on CD-LD and DA (Parkinson Study Group 2000; Rascol et al. 2000). At this time, it remains unclear whether the delay in development of early dyskinesias and fluctuations is worth the poorer efficacy and tolerability and greater expense of agonists. Clearly, by the second decade of therapy, all patients arc on L-dopa, often in combination with DA, and it is not yet clear whether initial treatment will influence overall function or quality of life at this point in the disease. In many specialty centers, otherwise healthy and cognitively intact patients younger than 70 years are usually treated first with DAs and less healthy, cognitively impaired, and elderly patients are started on L-dopa. Irrespective of initial treatment, virtually all patients with PD experience an evolution of their response to L-dopa that includes wearing off and other motor fluctuations. The middle years of PD treatment can best be characterized as Table 77.9: Frequency of common side effects in comparative trials of dopamine agonists and L-dopa Pramipexole f %;
L-Dopa
48.6 27.4 25.1 : 1.1 17.3 14.5 kO 14.0 11.7 , 1.7
36.4 32.4 25.8 25.8 9.3, 15.2 20.5 17.9 11.3 6.0
43.1 18.2 22.8 11.6 3.3 17.9 16.7 6.8 7.9 11.2
9.5
20.5
12.6
Ropinirole Side effect Nausea Somnolence Insomnia Dizziness Hallucination Depression Headache l\:km;l
Anxiety Orthostatic |blood pressure Constipation
••;.)
(%)
the years of optimizing drug delivery. The first step in rational pharmacotherapy of PD at this stage is characterizing the pattern of response to the therapeutic agents, a step wholly reliant on the patient history. The patient should be asked to describe the severity of symptoms in the morning on arising and the magnitude and duration of benefit from incremental doses of antiparkinsonian drugs. The usefulness of historical information may be augmented by careful patient education on symptom recognition and the development of a shared vocabulary. Completing motor diaries (Figure 77.6) helps both the patient and the treating physician recognize the patterns ot motor response and adjust the medications accordingly. Wearing off is the most common type of motor fluctuation. It is the predictable return of parkinsonism in advance of the next scheduled antiparkinsonian dose. On off is the unpredictable reappearance of parkinsonism at a lime when central
levels l Linlip.irkinsnninn drugs are
expected to be within the target therapeutic range. Delayed on is a prolongation of the time required for the central antiparkinsonian drug effect to appear. Dose failure is the completed failure to develop a favorable response to an incremental dopaminergic dose. Protein-related offs occur when the transport of L-dopa across the intestinal wall is impeded by competition for facilitated transport by large amounts of neutral amino acids. A variety of dyskinesias can further complicate the picture of midstage PD. Peakdose dyskinesias are usually choreiform or stereotypical movements present at the peak of the therapeutic response; dystonic movements are seen less commonly. Off-period dystonia usually appears in the more severely affected foot in the morning before the first daily doses, sometimes reappearing during wearing off. Diphasic dyskinesias arc usually large-amplitude dyskinetic movements of the lower body during the time of increasing and decreasing L-dopa levels. Armed with a few basic principles and a commonsense approach, the clinician can usually smooth out fluctuations for most patients (Table 77.10). Delay to onset of therapeutic benefit can be hastened by avoiding or reducing protein ingestion or by crushing the L-dopa tablet and mixing it with a carbonated beverage. The duration of benefit increases when the incremental dose is increased or dopamine metabolism is blocked with an MAO inhibitor or COMT inhibitor. The brittle patient with motor fluctuations and dyskinesia may do better on smaller, more frequent L-dopa doses. A homemade solution of liquid Ldopa allows very tight titration of the resulting 1-mg/mL of i.-dopa solution and is particularly useful in young fluctuators (Table 77.11). In addition to the fluctuating response typical of moderate PD, patients with advanced disease may have acquired j,-dopa-resistant motor symptoms such as freezing, progressive gait dysfunction, dysarthria and dysphagia, and recurrent falling. Other features of the advanced illness, including cognitive impairment, autonomic dysfunction,
MOVEMENT DISORDERS Medication
Time
Meal
Asleep
Midnight— 1:00 A
X
1:00 —2:00 A
X
2:00 —3:00 A
X
3:00 — 4:00 A
X
4:00 —5:00 A
X
On
Dyskinesia
X
5:00 — 6:00 A 6:00 — 7:00 A
Off
1 Sinemet Va Mirapex
X
X
7:00 — 8:00 A
X
8:00 — 9:00 A
X
X
X
X
9:00 —10:00 A
X
10:00—11:00 A
X
11:00 — noon
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1 Sinemet /2 Mirapex
X
X
1
X
1:00 — 2:00 P 2:00 —3:00 P 3:00 — 4:00 P
X
1 Sinemet
4:00 — 5:00 P
X
5:00 — 6:00 P
X
6:00 — 7:00 P 7:00 — 8:00 P
X
X Va Sinemet
X
X
8:00 —9:00 P
X
X
9:00 —10:00 P
X
X
X
10:00 — 11:00P 11:00 —midnight
X
FIGURE 77.6 Sample diary in Parkinson's or her disease. For each hour, the patient indicates whethet and which antipatkinsonian drugs he or she has taken then places a mark to indicate his or her motor state for most of the hour.
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NEUROLOGICAL DISEASES
Table 77.10: Management of drug-related motor fluctuations in Parkinson's disease Wearing off Adjust L-dopa dose and interdose interval Shorter interval Smaller increment, especially if dyskinesia is a problem liquid carbidopa/L-dopa Add catechol-O-methyl transferase inhibitor Entacapone Tolcapone Add dopamine agonist Add amantadine Add selegiline Dyskinesia Adjust L-dopa dose and interdose interval Smaller increment Shorter interval, if needed Add dopamine agonist and reduce L.-dopa dose Add amantadine Add atypical antipsychotic Morning dystonia Chew or crush first dose, take with carbonated beverage Add dopamine agonist Add baclofen Add anticholinergic On-off fluctuations Careful identification/management of predictable fluctuations Add dopamine agonist
and psychiatric complications, may limit the types and dose of tolerated medications. Freezing, sudden immobility of the feet while walking, often with falls, may be seen in the off period or in the on period. Although off-period freezing docs improve with optimization of medications, on-period freezing may be resistant to treatment. Behavioral strategies such as sensory cues may be helpful. Dysarthria and dysphagia are often treated by speech therapists, although documentation of improvement from these techniques is scant. Cognitive impairment increases mainly with the age of the patient and with disease severity. Pteliminary reports suggest that cholinesterasc inhibitors might be useful in PD-associatcd dementia, but these studies require confirmation in carefully controlled trials. Autonomic dysfunction can be managed conservatively, with salt
Table 77,11:
Liquid L-dopa
Recipe 10 tablets of car hi do pa/Ldo pa 1 liter of water 500 mg of ascorbic acid Powdered drink mix for taste Calculating the dose Divide rhe total daily dose into 13 increments Increase the first morning dose increment by 10-20% Give 13 hourly doses from 7:00 AM through 7:00 PM Give one dose of Sinemet CR at 8:00 PM i itriite .is needed using motor fluctuation diaries as a guide
supplementation, fludrocortisone, midodrinc for orthostatic hypotension, urological medications for bladder dysfunction, and dietary changes for constipation. Hallucinations occur in about 3 0 % of treated patients; a loss of insight that the visions are not real or the appearance of psychotic thinking signals a particularly disabling complication. Hallucinations often improve with atypical antipsychotics such as quetiapine and clozapine. Cholinesterase inhibitors may reduce hallucinations in some patients. Sleep disorders may respond to hypnosedatives, tricyclic antidepressants, or nighttime dopaminergic therapy. Excessive daytime sleepiness may respond to methylphenidate or modafinil. Surgical Treatment of Parkinson's Disease. Despite decades of experience with the medical treatment of PD, many patients with moderate to advanced disease have a poor quality of life because of fluctuating medication response, troublesome dyskinesia, or i.-dopa-unresponsive symptoms. For these reasons, there has been a resurgence of interest in surgical approaches to motor dysfunction in PD. Palliative surgical approaches include stereotactic destruction of physiologically defined overactive brain nuclei (thalamotomy, pallidotomy), deep brain stimulation (DBS) using implanted pulse generators, and the implantation of cellular sources of dopamine. Surgical approaches aimed more at the degenerative process itself include delivery of trophic factors using implanted pumps or by gene therapy and cellular transplantation. Stereotactic thalamotomy reduces or eliminates contralateral rest tremor and reduces rigidity in 7 5 - 8 5 % of patients, but there is no effect on bradykinesia, and bilateral procedures can harm speech and cognition. Thalamic DBS is similarly efficacious {Rehncrona et al. 2003) but is better tolerated and can be performed bilaterally without serious effects on speech and cognition. Stereotactic posteroventral pallidotomy effectively reduces contralateral L-dopainduced dyskinesia and modestly improves akinesia in the off state. Overall, about 7 0 % of patients improve. Contralateral dyskinesia improves most of the time, about 90%, Off-period motor disability improves by about 30%, although most studies showT no substantial improvement over that produced by L-dopa m the on state. There is a 1.2% risk of death and about a 3.8% risk of intracerebral hemorrhage or infarction from pallidotomy (de Bic et al. 2002). Pallida! DBS has had limited study, but its efficacy seems equivalent to structural pallidal lesions. In a large multiccnter study, 38 patients with bilateral pallidal DBS showed significant reductions in off time and in the severity of disability in the off period, dyskinesias were improved, but l.-dopa dose could not be reduced {Deep-Brain Stimulation for Parkinson's Disease Study Group 2001). Subthalamic DBS has become the preferred surgical procedure for patients with advanced PD, despite the lack of a well-designed randomized efficacy trial, STN stimulation is associated with 4 4 - 5 2 % improvement in
MOVEMENT DISORDERS motor severity in the off state and a smaller improvement in the on state. Unlike other surgical procedures, STN DBS allows reductions in antiparkinsonian drug dose (DeepBrain Stimulation for Patkinson's Disease Study Group 2001). Pharmacological suppression of excessive STN firing may be possible with a gene therapy approach that uses adc no-associated viral vector delivery of glutamic acid decarboxylase, the enzyme that synthesizes GABA. This technique is now in preliminary human trials. PD is a condition that seems ideally suited for neurotransplantation. Most symptoms relate to degeneration of a single cell type in a ncuro.inatrimically small defined region, and dramatic improvements can be obtained by replacing the product of the degenerating cells. Animal experimentation supports the concept that human fetal SN cells implanted into the striatum survive and establish functional connections with target neurons there. Early trials of adrenal medullary autografts showed disappointing results and unacceptable morbidity. Xenografts appear poorly efficacious and are haunted by concerns about cross-species mtivuon. Open trials ol bilateral human fetal SN transplants into the putamen suggested substantial improvements in the primary symptoms of PD, significant improvements in PET scan measures of dopaminergic function, and robust survival of engrafted cells. The first randomi/.ed, sham surgery-controlled study of human fetal transplantation involved 40 patients with advanced PD. These patients were randomly assigned to sham surgery (bilateral burr holes without dura! penetration) or implantation of tissue obtained from two fetal brains per side. Despite changes in PET scans that confirmed increases in dopaminergic innervation and autopsy evidence of cell survival, there was no improvement in the primary endpoint, a global measure of improvement. There were significant improvements (1834%) in objective rating scales, particularly in the subgroup of transplant recipients who were 60 years old or younger. However, some patients developed dyskinesias or dystonia, even in the absence of exogenous dopaminergic stimulation. In some cases, subsequent surgeries were required to control these dyskinesias (Freed et al. 2001). for the present, it is clear that without major refinements, human feral transplantation is not likely to be a useful intervention
for PD. Delivery of trophins or other substances directly to the brain parenchyma has been a recent focus of investigation. Glial-derived neurotrophic factor (GDNF) is a neuropeptide with neurotrophic properties for dopaminergic neurons. In rat models of PD, intracerebral administration has both protective and restorative effects. A phase II trial of monthly intracerebroventricular bolus injections of GDNF in 85 patients with moderately advanced PD showed the treatment was poorly tolerated. No efficacy was demonstrated, likely because the compound did not penetrate into the target tissue area (Nutt et al. 2003). Early clinical trials of intrastriatal GDNF pumps are in progress.
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Delivery of GDNF to the striatum using lentiviral or other vectors has shown some promise in animal models of PD, but clinical trials have not begun. Irrespective of the type of surgical approach, neurosurgery for PD should be performed only by experienced functional neurosurgeons in centers with multidisciplinary teams including movement disorders neurologists, physiologists, and other support personnel. Patient selection is very important. The best surgical results arc achieved in younger, cognitively unimpaired patients with a robust response to dopaminergic therapy and good function in the on state. Many surgeons will not operate on patients who arc older than 75 years, because of an increased risk of morbidity in the elderly. Other common reasons to exclude patients include cognitive or psychiatric impairment, insufficient clinical severity, neurounaging abnormalities, and poor motivation or comorbid systemic illness. It is important to recognize that long-term outcomes have not been established for most surgical procedures.
Genetic Parkinsonisms A number of genetic parkinsonisms have been described (Table 77.12). These discoveries have helped elucidate the ways in which single-gene abnormalities might predispose to a degenerative disease and have helped shed light on the cellular processes that underlie sporadic PD as well. Two missense mutations in the ;tlpha->yiniclcin gene on the fourth chromosome (PARK1) have been described in two Mediterranean pedigrees with highly penetrant asymmetrical I.ewy body parkinsonism (Polymeropoulos 1998), The onset of parkinsonism is often before age 45 years and affective disturbance is more common and prominent than in sporadic PD. However, clinical overlap with sporadic PD is considerable and individual cases of PARK1 are indistinguishable from sporadic PD. Both described mutations accelerate the production of alpha-synuclein protofibrils. High levels of oxidative stress in dopaminergic neurons and catecholamine-induccd inhibition of the conversion of toxic to stable alpha-synuclein may explain the selective vulnerability of dopaminergic neurons to the alpha-synuclein mutation. A much more common inherited parkinsonism is PARK1. PARK2 is a recessively inherited early onset parkinsonism linked to mutations on the sixth chromosome. PARK2 is an early onset parkinsonism with mean onset near 30 years of age. PARK2 is often a symmetrical parkinsonism, with prominent dystonia at onset. There is a robust response to antiparkinsonian therapy, although these patients are plagued by early and ultimately severe motor fluctuations. Dozens of causative mutations have been discovered. Homozygous mutations result in the absence or truncation of the parkin protein, a ubiquitin ligasc involved in the ubiquitin proteasome protein degradation system. The substrates for parkin have not
,
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NEUROLOCiCAL DISEASES
Table 77.12:
Genetic forms of parkinsonism Pathology
Variant (chromosome)
Onset Pattern (yr)
PARK1 (4) PARK2 (6) PARK3 {4} PARK4 (4) PARK5 (4) PARKS (1) PARK7(1) PARKS (12) PARK 10(1)
AD AR AD AD AD? AR AR AD ?
Dementia
30-50 ++ 20-50 50s ± Early ++ 50s 30s 30s 40-60 Eate ?
Asymmetry
Tremor
Dopa response
+++± 1 +++ +++ +++ +++ +++ ?
+++ ± +++ +++ +++ +++ ++ +++f
-H~H +++ 1+++ +++ +++ +++ +++ ?
been conclusively demonstrated, but rau and alphasynuclein may be among them. Because the proteins are not ubiquinated, Lewy bodies do not generally form. Parkin mutations are thought to cause up to 7 7 % of parkinsonism with onset before age 20 years, but only 3% of parkinsonism between 30 and 45 years (Lucking et al, 1998). A mutation in the ubiquitin carboxy-terminal hydrolase (UCH-L1) gene (PARKS) has been described in a German sibling pair with parkinsonism. This enzyme is important in dissociation of monomeric ubiquitin from the polyubiquirin chain after proteolysis, thus in tecycling ubiquitin. The pathology of this hereditary parkinsonism is not known. Two consanguineous pedigrees from the Netherlands and Italy (PARK?) have been found to have homozygous mutations in the DJ-1 gene on chromosome 1, with resulting loss of function of the highly conserved DJ-1 protein, believed to be involved in cellular protection against oxidative stress (Bonifati er al. 2002). Point mutations in the noncoding region of NR4A2 (Nl'RKl) gene on chromosome 2 have been described m some patients with otherwise typical idiopathic PD (Le et al. 2003). NR4A2 is a member of the nuclear receptor superfamily of proteins. It is thought to be essential for differentiation and maintenance of nigral dopaminergic neurons. In other forms of familial parkinsonism, linkage to various regions of the genome has been described, although the causative genes remain unknown. In some northern European families, parkinsonism is linked to the second chromosome (PARK3). Onset, presentation, and course are similar to idiopathic PD. A kindred from Iowa has an autosomal dominant parkinsonism with reduced penetrance that is linked to the fourth chromosome (PARK4). These patients show early onset, slowly progressive L-dopa-responsivc parkinsonism with behavioral and psychiatric distutbances and blepharospasm. A genetic locus on chromosome 1 is responsible for PARK6 and a locus on chromosome 12 is responsible for PARKS, a Iowpenetrance autosomal dominant parkinsonism seen in a Japanese family. One family with maternal inheritance and a mitochondrial DNA mutation has been reported, but
Other signs Dystonia Tremor
Dystonia
Nigral degeneration?
Lewy bodies?
Yes Yes Yes Yes Yes ? ? Yes ?
Yes Rarely Yes Yes Yes ? ? No ?
the relative importance of mitochondrial DNA abnormalities remains unknown in the PD population at latge.
Dementia with Lewy Bodies 1)1.B is the second most prevalent degcnenur, e dementia after Alzheimer's disease. It is a progressive dementia characterized especially by fluctuating cognitive impairment, prominent disruption of attention and visuospatial abilities, visual hallucinations, and parkinsonism. RBD and depression are also very common. Patients with DLB arc extremely sensitive to dopamine receptor antagonists and experience severe parkinsonism when treated with neuroleptics. Characteristic pathological changes include cortical and brainstem Lewy bodies. Spongiform changes, neurofibrillary tangles, and dystrophic Lewy neuritis may also be seen, and overlap with Alzheimer's disease is considerable. Treatment of DLB is difficult. Although antiparkinsonian agents are used to treat parkinsonian signs, the degree of sensitivity of parkinsonian signs to dopaminergic therapy has not been well defined. Psychiatric and behavioral changes may improve with atypical antipsychotics. An open-label study found improvements in delusions, apathy, agitation, and hallucinations with rivastigmine treatment, but these findings should be corroborated in controlled clinical trials.
Multiple System Atrophy MSA is a relatively new diagnostic designation that includes disorders with various combinations of pyramidal, extrapyramidal, cerebellar, and autonomic features. Within this category are subtypes named for their predominant clinical manifestations. The more purely parkinsonian MSA {MSA-P) replaces the term striatonigral degeneration. Cerebellar MSA {MSA-Q replaces the term olivopontocerebellar atrophy. Autonomic MSA [MSA-A) replaces the term Shy-Drager syndrome. MSA is considerably more rare than PD, with a prevalence of 4-5 per 100,000. It is a disease of adulthood
MOVEMENT DISORDERS affecting men and women, with a mean age at onset of 54 years. The clinical distinction between I'D and MSA can be difficult and misdiagnosis is common. The most common signs in pathologically confirmed cases are parkinsonism (87%), autonomic dysfunction (74%), cerebellar ataxia (54%), and pyramidal signs (49%). MSA-P usually presents with symmetrical parkinsonism, often without tremor. Although there may be a positive response to Ldopa, this is generally relatively short lived. Many patients develop midline dystonia, especially antecolic head posture and stridor, and dystonia that is induced or worsened by Ldopa is common (Plate 77.111). Patients often have involuntary gasping or deep sighing when awake and apnea during sleep. Autonomic signs include orthostatic hypotension, incontinence, and impotence. Patients with MSA-C have parkinsonism with prominent cerebellar signs, especially wide-based ataxic gait. Autonomic signs are variably present. Patients with MSA-A generally present with autonomic failure. Early signs are incontinence in women and impotence in men. Orthostatic hypotension is the rule. There seems to be substantial residual sympathetic tone in MSA, so orthostatic hypotension is generally accompanied by supine hypertension, making treatment difficult. Clinical tests of autonomic dysfunction may be helpful in diagnosis or treatment. Testing of cardiovascular reflexes such as heart rate variability- at rest and during forced respiration, as well as blood pressure changes during headup tilt, may help establish a clinical diagnosis of MSA. A lack of responsiveness of growth hormone to clonidine challenges and denervation on rectal sphincter electromyography (EMG) are also characteristic findings. T2weighted MRI brain scans may show a hyperintense rim at the lateral edge of the dorsolateral putamcn, with decreased signal within the putamcn. Cruciform hyperintensity within the pons, the "hot cross bun" sign, may also be a helpful sign. Although MRI brain scans differentiate MSA from PD, they do not adequately distinguish among the subtypes of MSA (Bhattacharya et al. 2002). At autopsy, MSA brains show neuronal loss and gliosis in the striatum, SN, locus ceruleus, inferior olive, pontine nuclei, Purkinje's cells, intermediolateral cell column, and Onuf's nucleus in the sacral spinal cord. There are characteristic cytoplasmic inclusions in the glia, especially the oligodendroglia. These glial cytoplasmic inclusions contain alpha-synuclcin (Plate 77.1V). There is a severe depletion of cholinergic neurons in the pedunculopontine nucleus and laterodorsal tegmental nucleus. The etiology of MSA remains unknown. There are no known genetic forms of the illness and no known risk factors. Treatment of MSA is very difficult. There arc no specific interventions, and symptomatic therapies provide only partial relief of disability. Parkinsonism may respond to i.-dopa, particularly early in the disease course, but the results are not dramatic or sustained. DAs are not helpful and may be poorly tolerated because of orthostatic hypotension. There is no effective treatment for the
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cerebellar signs. Orthostatic hypotension may improve with nonpharmacological measures such as liberal salt and water intake, compressive stockings, and sleeping with the head up, but most people require pharmacotherapy with fludrocortisone, midodrinc, or other agents. Treatment of orthostatic hypotension often worsens supine hypertension. Even in the best hands, MSA has a poor prognosis, with a mean survival of 7-9 years.
Progressive Supranuclear Palsy In 1964, Steele, Richardson, and Olszewski described a progressive illness characterized by vertical supranuclear ophthalmoplegia, axial rigidity, pseudobulbar palsy, and mild dementia. P.uholn^ical findings inckided neuronal loss, gliosis, neurofibrillary tangles, and granulovacuolar degeneration in neurons of the brainstem. PSP is a rare disease; prevalence estimates range from 1.39-6,4 per 100,000, Men are affected more often than women. PSP typically begins in the sixth to seventh decades of life with gait disorder and falling. Patients develop an akinetic-rigid state with symmetrical signs and prominent axial rigidity. In contrast to the flexed posture of patients with PD, those with PSP may have an extended trunk or retrocolic neck posture. A characteristic facial appearance with a wideeyed stare, furrowing of the forehead, and deepening of other facial creases allows experienced clinicians to make an instant diagnosis (Plate 77,V). Pseudobulbar palsy with dysarthria and dysphagia lend the patient a characteristic dysarthria with spasticity, hypokinesia, and ataxia, and often "silent" aspiration. Frontal lobe features are common. There is striking executive dysfunction early in the disease course and concrete thought, difficulty shifting set, decreased verbal fluency, and personality changes such as impulsiviry and poor judgment are nearly universal, Apraxia is often seen. A progressive apathetic dementia ensues. Supranuclear vertical gaze palsy may not appear until later in the disease course, and some patients may never develop gaze palsy. Atypical presentations are often seen, especially pure dementia, PSP is rapidly progressive. By the fourth year of illness, half of patients need assistance for walking and have dysarthria and visual symptoms, Dysphagia becomes prominent shortly thereafter. The median interval from onset to wheelchair dependence is 8.2 years. The diagnosis of PSP is usually made by clinical criteria. Electro-oculographic recordings in PSP show decreased amplitude and normal latency of horizontal saccadic eye movements. Typical MRI signs of PSP include midbrain atrophy, increased signal in the midbrain and GP, atrophy or increased signal in the red nucleus, third ventricle dilatation, and atrophy of the frontal or temporal lobes (Schrag et al. 2000a) At autopsy, the midbrain in PSP is atrophied and the sylvian aqueduct is dilatated. The SN is depigmented and appears orange and shrunken. The locus ceruleus may also
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NEUROLOGICAL DISEASES
show some depigmentation, but this is less prominent than in idiopathic PD. Other structures may also show atrophy, most notably the frontal lobe, STN, and superior cerebellar peduncle. Histopathologically, the degenerative process involves mainly the basal ganglia, dicncephalons, and brainstem. There are tufted astrocytes in the motor cortex and the striatum, and the typical neuronal lesion is the globose neurofibrillary tangle, made up of hypcrphosphorylated four-repeat tau protein filaments (Plate 77.VI). PSP almost always occurs sporadically, yet an increasing number of familial cases suggest a genetic etiology in some cases. Pedigrees with apparent dominant and recessive inheritance have been described. Affected families may show phenotypical heterogeneity, with some affected persons showing dementia, dystonia, gait disorder, or tics. Mutations in the tau gene have been reported in patients with a familial PSP-like illness, but these have been quite rare and mutations are not believed responsible for most PSP cases. However, patients with PSP are homozygous for a common haplotype that contains a normally occutring polymorphism in the tau intron immediately preceding exon 10 (Morris et al. 2002). No toxic, viral, or other environmental risk factors have been described. According to retrospective reviews of response to various treatments, dopaminergic agents, particularly i.-dopa, aid about 4 0 % of patients. A few patients improve with amitriptylinc, imipramine, methysergidc, or 5hydroxytryptophan, DAs have not shown efficacy in small clinical trials. A randomized placebo-controlled trial of donepezil showed modest cognitive improvements but poor tolerability (Litvan et al. 2001). Botulinum toxin injections may be useful to treat blepharospasm or retrocollic neck posture in PSP (Muller et al. 2002). The prognosis of PSP is poor with a median duration of survival of 10 years.
Corticobasat Degeneration In 1967, Rebeiz et al. described three patients with akinetic rigidity, apraxia, dystonia, tremor, and aphasia, who at autopsy had pale achromatic ballooned neurons similar to those seen in Pick's disease. The condition was named corticodentatomgral degeneration with neuronal acbromasia in 1989 but has since become known as CBD. Although CBD generally brings to mind a particulat motor syndrome of asymmetrical rigidity, apraxia, and cortical sensory dysfunction, its underlying pathological features may be seen in other clinical syndromes including progressive aphasia and frontal lobe dementia (Dickson et al. 2002). CBD is exttcmely rare. The mean age at onset is 60-64 years. In its most recognizable form, it is predominantly a motot disease, but it is a clinically heterogeneous disorder. Motor signs include parkinsonism with strikingly asymmetrical rigidity, asymmetrical dystonia, myoclonus, apraxia, alien limb, and cortical sensory loss. Cognitive signs range
from subfluent aphasia in patients with predominantly right-sided motor signs to a generalized dementia. Patients with CBD have cortical atrophy on MRI, with widening of the sylvian and interhemisphcric fissures and dilatation of frontal, parietal, and temporal sulci. In about half, atrophy is asymmetrical {Schrag et al. 2000a). Fluorodeoxyglucosc (FDG) PET scans show hypomcrabolism in the thalamus and motor cortex contralateral to the more involved arm {Luttc et al. 2000), SPKCT scans show significant asymmetry of cortical blood flow in CBD (Zhang et al. 2001). One study found elevated levels of tau protein in cerebrospinal fluid (CSF) in CBD patients, but this test is not clinically available. At autopsy, patients with a clinical syndrome consistent with CBD have gross brain atrophy. Typical microscopic changes arc tau-positive neuronal and glial lesions, especially gray and white matter astrocytic plaques and threadlike lesions, and neuronal loss in the cortex and SN. The inclusions are formed of hypcrphosphorylated four-repeat tau (Forman et al. 2002). Overlap with other conditions including Alzheimer's disease, l'SP. I'D, progressive aphasia, frontotemporal dementia (FTD), and hippocampal sclerosis is common. As with other tauopathies, the etiology of CBD is unknown. There are no familial forms of the illness and no mutations in the tau gene have been identified. There is clinical and pathological overlap with other tauopathies, and patients with CBD share a similar tau haplotype with patients with PSP. There is no treatment for the degenerative process. Parkinsonian features are not dramatically responsive to dopaminergic drugs, but about 2 0 % of patients have some improvement in parkinsonism with L-dopa. Benzodiazepines, particularly clonazepam, may help myoclonus. Botulinum toxin injections may improve function in dystonic limbs early in the disease and help relieve pain and facilitate care in advanced disease. The prognosis is poor, with a reported median survival after onset of about 7 years.
Lrontotempnr.il
Degeneration
Willi
1'arkiiiMiiiism
Linked
to Chromosome 17 FTD is a group of illnesses characterized by behavioral changes and neuropsychological evidence of frontal lobe dysfunction. They include Pick's disease, pallidopontonigral degeneration, disinhibition-dementia-parkinsonismamyotropby, familial multiple system tauopathy with presenile dementia, familial subcortical gliosis, FTD, FTD with ALS, FTD with inclusion body myopathy, and FTDP17. In up to 6 0 % of patients with FTD, there is a positive family history. Genetic loci on chromosomes 17 (FTDP17), 9 {FTD with ALS, and FTD with inclusion body myositis), and 3 (FTD) have been described. There is considerable phenotypical and genotypical heterogeneity in FTDP-17. The disorder most often begins
MOVEMENT DISORDERS
in the fifties or sixties with personality and behavioral changes, including disinhibition and aggressiveness, and frontal executive dysfunction. Other common signs include social misconduct, stereotyped verbalizations, impaired recent memory, and parkinsonism. Some families present with early parkinsonism. Many mutations have been reported in the tau gene. They comprise mainly three groups: mutations in the coding region for a microtubulebinding domain, resulting in a dysfunctional protein; mutations outside the microtubule-binding domains; and mutations that alter the ratio of three- to four-repeat tau isoforms. Pathological findings include tau-positive neuronal and glial inclusions distributed variably throughout the brain (Lantos et al. 2002). In patients with prominent parkinsonism, there is severe neuronal loss in the SN. The response of parkinsonism to symptomatic treatment is not known. The prognosis is poor, with death occurring within 10 years.
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resembles PSP. Familial aggregation of cases has been noted, but prior attempts to elucidate a hereditary basis to the illness proved fruitless. A similar constellation of ALS and PDC has been reported on the Kii peninsula of Japan. Pathologically, the disorder is characterized by neuronal degeneration and abundant neurofibrillary tangles in the brain and spinal cord. A recent reanalysis of a patient registry suggests that both the spouses and the offspring of persons with PDC have a significantly higher risk of themselves developing ALS-PDC, suggesting both environmental and genetic risk factors (Plato et al. 2002). The critical age for exposure to the environmental factor was adolescence or early adulthood. Despite extensive analysis of the diet and other environmental factors, the etiology of PDC Guam remains unknown, although neurotoxic damage from the cycad nut has been implicated.
Guadeloupean Parkinsonism Bilateral S tri at op a Hid o dentate Calcification (Fahr's disease) Calcification of the basal ganglia has many causes. It is an incidental finding in up to 1% of all CT brain scans. Basal ganglia calcifications can also be seen in infectious, metabolic, and genetic disorders affecting this brain region. There are familial and sporadic forms. When symptoms occur, they usually begin in adulthood, between age 30 and 60 years. Cognitive dysfunction, cerebellar signs, dysarthria, pyramidal signs, psychiatric illness, gait disorder, and sensory impairment are common. About half of symptomatic patients have movement disorders. Among these, parkinsonism and chorea are most common. Fewer than 10% of patients have tremor, dystonia, athetosis, or orofacial dyskinesia. The presence of symptoms correlates with the amount of calcification (Manyam et al. 2001). Calcification is most often seen in the GP but may also occur in the caudate, putamen, dentate, thalamus, and cerebral white matter, as well as internal capsules. Calcium is deposited in the perivascular extracellular space. Dominant and recessive inheritance patterns have been described. No specific information is available about treatment.
Parkinsonism-Demenria Complex of Guam A high incidence of an ALS-likc illness among the Chamorros, indigenous people of Guam, was noticed more than 50 years ago. In the same population, a smaller number of people had a syndrome of parkinsonism with dementia, the parkinsonism-dementia complex (PDC). Some people had both motor neuron disease and PDC. Early in its course, PDC appears variably, like PD, atypical parkinsonism, or PSP; however, in rhe end stages, it most
Over the past .5 years, a focus of atypical parkinsonism has been described in the French West Indies. So-called Guadeloupean parkinsonism shows clinical features of Ldopa-unresponsive parkinsonism, postural instability with early falls, and pseudobulbar palsy. More than 2 5 % of these patients have a phenotype like PSP (CaparrosLefebvre et al. 2002). The etiology of this form of parkinsonism is unknown, but exposure to dietary or other environmental toxins is suspected.
Vascular Parkinsonism (Lower Half Parkinsonism) As many as 3 - 6 % of patients with parkinsonism have a vascular etiology, but the true frequency is unknown. Vascular changes are common, but the cause and effect arc not always clearly established. Among stroke patients, parkinsonism is more common in patients with lacunar stroke. Vascular parkinsonism usually presents as a gait disorder with prominent start and terminal hesitation, as well as freezing. Postural instability and a history of falls are common. Many patients have dementia and corticospinal findings of incontinence. The pathology includes subcortical vascular disease with preservation of dopaminergic cells in the SN, The symptoms of vascular parkinsonism are unlikely to show a significant response to L-dopa, but a therapeutic trial is worth pursuing because as many as half of the patients improve somewhat. Amantadine may help some patients. Physical therapy may also be useful.
Postencephalitic Parkinsonism Between 1916 and 1927, there was a worldwide epidemic of encephalitis lethargica, which killed about 250,000
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NF.UROI.OGICAL DISEASES
persons and left an additional 250,000 with chronic disability. These survivors of the acute illness developed parkinsonism, usually within 10 years of the infection. PEP resembles PD, although more prominent behavioral and sleep abnormalities occur early in the disease course, extraocular movements are often abnormal, and oculogyric crises are common. Other common movement disorders include chorea, dystonia, tics, and myoclonus. Pyramidal tract signs are common. The pathological appearance of PEP includes degeneration of SN neurons with neurofibrillary tangles in surviving neurons. Although the etiology is presumed to be a virus, none has ever been identified. There have been no subsequent epidemics of encephalitis lethargica, although sporadic cases of PEP are occasionally reported. The symptoms of PEP tend to be Ldopa responsive, but behavioral complications such as hallucinations and delusions are common, limiting therapy.
Drug-Induced Parkinsonism Dopamine receptor-blocking drugs reproduce the major clinical features of PD, although signs arc usually symmetrica! and the tremor is more often present during posture holding than at rest. The most common causes of drug-induce parkinsonism (DIP) are the typical neuroleptic antipsychotic drugs, antidopaminergic antiemetics, and drugs that deplete presynaptic nerve terminals of dopamine, such as reserpme and tetrabenazine. Among the newer or "atypical" antipsychotics, the relative propensity to cause DIP is as follows: risperidone > ziprasidone > olanzapine > quetiapine > clozapine. This ranking reflects their respective affinity for the D2 receptor. A number of other drugs have been associated with DIP, including selective serotonin reuptake inhibitors, lithium, phenytoin, of-methyldopa, valproic acid, and the calcium-channel antagonists flunarizine and cinnarizinc, which are not marketed in the United States. DIP generally appears subacutely, after weeks to months of therapy. Although it is reversible, DIP may resolve very slowly, over a period of up to 6 months, and symptomatic treatment with anticholinergics, amantadine, or L-dopa may be required. Occasionally, parkinsonism docs not resolve, suggesting the offending drug likely has unmasked an underlying parkinsonism.
without Lewy body formation. Interestingly, despite the 10-year interval between exposure to the toxin and death, there was evidence of an active neurodegenerative process, including extracellular melanin and active neuronophagy. This suggests that intracellular mechanisms may promote neurodegeneration after a distant environmental insult (Langston et al. 1999). MPTP-induced parkinsonism is Ldopa responsive, but the response is complicated by the early development of motor fluctuations and dyskinesias, which may become severe, and psychiatric complications such as hallucinations. Cognitive function usually remains intact. Acute carbon monoxide poisoning is associated with parkinsonism, MRI scans show high-intensity white matter lesions and necrosis of the GP bilaterally. Cognitive signs including decreased short-term memory, attention, and concentration are common. Patients with neurological sequelae of carbon monoxide intoxication may experience gradual clinical and radiological improvement over months to years. Manganese toxicity is associated with L-do pa-unresponsive symmetrical parkinsonism with dystonic features such as oculogyric crisis. The disorder may progress for years following cessation of exposure. Striatal MRI T2-weighted hyperintensity may be present during the acute phase of the poisoning. F-dopa ]'TT -;c;uis in subjects with manganism show normal presynaptic dopamine function, suggesting postsynaptic pathology. The fungicide maneb (manganese cthylene-bis-dithiocarbamate) has also been shown to induce a toxic parkinsonism.
TREMOR Physiological Tremor A fine rremor of the outstretched limbs is a universal finding. Physiological tremor appears to originate in the heartbeat, mechanical properties of the limbs, firing of motoneurons, and synchronization of spindle feedback. Its frequency ranges from 7-12 Hz. It is usually not noticeable except with electrophysiological recording, but its amplitude is accentuated by fatigue, anxiety, fear, excitement, stimulant use, and medical conditions such as hyperthyroidism (Tabic 77.13).
Toxin-Induced Parkinsonism In 1982, a number of young California drug addicts developed acute and severe parkinsonism after intravenous injection of a synthetic heroin contaminated by MPTP. Subsequent study showed that the offending toxin was the metabolic product of MPTP produced by monoamine oxidase, 1 -methyl-4-phenyl-propion-oxypiperidine (MPP + ). Postmortem examination in patients 10 years after the original exposure showed severe loss of SN neurons
Essential Tremor Epidemiology and Clinical Features ET is one of the most common movement disorders. In population-based studies, the prevalence increases steadily with age, occurring in up to 5% of patients older than 60 years. The prevalence is higher in men than in women and in whites than in nonwhites. In its purest form, FT is a
MOVEMENT DISORDERS
Table 77.13:
Physiological classification of tremor
Mechanical oscillations Physiological tremor I ) s d l l : l l i < ! l ] K ll.lSL'll 1111
I F
Tensor veli palatini Levator veli palatini
Yes No
No Yes
None Olivary hypertrophy
214S
NEUROLOGICAL DISEASES
clicks. The movements usually disappear during sleep. In essential FT, the palatal movements are produced by rhythmic movement of the tensor veli palatini muscle. Symptomatic PT is more common than essential PT and affects men more often than women. Symptomatic or secondary PT is not associated with ear clicks, because the levator veli palatini rather than the tensor veli palatini is involved. Simultaneous tremor of other regional structures with cranial nerve innervation may be seen. Some patients have oscillopsia from pendular nystagmus. Laryngeal involvement may interrupt speech or may cause rhythmic involuntary vocalizations. Rhythmic limb tremor may be seen. In patients with symptomatic PT, hypertrophy of the superior olive is demonstrable on MRI brain scans. Causative structural lesions are found in the brainstem or cerebellum within the Guillaiu-Mollaret triangle, which connects the dentate nucleus with contralateral red nucleus and inferior olive (Deuschl and Wilms 2002), Many underlying etiologies have been reported, including neurodegenerative, infectious, inflammatory, dcinye I mating, traumatic, ischemic, and other disorders. Characteristic pathological changes include enlargement of olivary neurons with vacuolation of the cytoplasm. Astrocytic proliferation with aggregates of argyrophilie fibers may also be seen. The pathophysiology of PT is incompletely understood, but it is believed that in symptomatic PT, damage to the dentato-olivary tract induces synchronization of cells in the inferior olive. The firing rhythm appears to be determined by membrane properties of the olivary neurons. This rhythm is then propagated through the inferior cerebellar peduncle to the contralateral cerebellar hemisphere, where it interferes with oculomotor, cerebelloreticular, and cerebellospinal system*. [Vii^thl and Wiims 200.V:. Treatment of PT is difficult. Because of the rarity of the condition, there ate no randomized controlled clinical trials of therapeutic agents. Phenytoin, carbamazcpinc, clonazepam, diazepam, trihexyphenidyl, and baclofen are considered first-line agents in the treatment of PT, Second-line drugs include 5-HTP, and presynaptic amidopaminergic drugs such as tetrabenazine. Sumatriptan has been reported to aid a single patient. Injections of hotulinum toxin into the tensor veli palatini muscle have been reported beneficial in essential PT.
CHOREA Huntington's Disease The first complete description of I 11) is attributed to George Huntington, in 1872. He accurately reported the salient clinical features of the disease, its pattern of transmission from parent to child, and its dismal prognosis, HD is a highly penetrant autosomal dominant disease characterized by a progressive movement disorder
associated with psychiatric and cognitive decline, culminating in a terminal state of dementia and immobility. Epidemiology and Clinical Features Prevalence figures for HD vary depending on the geographical area, but the best estimate is 10 per 100,000. The disorder is reported in all races, although it is much more common in Scotland and Venezuela and less common in Hnland, China, Japan, and black South Africans. HD usually begins between the ages of 30 and 55 years, although it has been reported to begin as early as age 2 years and as late as age 92 years. About 5% of cases begin in patients younger than 21 years; the juvenile phenotype differs from the adult phenotype, and patients are often misdiagnosed. HD is a progressive degenerative disease that affects movement, behavior, and cognitive function (Kirkwood et al. 2001). Common symptoms of the early, middle, and advanced stages of the illness are outlined in Table 77. Id. When clinical illness begins, it does so gradually and it is best to define a "zone," rather than a time of onset. Patients with HD may present with motor signs (about 60%), with behavioral signs (about 15%), or with both motor and behavioral signs (about 25%). Patients themselves may be unaware or unconcerned about early cognitive and motor changes. Concerned family members often bring them to medical attention. A change in the ability to generate saccadic eye movements and their speed is often the earliest sign. A blink or head thrust may be required to initiate saccadic eye movements. The motor disorder usually begins with clumsiness and fidgetiness that evolves into chorea. The presence and severity of chorea vary markedly from subject to subject and over time. In addition to chorea, patients with HD have hradykmesia and motor impersistence, with difficulty sustaining ongoing movement. They may be unable to maintain forced eye closure, hold the mouth open, or protrude the tongue for long periods. With advancing disease, there is progression of bradykinesia and dystonic movements appear. The chorea may become
Table 77.16: Early Clumsiness Chorea Irritability Sadness Depression
Symptoms of Huntington's disease Middle
Unsteadiness Dropping things Gait disorder Sleep disorder < ognim c dysfunction Decreased motivation Decreased memory Sexual dysfunction
Late Weight loss Speech disorder V.\ allow ing disorder Bladder incontinence Bowel incontinence
Source: Adapted with permission from Kirkwood, S.C., Su, J. L., Couneally, P., &C Foroud, T. 2001, "Progression of symptoms in [he early and middle stages of Huntington disease," Arch Neurol vol, 58, no. 2, pp. 273-278.
MOVEMENT DISORDERS
somewhat less prominent or may continue to worsen. The gait disorder of HD is complex, with chorea, parkinsonism, lapses in tone of antigravity muscles, and ataxia. The walking patient with HD resembles a marionette, lurching, swaying, dipping, and bobbing. Tandem walking becomes difficult, then impossible. Ultimately, intractable falls lead to the wheelchair- or bed-bound state. Dysarthria and dysphagia progressively impair communication and nutrition, Most patients spend the last several years of their lives in nursing home settings and die of complications including pneumonia and head injury. Mean survival is 17 years, but the natural history varies and is influenced by genetic and environmental factors. Generally, patients with onset at a younger age have the largest number of CAG repeats and tend to progress more rapidly than patients with onset at an older age (see later discussion). The juvenile phenotype differs from the adult phenotype, with prominent parkinsonism and dystonia, even early in the course, and with myoclonus and seizures. Behavioral changes contribute mightily to disability in HD. Ninety-eight percent of patients show one or more behavioral symptoms (Paulsen et al. 2001) (Table 77.17). The most common changes in early disease are irritability, anxiety, and mood disturbance, irritability may be accompanied by verbal or physical aggression. Patients with HD often have a low threshold for anger and react to minimal provocation with an explosive response. Depressed mood is very common and 3 0 % of patients meet criteria for major depressive disorder. Mania and hypomania are seen less commonly than depression. The risk of suicide is increased as much as sixfold over the general population. Unmarried and childless persons living alone, those who are depressed, and those with a family history of suicide are particularly at risk. Fear of the disease leads to an increased risk of suicide, even in firstdegree relatives of affected individuals who are at autopsy found not to have inherited the mutant gene. Psychosis is rare and it may be difficult to treat. Obsessive-compulsive disorder has been reported but can be difficult to
Table 77.17:
Behavioral symptoms in Huntington's disease
Symptom
%
Dysphoria Agitation Irritability Ap:llh\ Anxiety Disinhibicion Euphoria Delusions Hallucinations
69 61 65 56 52 35 31 12 2
Source: Adapted with permission trtmi Paulsen, J. S., Ready, R. E., Hamilton, J. M., et al. 2001. "Neuropsychiatry aspects of Huiiiin^mn's diseasu," / Xrtirnl Nctirositrg Fsychialry vol, 71, no. 3, pp. 310-314.
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differentiate from frontal lobe personality with perseveration. Apathy increases in concert with disease severity and is a nearly universal feature of advanced disease. Behavioral and psychiatric disorders may predate the onset of overt HD by as long as a decade, reflecting early pathological changes in the nonmotor areas of the striatum. Because some behavioral signs may be episodic and respond to pharmacotherapy, their severity does not progress in a linear fashion with cognitive and motor cl!;in;:cs. Ik'h.u ior.il signs seem to ntiprow :n ilu KTIIUM.II stages of the illness, but ascertainment may be hindered by the severe physical disability of such patients. Cognitive changes are universal in HD. The dementia of HD tits the description of subcortical dementia with disordered attention, concentration, motivation, insight, judgment, and problem solving rather than traditional cortical signs such as aphasia and apraxia. Executive dysfunction renders affected persons unable to work, drive, and manage family finances relatively early in the disease course, but prominent global dementia occurs later. The diagnosis of HD in a patient with a typical clinical picture and a confirmed family history is straightforward. Unfortunately, the family history may be vague or it may be negative because of competitive mortality, misdiagnosis, denial, inaccurate parental information, or obfuscation. In addition, there is a small but definite new mutation rate as expansion occurs with transmission of a premutation. Although there is a broad differential diagnosis of chorea, there are few alternative causes of the fully developed syndrome. When the clinical suspicion of HD is high, the most cost-effective diagnostic procedure is genetic testing. Neuroimaging studies can show generalized or preferential striatal atrophy, but these findings are not specific for the disorder. Although volumetric analysis of the striatum shows declining volume even in presymptomatic gene carriers, many obviously symptomatic patients do not have clinically apparent striatal atrophy. Somatosensory evoked potentials are abnormal in 94% of patients with HD and abnormalities correlate with clinical signs of the illness. However, the use of these and other electrophysiological studies for diagnosis or measuring illness progression remains unproven. The direct DNA test for the CAG repeat expansion in the huntingtin gene is highly sensitive and specific. The availability of the HD genetic test makes possible the identification of mutant gene carriers long before they become symptomatic. However, because of concerns about the potential for occupational, insurance, and social discrimination and the lack of neuroprotective treatment interventions, only 3 - 5 % of eligible at-risk subjects pursue testing. Those who pursue testing do so either to help with reproductive choices or because their uncertainty about the future is unbearable. Women are more likely to request presymptomatic resting than men at equal risk. Although prenatal testing is also available, relatively few prenatal
2150
NEUROLOGICAL DISEASES
tests have been performed. Interested researchers, working in concert with lay organizations, have outlined principles that guide clinicians in the preparation of potential gene carriers for predictive genetic testing. These guidelines discourage genetic testing in asymptomatic minors and recommend genetic and psychological counseling before and after testing. One obvious concern is the risk that once given a positive genetic test result, the patient may have a major depression or other psycho pathology or may attempt suicide. When carefully managed, presymptomatic test programs are safe. In studies of life events after gene-carrier detection, less than 1% of patients have a potentially severe adverse outcome such as attempted or completed suicide or hospitalization for psychiatric illness (Almqvist et al. 1999). Adverse outcomes may be seen in patients whose predictive test suggests they are not gene carriers, the "survivor guilt" phenomenon. Depressive symptoms in such patients tends to become apparent several months after the testing process is completed, A premorbid history of depression increases the risk of an adverse outcome of testing, irrespective of test result, confirming the need for careful screening and counseling in genetic testing programs. Pathology The pathology of HL) includes prominent neuronal loss and gliosis in the caudate nucleus and putamen along with regional and more diffuse atrophy (Plate 77.VIII). At autopsy, only 2 0 % of the loss of total brain weight is explained by the striatal atrophy, suggesting a very widespread degenerative process. Large cortical neurons in layer VI are also involved, as are neurons in the thalamus, SNr, superior olive, lateral tuberal nucleus of the hypothalamus, and deep cerebellar nuclei. Within the striatum, GABAergic medium spiny neurons bear the brunt of the degenerative process. Early, there is preferential loss of GABAergic neurons that co-localize enkephalin, dynorphin, and substance P. These neurons are thought to predominate in the indirect pathway, accounting for difficulties suppressing adventitious movement early in the disease course. With disease progression, all GABAergic medium spiny neurons are affected, including those in the direct pathway, explaining the emergence of parkinsonism in later disease. Juvenile-onset disease, more severe from the beginning, resembles late-stage HD with degeneration of GABAergic neurons in both pathways. Etiology HD is a dominantly inherited condition caused by an unstable expanded GAG trinucleotide repeat in exon 1 of the huntingtin gene on the tip of the short arm of chromosome 4. Normal alleles have fewer than 30 GAG repeats in this region. Alleles with 30-35 repeats do not cause clinical disease but may become unstable, particularly
when transmitted by a man. Alleles with 36-39 repeats may cause disease, but the penetrance is reduced. Everyone with 40 or more CAG repeats in the huntingtin gene will develop the clinical illness unless there is early mortality due to another cause. Because of the inherent instability of the huntingtin gene, there may be expansion of the mutation with an increase u: repeat number during inrergenerational transmission. Because repeat instability of this mutation is much more common in spermatogenesis than in oogenesis, the offspring of men may have substantially greater CAG repeat lengths than their fathers. This feature accounts for the phenomenon of anticipation in HD. In large studies, there is an inverse correlation between the CAG repeat length and the age at disease onset. The extreme manifestation of this relationship is the association of juvenile-onset illness with repeat lengths of 60 or greater and onset within the ri:-,r decide with repeat k-iiiuhs o: 80 or greater. About 5% of patients present before the age of 21 years; in nearly all cases of juvenile-onset disease, the mutant allele is inherited from the father. Likewise, very late disease presentations often are associated with repeat lengths between 36 and 4 1 . The correlation between repeat length and age at onset is driven by a very tight relationship of these two factors at the two ends of the mutation spectrum. Indeed, although one can construct tables of median age at onset versus CAG repeat length (Table 77.18), the repeat length accounts for only abour 7 0 % of the variance in age at disease onset, suggesting that other genetic or environmental factors ate important. For this reason, the CAG repeat length is not a particularly useful tool for making predictions about disease onset and severity in individual patients. HD is a true dominant condition. Homozygotes do not have an earlier onset or more severe form of the illness, suggesting the disorder results from a toxic effect of the mutant protein, a so-called "gain of function." The huntingtin gene controls the synthesis of huntingtin,
Table 77.18: CAG-repeat length and age at onset of Huntington's disease CAG ffl
Median onset (95% confidence interval)
V)
66 (72-59) 59 (61-56) 54 (56-52) 49 (50-48) 44 (45^2) 42 (43-40) 37 (39-36) 36 (37-35) 33 (35-31) 32 (34-30) 28 (32-25) 27 (30-24)
•in
41 \2 43 44 45 46 I" IS 49 50
Source: Data used with permission from Rubinsztein, R., et al. Am J Hum Genet vol. 59, pp. 16-22.
Early Parkinson's disease Dopamine Transporter PET Studies [C-ll]RTI-32
Control
Parkinson's Disease
PLATE 77.1 Positron emission tomography scan with [' 'CJ-RTI-32, which labels the presynaptic dopamine transporter in a normal control (A) and a subject with early Parkinson's disease (B). There is asymmetrically reduced uptake in the Parkinson's disease, indicating asymmetrical loss of presynaptic dopaminergic neurons. (Courtesy Mark Guttman, M.D.)
PLATE 77.11 Brainstem Lewy bodies. (A) Hematoxylin and eosin-stained section of substantia nigra with a pigmented neuron containing two Lewy bodies. Each is an eosinophilic cytoplasmic inclusion with a halo, displacing neuromelanin. (B) Alpha-synuclein-immunostaincd Lewy body in a neuron of the substantia nigra. The alpha-synuclein protein is stained red in this preparation. (Courtesy Elizabeth Cochran, M.D.)
PLATE 77.111 Still images from videotapes taken 5 years apart in a woman with symmetrical parkinsonism and poor response to L-dopa. The images Illustrate the development of antecollis, suggestive of the diagnosis of parkinsonian multiple system atrophy.
PLATE 77.IV Glial cytoplasmic inclusion, immunostained with alpha-synuelcin, in the basal ganglia, typical of multiple system atrophy. Pathological section obtained from the brain of the patient illustrated in Plate 77.111. (Courtesy Elizabeth Cochran, M.D.)
PLATE 77.VI Globose neurofibrillary tangle and tufted astrocytes in progressive supranuclear palsy. (A) Tau-immunostained globose neurofibrillary tangles in neurons of the globus pallidus. (B) Gallyas silver-stained tufted astrocytes in the globus pallidus of a patient with progressive supranuclear paisy.
PLATE 77.V Typical facial expression of a patient with progressive supranuclear palsy, illustrating worried or surprised appearance, with furrowed brow and fixed expression of lower face.
Right Hand PLATE 77.VII sential tremor.
Left Hand
Writing sample from a man with asymmetrical postural and action tremor of es-
PLATE 77.VIII Pathology of Huntington's disease. (A) Glial fibrillary acidic protein immunostain of the caudate nucleus of a normal brain. (B) Glial fibrillary acidic protein immunostain of the caudate nucleus of a patient with Huntmgton's chorea. Note the decreased neuronal density and marked reactive astrocytosis, in comparison to the normal brain. (Courtesy Elizabeth Cochran, M.D.)
Huntington's Disease Dopamine D-2 Receptor PET Studies [C-ll]Raclopride
Control
Asymptomatic gene carrier
Symptomatic
PLATE 77.IX [ ''CJ-Raclopride positron emission tomography scans of a normal control subject, an asymptomatic carrier of the Huntington's disease gene, and a person with symptomatic Huntington's disease, showing progressive loss of D2-receptor-bearing striatal neurons.
MOVEMENT DISORDERS
a widely expressed protein of uncertain function. Huntingtin is a cytoplasmic protein, hut ubiquinated, mutant, proteolytic N-terminal huntingtin fragments form protein aggregates in the cytoplasm and nucleus of neurons. Mutant huntingtin causes misfolded protein stress. Huntingtin interacts with huntingtin-associated protein, a protein selectively exptesscd in the striatum, and glyceraldehyde3-phosphate, an enzyme essential for glycolysis, and other proteins (huntingtin-interacting proteins 1 and 2), A number of lines of evidence point to impaired mitochondrial function in HD, including abnormalities in complex I, II, III, and IV in caudate nuclei of affected brains. PET studies show reductions in striatal glucose metabolism and loss of dopamine Dj-receptor-bearing neurons in the striatum (Plate 77.IX) and MRS studies have suggested increased brain lactate levels. Systemic administration of the mitochondrial toxin 3-nitroproprionic acid models the disease in animals. Intrastnatal administration of the excitotoxins kainate and qurnolinic acid also reproduce the striatal lesions of HD. One theory that tics these animal models together is that of indirect excitotoxicity. Mitochondrial energy failure increases the vulnerability of the cell to excitotoxic injury because the resulting change in cell membrane potcnii.il result in '.o.ss ol thr magnesium ion ftom the KMDA-receptor-associated ion channel, allowing ligand-associated depolarization of the postsynaptic receptor and excitotoxic-mediated damage. Huntingtin may also interfere with the function of |n>-a-,vjiap:it density proum-95, a scaffolding protein associated with NMDA and kainate receptors, rendering these gluramate receptors hypersensitive. Mutant huntingtin also interferes with gene transcription, leading to an alteration in cell phenotypc and disrupting many cell functions. Mutant huntingtin may block the normal function of huntingtin to upregulate brain-derived neurotrophic factor. Mutant huntingtin likely also triggers apoptotic cell death (Evert et al. 2000).
Treatment As in all other neurodegenerative disorders, no treatment is yet proven to favorably influence disease progression. [.ike other neurodegencrations, many potential types of interventions might prove useful, such as blocking transcription of the mutant gene, enhancing chaperonc function, interfering with association and aggregation of the protein, improving cell biocnergctics and mitochondrial integrity, and interfering with the triggers of and the ultimate steps in the process of apoptosis. Clinical trials of antioxidants designed to slow down the progression of the disease have been disappointing. One large-scale study assessed the potential neuroprotective effects of the mitochondrial complex I booster coenzyme Q ! 0 (600 mg per day) or the antiexcitotoxic agent remacemide (600 mg per day) on the decline of the total functional capacity score over 30 months. The study demonstrated a
2151
trend toward slowing the decline in this measure of disability in the coenzyme Q]o treatment arm, but this did not achieve statistical significance. Remacemide showed no evidence of neuroprotection. A number of other potential strategies have shown promise in transgenic disease models, although they have not been studied in human safer)' and efficacy trials. These include the caspase inhibitor minocycline, creatine, lithium, ethyl eicosapentaenoic acid, cystaminc, bile acids, inhibitors of transglutaminase, and others. Like other neurodegenerative disease, there is no gold standard for determining disease severity or its rate of change over time. Studies relying on clinical rating scales must be quite large. For example, if one were to design a study of a neuroprotective agent that would slow HD progression 2 0 % , it would require 940 subjects per treatment arm and a 30-month study duration to achieve 8 0 % power to detect the protective effect (Marder et al. 2000). Because the number of potential subjects is relatively small (35,000), prioritizing agents for clinical testing are important, One intriguing discovery in HD is that in ttansgenic models, turning off the huntingtin gene not only stops progression of the experimental illness but also teverses pathological findings, including aggregates, and is associated with clinical improvement (Yamamoto et al. 2000). Apparently, continued production of the mutant protein is required for maintenance of cell dysfunction and ultimately for cell death. This argues for a period of cellular dysfunction before death and raises the possibility that neuroprotection might have the potential to at least partially reverse extant clinical features of the disease. Appropriate symptomatic treatment of HD begins with an assessment of the nature of the patient's complaint. Patients with chorea are often unaware of or untroubled by their involuntaty movements. Although typical neuroleptics represent the conventional approach to chorea, they have been shown not to improve function in HD and arc not used as much as in the past. Preliminary study suggests the glutamate antagonist amantadine may improve chorea in HD and is well tolerated in doses up to 400 mg (Verhagen Metman et al. 2002). Antidopaminergic drugs, particularly tetrabenazine, have been found effective in reducing chorea in patients with HD (Ondo et al. 2002). Tetrabenazine is available in many European countries and Canada and is currently studied in multiple centers in the United States. Atypical antipsychotics such as olanzapine may also be useful and may be preferable to typical neuroleptics because of lower risk of tardive dyskinesia (TD) with long-term use. Some patients * with prominent bradykinesia improve on dopaminergic therapy. Although psychiatric symptoms are ubiquitous in H D , there is little literature on the classification and appropriate treatment of these symptoms. Selective serotonin reuptake antagonis seem to improve irritability. aggression, depression, and obsessive-compulsive symptoms.
2152
NEUROLOGICAL DISEASES
Irritability may respond to carbamazepine or valproic acid. Olanzapine has been reported to be useful in patients with irritability and aggression.
Dentatorubral-Pallidoluysian Atrophy (Haw River Syndrome) DRPLA is an inherited neurodegenerative disease that appears to be rare outside Japan. Typical symptoms of DRPLA include chorea, ataxia, myoclonic epilepsy, dystonia, parkinsonism, psychosis, and dementia. Onset is usually in the twenties with death about 20 years later. Anticipation occurs with paternal transmission of the gene. The pathology of DRPLA includes degeneration of the dentate and red nuclei, the GP, and the STN. Ncurodegeneration may also be found in the cerebral white matter, putamen, medulla oblongata, and spinal cord (Oyanagi 2000). Neuronal nuclear inclusions stain for uliKjuitin and atrophin-1. There is also evidence for aberrant phosphorylation of the DRPLA protein complex and the nuclear membrane (Yazawa 2000). DRPLA is associated with an expansion of CAG trinucleotide repeat, in a gene on chromosome 12. In this region of the genome, the normal trinucleotide repeat length is 7-23. In DRPLA, the CAG repeat length is between 49 and 75. Because of the polyglutamine stretch in the mutant protein, neurodegeneration likely relates to interactions between the protein, other cellular components, and cellular proteins. The Haw River syndrome, described in a multigenerational African American family, is caused by the same repeat expansion as DRPLA. Clinical differences include lack of myoclonic epilepsy and the presence of subcortical white matter demy el i nation, basal ganglia calcifications, and neuroaxonal dystrophy. No information is available about the treatment of DRPLA, but as in HD, the clinician should be guided by the nature and severity of symptoms.
Neuroacanthocytosis and the McLcod Syndrome The term acantbocyte is derived from the Greek word for "thorn." Acamhocytes arc contracted erythrocytes with unevenly distributed thorny projections, often with terminal bulbs. Acamhocytes are seen in peripheral blood smears in patients with three neurological syndromes: abetalipoproteinemia neuroacanthocytosis and the McLeod syndrome (Rampoldi ct al, 2002). A broad spectrum of movement disorders is seen in neuroacanthocytosis and the McLeod syndrome. Epidemiology and Clinical Features All forms i>i iicuroacanthocyrosis are rare disorders. Autosomal recessive neuroacanthocytosis is characterized
by onset at around age .35 years of a progressive syndrome that includes a movement disorder and behavioral and cognitive changes. The movement disorder predominantly consists of chorea, dystonia, and tics; parkinsonism may occur in more advanced stages. There is also prominent orofacial dystonia with dystonic tongue protrusion interfering with eating. In addition, many patients exhibit lip and tongue biting and prominent dysarthria and dysphagia. Behavioral changes resemble those seen in HD with anxiety, depression, obsessive-compulsive disorder, and emotional lability. Subcortical dementia is a late feature. Seizures develop in about 5 0 % of patients. There may he myopathy or axonal neuropathy, and the creatine kinase level is elevated. In patients with neuroacanthocytosis, acamhocytes usually make up 5-20% of peripheral blood erythrocytes. Autopsy changes include atrophy of the caudate, putamen, GP, and SN with marked neuronal loss and gliosis. The cerebral cortex is relatively spared. Mutations in the CHAC gene on chromosome 9 that lead to the production of a truncated protein, chorein, of unknown function have been found in this syndrome. Homologous proteins in animals seem important in intracellular trafficking. McLeod's syndrome is an X-linked recessive disorder linked to a number of mutations in the XK gene, a gene for the Kell group of erythrocyte membrane glycoprotein antigens on the X chromosome. McLeod's syndrome usually begins around 50 years of age and has a slowly progressive course. The most common clinical feature is an axonal peripheral neuropathy. Some patients have evidence of myopathy as well, and all have elevations in serum creatine kinase level. The central nervous system illness is characterized by limb chorea. Oral movements and lip and tongue biting are less common than in neuroacanthocytosis. Facial tics are common, and some patients have dystonia. Seizures may be seen. Subcortical dementia and behavioral changes occur later in the disease course in about 5 0 % of patients. Cardiomyopathy and hemolytic anemia are other common manifestations. Neuroimaging studies may show caudate atrophy with secondarily enlarged lateral ventricles. Increased T2weighted signals in the lateral putamen may be seen on MRI scans. Pathological changes include intense caudate atrophy, loss of small cells, and gliosis in the dorsolateral putamen with less severe changes in the GP. Milder changes may be present in the thalamus, SN, and anterior horns of rhe spinal cord. Neurons in the cerebral cortex, STN, and cerebellum are spared. The reported mutations in the XK gene result in absence or truncation of the protein product. Kell is an endothelin processing enzyme. Endothelins arc important in proliferation and development of neural crest-derived cells and arc thought to be important in neurotransmitter release in dopaminergic neurons. No information is available about treatment of neuroacanthocytosis, but the physician should be guided by the clinical manifestations.
MOVEMENT DISORDERS Benign Hereditary Chorea Benign hereditary chorea (BHC) has been defined as a nonprogressive syndrome of inherited childhood-onset chorea wirh a good outcome in the absence of an underlying degenerative disease. Chorea is presenr from early childhood, usually from the first decade of life. It is nonprogressive and often associated with mild cognitive impairment (Brccdvcld et al. 2002). Some patients have dysarthria and dystonia. In many cases, the chorea improves during adolescence and young adulthood. The diagnostic rubric has been applied somewhat sloppily. Review of cases in the literature suggests that many cases so classified are more consistent with alternative diagnoses such as HD, myoclonic or other dystonias, ataxia-telangiectasia, or myoclonus. BHC is genetically heterogenous, but some families have a mutation in a region on chromosome 14 that harbors the 7777-'J gene, a transcription factor essential for lung, thyroid, and basal ganglia organogenesis (Breedveld et al. 2002). Symptomatic therapy of chorea with dopa mine-receptor blockers or dopainme-depleting drugs may be necessary.
Sydenham's Chorea Sydenham's chorea (SC) is one of the major manifestations of rheumatic fever, but it typically appears months after the index infection. Because of the widespread availability of antistreptococcal therapy, SC is extremely rare in developed conn tries. It is a disorder of children, mainly girls, between the ages of 5 and 75 years, with a mean age at onset of 8.4 years. The chorea begins insidiously but progresses over a period of weeks, and it generally resolves within about 6 months. Choreic movements arc usually generalized, but hemichorea may also be seen. Behavioral accompaniments such as restlessness, irritability, and obsessive-compulsive traits are common. It is a self-limited disorder, usually lasting up to 6 months. About 2 0 % of cases recur and multiple recurrences occur rarely. Knlargemeni oi the basal ganglia may hi- seen on MRI brain scan. Pathologically, SC is characterized by inflammation of the cortex and basal ganglia. Ann -basal ganglia antibodies can be detected by enzyme-linked immunosorbent assay and Western immu nob lotting and have a high sensitivity and specificity (Church et al. 2002). The mechanism of basal ganglia damage is likely molecular mimicry with cross-reaction between antibodies directed againsr streptococcal antigens and striatal antigens. Because it is often self-limited, the decision to treat SC depends on the magnitude of each patient's disability. A recent comparative trial suggested that valproic acid is the most effective treatment, followed by carbamazepinc and haloperidol. Because SC tends to be self-limited, periodic attempts should he made to wean therapy. Later in life, people who have survived SC may have a
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recrudescence of chorea in the presence of hormonal stress such as during pregnancy or estrogen treatment.
Ballismus (Hemiballismus, Hemichorea) Ballismus is a dramatic proximal, ballistic, flinging movement. Ballism most commonly affects the limbs on one side of the body (HB), but involvement in both legs (paraballismus) and both sides of the body (biballismus) has been reported. Ballism is usually classified with the choreas for a number of reasons: Ballistic and choreic movements typically coexist, over time ballistic movements arc often replaced by choreic ones, and animal models employing subthalamic lesions result in a mixture of choreic and ballistic movements. HB is relatively rare, but its true prevalence in an at-risk population, such as patients with acute strokes, is unknown. The mean age at onset is 48-75 years. The tempo of development of the movements varies with its underlying etiology. HB related to stroke appears suddenly or emerges more slowly in a recovering plegic limb. HB related to inflammation or tumor arises gradually. HB usually results from a relatively small lesion in the contralateral STN or in its afferent or efferent connections. Rarely, lesions in other locations, including even ipsilateral cerebral cortex and striatum have been linked to HB. Although the underlying lesion is usually cerebrovascular disease in the elderly and infectious or inflammatory disease in younger patients, any type of structural lesion, appropriately placed, can produce the characteristic movement. Metabolic disorders such as nonketotic hyperglycemia and drug exposure may also cause HB (Table 77.19). Loss of subthalamic excitation of the GPi results in a loss of inhibitory drive to the thalamus, thus excessive motor activity. Low firing frequency of the STN has been confirmed in a few cases using intraoperative recording. In the past, HB was thought to have a uniformly grave prognosis, with death resulting from exhaustion or cardiovascular collapse. In parr, this is related to a literature that was heavily based on clinicopatbological material. Better symptomatic and supportive care doubtless has improved survival and quality of life for patients with HB. More recent literature suggests that survival closely relates to the mortality of the underlying etiology, for example, survival rates following vascular HB mirror those of vascular disease, with only 3 2 % survival and 2 7 % stroke-free survival 150 months following the onset of the movciiK-111 disnrdi-v iRisfic ct al. 2i'^2;. The movements often regress or become more choreic over several months. However, they can be quite exhausting or disabling when present, and treatment is usually indicated acutely and in patients whose movements do not resolve spontaneously. Drugs with antidopaminergic properties arc expected to reduce this excessive thalamocortical drive, and thus benefit patients with HB. Although the rarity of the condition has
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NEUROLOGICAL DISEASES
Tahle 77.19:
Etiology of hemiballismus
Structural lesions Cerebrovascular disease Infarction Transient ischemic attack Hemorrhage Arteriovenous malformation Subarachnoid hemorrhage Subclavian steal syndrome Infection Syphilis Tuberculoma Toxoplasmosis Acquired immunodeficiency syndrome Influenza A Tumor Pituitary microadenoma Metastasis Immune mediated Systemic lupus erythematosus Sydenham's chorea Behcet's disease Scleroderma Other Static encephalopathy Head injury Demyelinating disease Thalamotomy Heredodegenerative disease Metabolic Nonketotic hyperosmolar hyperglycemia Drug induced Phenytoin and other anticonvulsants Oral contraceptives Neuroleptics (tardive)
precluded controlled clinical trials, there is ample evidence from case series and reports that dopamine antagonists and dopamine depletcrs effectively decrease choreic movements. Beneficial results have also been obtained using gabapentin and valproic acid. Periodic efforts should be made to taper or discontinue these therapies when possible. Stereotactic thalamotomy or pallidotomy may be considered in patients who prove refractory to medications (Suarez et al. 1997).
Senile Chorea Senile chorea is an idiopathic disorder characterized by the development in old age of continuous mouthing, chewing, or tongue movements. Prevalence estimates vary, but as many as one third of some populations may be affected. The diagnosis of senile chorea should be made with caution, because extensive investigation often reveals an alternative diagnosis, For example, among 12 senile patients with chorea, 11 were found to have H D , antiphospholipid antibody syndrome, hypocalcemia, TD, or
Fahr's disease. Pharmacological therapy should be considered for patients with disabling movements. Antidopaminergic drugs are the most effective, but their use should be accompanied by close surveillance for the development
of TD.
TARDIVE DYSKINESIA TD is a movement disorder that develops in the context of chronic dopamine-receptor blockade, usually in patients who arc chronically treated with neuroleptic drugs or antiemetics. The prevalence of TD is as high as 2 0 % of patients treated with typical neuroleptics. TD usually requires a minimum of 6 weeks or more of dopaminereceptor blockade, but onset as soon as after the first dose has been reported. Reported risk factors include age, female gender, affective disorder, and edentulousness. Although the stereotypical form of TD is most common, other movement disorders, such as chorea, akathisia, dystonia, tics, and myoclonus, may be seen as part of TD. Tardive parkinsonism has also been reported, but some of the patients with parkinsonism persisting years following withdrawal of the offending neuroleptic have been found to have pathological evidence of PD. The classic appearance of TD is repetitive, stereotypical (e.g., chewing) movements of the mouth, tongue, and lower face {oralbuccolingtial dyskinesias). In contrast to HD, the upper face tends to be spared (sec Chapter 24). Choreic movements may also affect the trunk and pelvis, causing respiratory dyskinesia and pelvic thrusting. Limb chorea and restlessness (akathisia) may also be seen. The pathophysiology of TD is incompletely understood. Denetvation supersensitivity of the dopamine receptor is the most likely cause. PET studies document upregulation of D2 receptors in neuroleptic-treated patients (Silvestri et al. 2000). There are other theories including oxidative stress and insufficiency of GABA. Genetic susceptibility factors that might be involved in increased risk of TD include polymorphisms of the dopamine D 3 receptor gene and the 5-HTc serotonin receptor gene (Scgman et al. 2000). The most important intervention in TD is to prevent its occurrence. For example, in prospective studies, high-risk subjects treated with atypical rather than typical antipsychotics appear to have a reduced risk of TD compared with historical controls. Because patients may not complain about early or mild movements, the clinician must carefully examine neurolep tic-treated patients for early signs of TD, Neuroleptics should be discontinued, if possible, or an atypical antipsychotic drug should be substituted. Some studies suggest tocopherol might improve TD symptoms. Mild TD may improve with benzodiazepines or baclofen, Catecholamine-depleting drugs, particularly tetrabenazine, are often very useful in the treatment of severe TD (Jankovic and Beach 1997).
MOVEMENT DISORDERS
DYSTONIA Childhood-Onset Generalized Primary Dystonia Epidemiology and Clinical Features Most cases of primary generalized dystonia are inherited and begin in childhood (Nemeth 2002). Generalized dystonia is quite rare, with an estimated prevalence of about 1.4 per 100,000. The most common form of childhood-onset primary generalized dystonia, also referred to as DYT7 or Oppenbeirri's dystonia and previously called dystonia musculorum deformans is an autosomal dominant disorder with relatively low penetrance. Particularly common in persons of Ashkcnn/i Jewish descent, the reported prevalence of DYT1 dystonia is as high as 2 0 30 per 100,000. Half of patients are affected by age 9 years and onset in patients older than 40 years is extremely rare. The earliest symptom is usually an action-induced dystonia in the leg or arm. Onset in the cervical, facial, laryngeal, or pharyngeal region is rare. In about 7 0 % of patients, dystonic movements spread to the trunk and other limbs, and the condition generalizes over about 5 years. Patients with earlier onset and onset in the leg are more likely to develop generalized dystonia than those presenting later or with arm dystonia. Generalized dystonia produces severe disability, and most patients with this severe form of the illness are nonambulatory. Even in generalized disease, however, laryngeal and pharyngeal dystonia remains rare. The diagnosis of childhood-onset primary generalized dystonia is made clinically in a patient with onset after the age of 26 years of limb dystonia, with subsequent spread, the absence of other movement disorders with the exception of tremor, normal intellect and neurological examination, and absence of a pronounced response to L-dopa. A number of other childhood-onset generalized dystonias have been described, but none accounts for large numbers of cases. DYT2 has been assigned to recessively inherited limb-onset dystonia in gypsies. However, there have been no families in whom recessive inheritance can be eon tinned, so the existence of this syndrome is tentative. The designation DYT4 applies to an Australian family with dominantly inherited laryngeal and cervical dystonia that often generalizes over time. The disorder begins between adolescence and 40 years. Its genetic locus is unknown. DYT6" is a dystonia seen in Mennonite families that localizes to the chromosome 8. This autosomal dominant dystonia begins during the late second decade of life with a DYTI-like phenotype or with cranioccrvical or focal dystonia. DYT13 mapped to chromosome 1 presents as cranioeervical or arm dystonia with some tendency to generalize. Routine laboratories and neuroimaging studies do not contribute to the diagnosis. Simultaneous recording of EMG activity from antagonist muscles often reveals simultaneous contraction of antagonistic muscles and spread or
2155
overflow of activity to muscles not involved in the intended action. Such studies are not required for the diagnosis. DNA testing is available for DYT1 dystonia, but the low penetrance of the disease limits the usefulness of this test for prenatal or presymptomatic diagnosis. Pathology Pathological studies in childhood-onset primary generalized dystonia arc limited. No consistent structural or pharmacological changes have been detected in postmortem brain. Etiology and Pathogenesis The low penetrance of DYT1 dystonia, combined with variable expression that may range from an asymptomatic state to severe life-threatening dystonia (dystonic storm), may obscure its hereditary nature in many families {Opal et al. 2002). The disorder is genetically homogeneous in Ashkenazi Jews, 9 0 % of whom are found to have the DYT1 mutation. Non-Jewish patients are genetically more heterogeneous. The DYT1 mutation is a GAG deletion in the torsin A gene on chromosome 9 with an estimated frequency of 1 per 2000 to 1 per 6000 in Ashkenazi Jews and about 1 per 20,000 to 1 per 30,000 in non-Jewish populations. The high prevalence of DYT1 in Ashkenazi jews is related to a founder mutation estimated to have originated about 350 years ago in Lithuania or Byelorussia and the subsequent large increase in the population from a limited number of ancestors. The pathogenesis of generalized dystonia remains poorly understood. Torsin A is a protein of unknown function that is homologous to the adenosine triphosphatases and heatshock proteins. Its structure suggests a role in endoplasmic reticulum function, intracellular trafficking, or vesicular release. Mutant torsin A may interfere with these functions or may contribute to misfolded protein stress. There is experimental, clinical, neuroimaging, and electrophysiological evidence of dysfunction at the cortical, subcortical, brainstem, cerebellar, and spinal levels. Dystonia produced in nonhuman primates by repetitive hand movements is associated with inappropriate spread of the cortical representation of the affected hand. There is disordered sensory function in human dystonics and certain sensory inputs influence motor output in these patients. Deep brain recordings support abnormally low firing rates in the GPi with an abnormal pattern of firing as well. During sustained dystonia, there is increased metabolic activity in the midbrain, cerebellum, and thalamus. Functional neuroimaging of the dopamine system suggests decreased dopamine neurotransmission in the striatum, but decreased striatal dopamine has not been confirmed in postmortem tissue {Hurukawa et al. 2000b), Because dystonia may respond to pallidal lesions or stimulation, a central role of the GPi has been proposed. It is likely, however, that
2156
NEUROLOGICAL DISEASES
the pathophysiology of dystonia involves many factors including changes in the rate and pattern of neuronal firing, the degree of synchronization of firing, and aberrant focusing of sensory input (Vitek 2002). Treatment Rather limited information is available on the medical treatment of child hood-onset primary generalized dystonia. Absent an obvious neurotransmitter deficiency or excess, there is no compelling rationale for the use of any particular pharmacotherapy, and no drug has been found to be universally effective for symptom control (Table 77.20). In the absence of genetic confirmation of the DYT1 mutation, a trial of dopaminergic therapy should be considered, because patients with dopa-responsive dystonia {see later discussion) have such a gratifying response. In patients younger than 20 years, about 5 0 % will respond well to high-dose anticholinergic therapy. The response rate is better in patients treated within 5 years of onset. Baclofen, clonazepam, benzodiazepines, and dopamine-depleting medications may be useful in some patients. The treatment of childhood-onset primary generalized dystonia is a trialand-crror process. Treatment should be initiated with very small doses and the dose should be increased slowly and gradually. Botulinum toxin injections may be considered to treat one or a few particularly problematic body areas in patients with generalized dystonia. Chronic intrathecal baclofen has been reported to help some patients with dystonia, especially those with concomitant spasticity, Stereotactic thalamotomy is said to benefit about 6 6 % of patients who have been operated on, but some patients
Table 77.20;
Medical treatment of dystonia
Drug Anticholinergics Trihexyphenidyl Procyclidine Bcnztr opine Baclofen Benzodiazepines Clonazepam I. o raze pa m Diazepam Carbidopa/
Starting dose (tug/day)
Usual dose (tng/day)
1 2.5 0.25 10
6-80 10-30 4-15 30-120
0.25 0.5 2.5 12.5/50
4 1-16 10-100 37.5/150-75/300
51
i -dnpa
Dopamine deplctcrs Reserpine Mc tyro sine Tetrabena/inc
Response rate {%)
0.25 250 12.5
4-6 1000-3000 50-300
20 10-16
Good response in doparesponsive dystonia 25
worsened and side effects were common. Thalamotomy may he most useful for patients with dystonia of the distal limb. More recent reports suggest that axial symptoms might improve after bilateral pallidotomy or pallidal DBS. Patients with the DYT1 mutation seem most likely to improve (Coubes et al. 2000).
Adult-Onset Primary Focal and Segmental Dystonia Epidemiology and Clinical Features A community-based postal survey of primary dystonia suggested the prevalence of adult-onset primary focal or segmental dystonia was 12.9 per 100,000. Cervical dystonia and blepharospasm were most commonly represented. The focal and segmental primary dystonias generally begin in adulthood with dystonic movements in the band and arm, neck, or face. When spread occurs, the ultimate distribution tends to maintain a segmental pattern. For most such dystonias, the women are somewhat overrepresented, Cervical dystonia is the most frequently diagnosed form of focal dystonia, accounting for about half of focal dystonia cases. Patients with cervical dystonia present with neck pain, difficulty maintaining a normal head position, and sometimes tremor. Although across patient populations, the movements may occur in any single plane, or commonly in several planes, there is a directional preponderance to the movements. Sensory tricks are common (see Chapter 24) and include resring the head against a wall or high-backed chair or touching the chin or back of the head lightly with one hand. Spontaneous remissions may be seen in as many as 2 0 % of patients, although recurrence is very common. About 2 0 % of patients with focal dystonia have dystonic movements of the eyelids, blepharospasm. Symptoms of blepharospasm are often preceded by a gritty or otherwise abnormal sensation in the eye. Increased blinking may follow, or frank spasms of eyelid closure m.n begin. Symptoms of blepharospasm are typically worse with driving, reading, or watching television. Improvement induced by placing a finger alongside the eye is a common finding. Blepharospasm may be accompanied by oromandibular dystonia (cranial dystonia), or the latter may occur in isolation. Otomandibular dystonia typically causes involuntary jaw opening or closure, tongue prorrusion, dysarthria, and dysphagia. Because the actions of eating and speaking activate the dystonia, these tasks are particularly affected. Sensory tricks in oromandibular dystonia include touching the face or inserting something, such as candy or the tip of a pencil, into the mouth. Vocal cord involvement with adductor or abductor dysphonta affects pdonation, resulting in a harsh and sttanglcd, or breathy voice, respectively. Whispering and singing are often relatively unaffected in such patients. The occupational or taskspecific dystonias are those that arise in the context of
MOVEMENT DISORDERS
repetitive or skilled use of a body part. The most common task-specific dystonia is writer's, cramp, in which action dystonia of the arm and hand develop during writing. Hair stylists, musicians, court reporters, and others who work repetitively with the hands may find these specific skills similarly affected. Players of wind instruments may develop dystonia of embouchure, with difficulty maintaining the proper mouth and lip posture. Occasionally, an adult patient will present with a pure truncal dystonia, with flexion, extension, or lateral bending. Isolated foot dystonia in an adult is very rare and suggests an underlying structural lesion, a parkinsonian disorder, or 5PS. The diagnosis of adult-onset primary focal or segmental dystonia is made clinically. Ncuroimaging studies are useful if an underlying cause is suspected (see Secondary Dystonia, later in this chapter) but arc generally normal. Simultaneous recording of agonist and antagonist muscles may show inappropriate co-contraction, but this is not required for diagnosis. Etiology and Pathogenesis Many studies have suggested that focal and segmental dystonia might have a genetic basis. About 2 5 % of adultonset focal or segmental dystonia patients have a positive family history of dystonia, which would be consistent with an autosomal dominant condition with low penetrance. Some families with clear dominant inheritance have been reported and there is already one identified locus of focal dystonia, DYT7, in a large German family. This familyshows an autosomal dominant pattern of inheritance with reduced penetrance and adult onset of cervical dystonia, dysphoria, or hand tremor. The locus has been mapped to chromosome IS. The pathogenesis of adult-onset primary focal or segmental dystonia is unclear, but similar mechanisms to childhood-onset primary generalized dystonia are proposed. Studies suggest that there is reduced inttacortical inhibition in dystonia, believed related to impaired cortical and striatal GABA levels (Levy and Hallett 2002). Several lines of evidence suggest that abnormal central somatosensory processing may lead to insufficient sensorimotor integration in dystonia. PET scans suggest an abnormal pattern of regional glucose metabolism with hypermetabolism of the basal ganglia, cerebellum, and supplementary motor area (Trost et al. 2002). Recent studies have suggested disordered copper metabolism with increased lenticular concentrations of copper and manganese. Changes in trace minerals may affect cellular function or lead to cellular death (Becker et al. 1999). Treatment Medical treatment of adult-onset primary focal and segmental dystonia is difficull and employs those agents typically used in generalized dystonia. Adults are less able
2157
to tolerate effective doses of these agents, so the response to therapy is somewhat more disappointing than that seen in children. Botulinum toxin injections, on the other hand, are very helpful in the treatment of focal and segmental dystonia. Botulinum toxin is injected subcutaneously over the facial muscles or directly into larger deeper muscles that underlie pain and inappropriate movement in other focal dystonias. Many, though not all, clinicians use EMG to help guide toxin injection. Botulinum toxin injections have been proven effective in the treatment of blepharospasm and other facial dystonias, as well as cervical dystonia. Clinical experience suggests they are very useful in the treatment of oromandibular, laryngeal, truncal, and limb dystonia. Overall, more than 7 5 % of treated patients report moderate to marked improvement in dystonic pain or posture. The procedure is generally well tolerated, with excessive weakness of injected muscles or occasionally neighboring muscles (he most often reported side effect. The mechanism of action of botulinum toxin appears complex. Botulinum toxin not only blocks neuromuscular transmission, producing weakness in the injected muscles, but also normalizes intracortieal reciprocal inhibition, possible by an effect on muscle spindle input. Botulinum toxin injections have a brief duration of action, requiring repeated injections every 3-6 months. Secondary resistance occurs in some chronically treated patients, especially those injected frequently with higher doses of the toxin (Jankovic, Vuong, and Ahsan 2003). Patients who fail to respond to botulinum toxin injections may be offered surgical interventions. Blepharospasm can be tteated by orbital myectomy. Good results are obtained in some patients with cervical dystonia following selective peripheral denervation of the muscles participating in the production of abnormal head movement. A prospective open study of selective peripheral denervation for patients with cervical dystonia with botulinum toxin resistance showed 6 8 % of patients wetc functionally improved after surgery. Pain control was less sustained than control of movement, and posterior cervical dysesthesias were a common side effect. Pallidal DBS has been tried in some patients with refractory cervical dystonia with good results. More study is required to determine the utility of the technique in this diagnosis (Volkmann and Benecke 2002).
X-Linked Dystonia-Parkinsonism (DYT3; Lubag's Syndrome) DYT3 or Lubag's syndrome is an X-linkcd condition with progressive dystonia and parkinsonism affecting Filipino adult men descended from maternal lines from the Panay Island. The disorder is heterogeneous, and affected men may show dystonia, parkinsonism, tremor, chorea, or myoclonus. This phenotypical heterogeneity is evident in colorful descriptions of the disorder in the local dialect.
2158
NEUROLOGICAL DISEASES
"Lubag" means intermittent and "Wa-eg" sustained twisting or posturing, suggesting the predominantly dystonic form of the illness. "Sud-Sud" refers to shuffling gait, suggesting the parkinsonian form of the illness. Lubag affects men in the fourth or fifth decades, although much earlier onset cases have been described. Symptoms predominantly relate to dystonia, although parkinsonism is present in more than 30% of patients. A nearly pure parkinsonian phenotype is thought to predict a more benign prognosis. PET studies have shown both postsynaptic and presynaptic dopaminergic changes. In some patients, parkinsonian symptoms are r-dopa-responsive, although there are reports rh.it t.-dopa worsens symptoms in some predominantly dystonic patients.
D op a-Responsive Dystonia (DYT5) Dopa-responsive dystonia (DRD) is an uncommon condition, with a prevalence of 0.5-1.0 per 1,000,000. Girls are preferentially affected. DRD is a childhood-onset generalized dystonia with a dramatic, sustained and uncomplicated response to low doses of i.-dopa. The disorder begins in the first decade of life with an action dystonia in the foot. The condition then progresses to the fully formed illness that ranges in severity' from mild focal to disabling generalized dysronia. Early onset cases may be mistakenly diagnosed as cerebral palsy. The most characteristic historical feature is prominent diurnal fluctuation. Affected patients may be almost normal in the morning, becoming progressively more disabled over the course of the day with peak disability late in the evening. Parkinsonian symptoms become part of the clinical picture over time. DRD is usually dominantly inherited with incomplete penetrance (DYT5). DYT5 results from mutations in the guanosine triphosphate cyclohydrolase-l (GTPCH1) gene on chromosome 14. (Eurukawa et al. 2000a). More than 50 mutations of the gene have been discovered, and therefore DMA testing is currently not feasible. GTPCH1 is an enzyme involved in the synthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase. Other mutations affecting enzymes involved in tetrahydrobiopterin synthesis have also been i in plica red in DRD. A recess ively inherited DRD relates to mutations in the gene for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of i.-dopa. Patients with the DRD have low levels of tyrosine hydroxylase, and therefore low levels of dopamine. F-dopa PET and postmortem studies confirm normal numbers of dopaminergic neurons. DRD responds very well to lowr doses of L-dopa (100-300 mg daily) in combination with carbidopa. Patients with DRD do not develop the motor fluctuations and dyskinesias associated with chronic L-dopa therapy in PD. Anticholinergic drugs may also be useful.
Another childhood-onset dystonia related to deficient dopaminergic neurotransmission is aromatic acid decarboxylase deficiency. This disorder is recessively inherited. Dystonia, parkinsonism, oculogyric crises, autonomic symptoms, and progressive neurological impairment begin in childhood. There are deficiencies in central biogenic amines including dopamine, norepinephrine, epinephrine, and serotonin. i'>ce.uise llie enzyme deficiency is distal to l. dopa in the dopamine synthetic pathway, the symptoms are not L-dopa responsive. However, direct-acting DAs and MAOIs may be useful (Swoboda et al. 1999).
Myoclonus Dystonia (DYT11) In myoclonus dystonia (MD), dystonia is the predominant symptom, but tremor and myoclonus are present as well. Some patients have pure myoclonus. Symptoms usually begin before the teenage years and predominantly affect the head, arms, and upper body. Ehe involuntary movements may be exquisitely sensitivity to ethanol. Psychiatric features including affective disorder, obsessive-compulsive disorder, substance abuse, anxiety, phobic or panic disorders. and psychosis have been described. Cognitive decline has also been reported (Dohcny et al. 2002). No other neurological deficits are seen and the course is usually benign. Ehe pathology is unknown. A number of heterozygous mutations in the E-sarcoglycan gene on chromosome 7 have been reported in families with MD. Another suggested locus is on chromosome 18. Mutations in the torsin A {DYT1) gene and the D 2 dopamine receptor gene have also been described, but e-sarcoglycan mutations were subsequently described in these families as well. There is likely another locus on chromosome 18 (Furukawa and Rajput 2002). MD responds poorly to medical therapy, but beneficial responses to valproic acid and trihexyphenidyl have been reported. VIM stimulation has been reported to be beneficial in MD in a single case (Trottenberg et al. 2001).
Rapid-Onset Dystonia Parkinsonism (DYT12) Rapid-onset dystonia parkinsonism (RDP) is a very rare disorder in which signs of parkinsonism and upper body dystonia develop subacutely. Onset ranges from childhood ro adulthood. Dystonia preferentially affects bulbar muscles and progresses over a period of days to weeks but then remains stable. Although sporadic cases have been reported, most cases belong to a small number of families showing dominant inheritance with incomplete penetrance. A genetic locus on chromosome 19 has been discovered. Eow levels ot homovanillic acid (IIVA) have been detected in the spinal fluid, but PET scans using presynaptic markers fail to demonstrate a loss of dopaminergic neurons (Brashear et al, 1999), There is no evidence of
MOVEMENT DISORDERS
neurodegeneration and RDP symptoms do not improve with administration of L-dopa, suggesting a functional deficit (Nemeth 2002).
Alzheimer's types I and 11 astrocytes, as well as Opalski's cells, cells of microglial origin. Etiology and
Wilson's Disease (Hepatolenticular Degeneration) Epidemiology and Clinical features Wilson's disease (WD) is a rare heredodegenerative disorder thought to affect 1-2 per 100,000 persons. It is related to abnormal copper disposition. In childhood, the liver progressively accumulates copper. Many patients present in childhood wiE 1 I •.ympmniN and signs ol liver disease, ranging from cirrhosis to fulminant liver failure. Once cirrhosis has deyelopcd, extrahepatic copper deposits begin to form, especially in the brain, eyes, and kidneys. Some patients present with hemolytic anemia, hypersplenism, or renal failure. Nearly half of all patients with WD present with central nervous system symptoms and signs (l'andit et al. 2002). Neurological signs usually present during adolescence or early adulthood, but presentations up to the age of 51 years have been reported. Neurological presentations include parkinsonism, postural and kinetic tremor, ataxia, titubation chorea, seizures, dysarthria, or dystonia. A fixed stare with a smiling exptcssion and drooling are classic features of the illness but are not seen in all cases. Dystonia is a common sign, ptescnt in 3 7 % at presentation in one series. Dystonia may he focal, segmental, or generalized (Svetel et al. 2001). Sensation is spatcd. Dementia, if present, is mild. Psychiatric signs are very common and may be quite disabling. Mood and personality disorders, behavioral changes, and psychosis are reported. In the ptesence of neurological signs, ophthalmological examination, including slit-lamp examination essentially always demonstrates copper deposition in Descemet's membrane (Kayser-Fleischer rings) (sec Chapter 24). Many patients with WD also have sunflower cataracts. Laboratory studies often show abnormalities in hepatic enzymes, aminoaciduria, low uric acid, and demineralization of bone. MRI scan usually shows decreased signal intensity (hypodensity) in the striatum and supetior colliculi and increased signal intensity in the midbrain tegmentum {except for red nucleus) and in the lateral SNr giving the appearance of "face of the giant panda" on T2-weighted images. Low serum ceruloplasmin, elevated 24-hour copper excretion, and the presence of Kayser-Fleischer rings are useful in making the diagnosis, which is confirmed by demonstrating elevated hepatic copper (Pandit et al. 2002).
Pathology Gross inspection of the brain often reveals cerebral atrophy and shrunken, discolored putamen and GP. Microscopically, WD brains show both preferential striatal and generalized neuronal loss. There is diffuse gliosis with
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Pathogenesis
WD is an autosomal recessive disorder of copper metabolism related to mutations in the ATP7B gene on chromosome 13 (Pandit et al. 2002). riecause there are so many different mutations, genetic testing is not clinically available. This gene regulates a copper-transporting adenosine triphosphatase. Although the neurological disorder clearly relates to harmful effects of intracellular copper, the precise mechanisms of cell dysfuncrion and death are not well understood. Treatment The goal of treatment of WD is to reduce the body burden of copper and to prevent its reaccumulation. Traditionally, acute chelation began with n-pcnicillamine, but more recent treatment strategics stress somewhat less toxic therapies such as tticntine and zinc or tetrathiomolybdate. The effectiveness of initial de-coppering is monitored by serially measuring urine copper excretion and plasma copper levels. Although there may be an acute deterioration associated with the mobilization of copper stores, most patients improve over time. Long-term therapy must be maintained, usually with tricntine and zinc. D-Penicillaminc is associated with a number of systemic toxicities including dermatopathy, neuromuscular junction disorders, thrombocytopenia, and Goodpasture's syndrome. Asymptomatic siblings should be tested for the disease, because timely treatment prevents the illness. Orthotopic liver ttansplantation is curative but has been used largely in patients with luhuinaiit hepatic failure who have not yet devel oped significant neurological signs (Emre et al. 2001), The response of neurological symptoms to liver transplantation is not completely understood. Neurodegeneration with brain iron accumulation (pan tothenate kinase-associated neurodegeneration [PKAN], Hallervorden-Spatz disease; hypoprebetalipoptotcinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration [HARP]). A number of disorders cause neurodegeneration with brain iron accumulation (Hayflick et al. 2003). The classic form of neurodegeneration with brain iron accumulation is PKAN formerly known as I lallcrvorden-Spatz disease. It is an autosomal recessive neurodegenerative disorder presenting in childhood with the insidious onset of dystonia and gait disorder. Rigidity, dysarthria, spasticity, dementia, retinitis pigmentosa, and optic atrophy develop and progress relentlessly until death in early childhood. "12weighted MRI brain scans show areas of reduced attenuation in the GP surrounding an area of hyperintensity, the "eye of the tiger" sign. Autopsy studies show a brown discoloration of the GPi and SNr, reflecting pathological
21(it)
NEUROLOGICAL DISEASES
accumulation of iron. Microscopic changes include neuronal loss, gliosis, loss of myelinated fibers, and axonal swellings (spheroids). Virtually all families with typical PKAN have mutations in the pantothenate kinase gene (PANK2) on chromosome 20. Pantothenate kinase is an important regulatory enzyme in coenzyme A synthesis. There are atypical forms of the illness that begin later and are more slowly progressive. These cases often present with early speech disorder and often have personality changes suggesting FTD. Although the Mill scan shows evidence of iron accumulation, the "eye of the tiger" sign is not seen, and these patients do not have mutations in the PANK2 gene. HARP syndrome, a constellation including hypoprebetalipoproteincmia, acanthoeytosis, retinitis pigmentosa, and pallidal degeneration, has also been linked to mutations in this gene (Ching ct al. 2002). The precise mechanism of neurodegeneration is unknown (Zhou et al. 2001).
Post-Traumatic Dystonia Dystonia resulting from brain trauma most often presents as hemidystonia, but cervical, segmental, axial, or spasmodic dysphonia can also be seen (Krauss and Jankovic 2002). Most reported post-traumatic dystonias occur in men, reflecting a male preponderance among patients with head injury. Most cases have occurred in children or adolescents who have survived severe head injury. Often, the dystonia emerges as a traumatic hemiparesis improves or resolves. There may be a latent period between the trauma and the development of the dystonia from 1 day to 6 years, followed by slow progression of dystonic symptoms. Younger patients tend to have longer latencies than those who are older at the time of the head injury. Focal lesions in the caudate, putamen, or thalamus contralatetal to the affected side arc usually found on neuroimaging studies. Lesions of the mesencephalon or dentatothalamic pathways have also been found. The prognosis of this form of post-traumatic dystonia is poor, with a low rate of spontaneous improvement. Most cases arc refractory to medical therapy, although some may respond to anticholinergic drugs. Botulinum toxin injections may be helpful. DBS or stereotactic thalamotomy, or pallidotomy may be helpful, although the magnitude of response is much less than that seen in patients with primary dystonia. Dystonia may also occur after peripheral injury (Jankovic 2002). For example, oromandibular dystonia may follow dental surgery or facial and jaw trauma. Limb dystonia has also been reported to occur after peripheral trauma, often in the context of causalgia or reflex sympathetic dystniphy. TJii-ic .i:e no ..Kveptcd clniic.il criteria for this diagnosis, and differentiation from psychogenic disease may be difficult. The response of this condition to medical or other therapies is disappointing.
Tardive Dystonia Tardive dystonia (TDy) should be differentiated from transient acute dystonic reaction and from the more typical TD. In a review of 11 studies of psychiatric patients chronically exposed to neuroleptics, 2.7% developed TDy. Men are more likely to develop TDy, and they develop it at a younger age than women. All of the typical antipsychotics, as well as antiemetics with dopamine-receptor-blocking properties, have been associated with the development of TDy (Kiriakakis et al. 1998). Symptoms of TDy begin insidiously after days to decades of neuroleptic therapy, Although rare cases have been re ported after a , will; I I )\ KiriaLikis ci al. I '''JSi. Botulinum toxin injections can be particularly helpful in patients having disability from blepharospasm or with cervical or truncal dystonic movements.
Paroxysmal Kinesigenic Dyskinesia (DYT10) Paroxysmal kinesigenic dyskinesia (PKD) is a disorder of childhood onset characterized by attacks of involuntary
MOVEMENT DISORDERS movements that include prominent dystonia, chorea, or other hyperkinesias. Because the attacks are often nor witnessed and therefore appropriate phenomenological categorization is not possible, the less specific term paroxysmal dyskinesia is preferred to the alternative term, paroxysmal kinesigenic epilepsy (Jaiikovic and Deinirkiran 2002). Boys make up 80% of cases. There is often a family history. Patients typically recount that episodes are triggered by rapid movement, often in response to an unexpected stimulus such as the telephone ringing. There may be a premonitory sensation in an affected limb. The movements may be unilateral or bilateral. The spells last less than 1 minute and occur up to 100 times daily (Houser et al. ]999). There is a tendency for spells to decrease in adulthood. Diagnosis depends on careful history taking, because the examination usually shows no abnormalities, typical spells may not be elicited in the examination setting, and neuroimaging and electrophysiological studies are usually normal. Two loci for PKD (DYT10) have been localized to chromosome 16, suggesting a family of genes on that chromosome that might be important in producing the syndrome, although causative genes have not yet been discovered. PKD is usually very responsive to anticonvulsant medications. Carbamazepine and phenytoin are most frequently used, but there have been recent reports that levctiracctam is effective and well tolerated.
Paroxysmal Nonkinesigenic Dyskinesia (DYT8) Paroxysmal nonkinesigenic dyskinesia (PNKD) usually licgiiis in ir.tiiik;-. .iii!: .itlciis boys more than girls. I he spells of PNKD occur less often but are more prolonged than those in PKD. Their frequency ranges from several episodes per month to several episodes per day and their duration is generally between 10 minutes and several hours. They are not precipitated by action but may be triggered by ethanol, caffeine, fatigue, or stress (Jankovic and Deinirkiran 2002). Genetic loci for PNKD (DYT8) have been discovered on chromosomes 1 and 2. CSF monoamine metabolites have been reported to decrease during an attack (Jarman et al. 2000). MRS and PET scans using the D2-selective radioligand raclopridc do not show any significant abnormalities in these patients. Unlike PKD, PNKD does not show a dramatic response to anticonvulsants. Some patients respond to clonazepam, other benzodiazepines, carbamazepine, gabapentin, anticholinergics, L-dopa, acetazolamide, and neuroleptics.
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disease (Blakeley and Jankovic 2002). Underlying etiologies include cerebrovascular disease, trauma, infection, and metabolic encephalopathy. The clinical manifestations of secondary paroxysmal dyskinesia are heterogeneous. Some are kinesigenic and some are not. Some are associated with premonitory sensations and others have no warning signs. Treatment of the underlying cause may improve the dyskinesia.
TICS Tourette's Syndrome Epidemiology and
Clinical Features
Prevalence estimates for Tourette's syndrome (TS) vary from 10-700 per 100,000, depending on the population studied and the study methods used. Although the prevalence is greater among children in special schools and those with disorders in the autism spectrum, the vast majority of patients with TS have normal intelligence. Boys are more commonly affected than girls. TS begins in childhood or during early adolescence, but most often begins between the ages of 2 and 10 years. Typical early signs of TS are cranial motor tics including eye blinks, stretching of the lower face, and shaking the head (see Chapter 24). Vocal tics include sniffing, throat clearing, grunting, whistling, chirping, and words, including profane words (coprolalia). Over time, the tics wax and wane and new tics enter and leave the repertoire. Tics may be simple or complex and can resemble any voluntary or involuntary movement. Patients with TS have both motor and vocal tics. Symptoms tend to increase throughout childhood, with peak expression in adolescence, and become somewhat less troublesome in adulthood. Behavioral changes arc very common in TS, especially attcntion-deficit/hyperactivity disorder (ADHD), conduct disorder, or obsessive-compulsive disorder. The latter association is particularly intriguing, because girls in families with a history of TS may have pure obsessive-compulsive disorder without tics. Obsessions in TS predominantly concern symmetry and counting. The diagnosis of TS rests entirely on the history and physical examination. The neurological examination is usually normal, as are neuroimaging and electrophysiological study results. No pathological changes have been described in patients with TS, but limited study of postmortem brains has suggested reduced levels of brainstem serotonin, pallidal glutamate, and cortical cyclic adenosine monophosphate.
Etiology and
Pathogenesis
Secondary Paroxysmal Dyskinesia Secondary paroxysmal dyskinesia has been thought to be rare. However, in one series, 2 6 % of paroxysmal dyskinesia cases occurred in the context of another nervous svstem
Clinical evidence strongly suggests that TS is a hereditary disease {Jankovic 1991:. The concordance of i'S among monozygotic twins is 8 6 % , and segregation analyses are consistent with an autosomal dominant, sex-influenced
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NEUROLOGICAL DISEASES
trait. However, despite this evidence, definite mendelian inheritance has not been established and no genetic locus has yet been identified. Because there is a robust response to dopa mine-receptor-bloc king medications, altered central neurotransmission has been proposed to underlie TS. PET studies suggest increased dopaminergic innervation of the ventral striatum, and abnormal regulation of dopamine release and reuptake, Treatment The first step in the treatment of TS is the definition of the sources of disability. Treatment should be reserved for patients who arc experiencing interference from tics in the educational, social, or family spheres. Disabling tics are most effectively suppressed by neuroleptic medications such as haloperidol and pimozide. In a double-blind controlled comparison, pimozide was more efficacious and better tolerated than haloperidol. Sulpiride and tiapride, which are not available in the United States, may also be helpful in the treatment of tics. Risperidone and olanzapine have been shown to be effective' in small uncontrolled trials, and ziprasidone has shown preliminary efficacy, although clozapine has not. Fluphenazine and tetrabenazine are also very effective in the treatment of tics with minimal side effects. Very-low-dose pergolidc (0.15-0.3 mg daily) has also shown some preliminary efficacy for tics (Gilbert et al. 2000). It is thought to work by selective action at presynaptic dopamine autoreccptors. Baclofen has been said to effectively decrease tic-related impairment, though not tics themselves in a small placebo-controlled trial (Singer et al. 2001). Other treatments suggested to be effective in small or uncontrolled studies include cannabinoids, nicotine, donepezil, antiandrogenic agents, kctanserin, ondansetron, and selective serotonin reuptake inhibitors. Obsessive-compulsive disorder responds to selective serotonin reuptake inhibitors. Comorbid ADHD can be safely treated with clonidine, methylphenidate alone, and in combination (Tourcttc Syndrome Study Group 2002). Guanfacine, tomoxetine, desipramine, deprenyl, and nortriptyline have also been proposed to treat ADHD inTS.
Adult-Onset Tics Adult-onset tics are much rarer than childhood-onset tics and usually represent recurrences of child hood-onset tics. .Many affected patients have childhood histories of obsessive-compulsive tendencies and family histories of tic disorders. Adult-onset tic disorders often develop after a triggering event and are more severe and socially disabling than the more typical early onset disease. Tics in adulthood are relatively resistant to pharmacotherapy (Eapen et al. 2002). Other causes of adult-onset tics, such as the use of cocaine or other central nervous system stimulants, tardive
tics, and neuroacanthocytosis, should be considered in the differential diagnosis.
POSTINFECTIOUS AUTOIMMUNE NEUROPSYCHIATRY DISORDERS ASSOCIATED WITH STREPTOCOCCAL EXPOSURE Postinfectious autoimmune neu to psychiatric disorders associated with streptococci (PANDAS) is a controversial entity that has been recently linked to TS. Children with PANDAS have explosive onset of obsessive-compulsive disorder, tics, hyperactivity, and choreiform movements in the prepubertal years. There is an association with prior group A beta-hemolytic streptococcal infection, although the syndrome is distinct from rheumatic fever and Sydenham's chorea (Garvey et al. 1998). Affected children have enlargement of the caudate, putamen, and GP by volumetric MRI. Antineuronal antibodies against putaminal antigens have been detected in the plasma of patients with TS. An autoimmune molecular-mimicry mechanism has been proposed. A double-blind placebo-controlled crossover study of penicillin in patients with PANDAS failed to show that penicillin prevented symptom recurrences, but adequate prevention of streptococcal infection was not achieved. Intravenous immune globulin and plasmapheresis reduced obsessive-compulsive symptoms, but tic scores were improved only in the plasmapheresis group. These improvements were sustained for 1 year. PANDAS is not a universally accepted syndrome and additional research is required to better define its role in TS (Garvey et al. 1998).
MYOCLONUS Essential Myoclonus Essential myoclonus (EM) is diagnosed when myoclonus is present as an isolated neurological sign or is accompanied only by tremor or dystonia. EM can be sporadic or inherited. Dominantly inherited EM usually presents before the age of 20 years. EM is usually multifocal myoclonus with upper body predominance. Although spontaneous jerks are seen, they are exacerbated by action. Alcohol may dramatically suppress the myoclonus. Sporadic forms of this illness are also described. (MD is discussed earlier in this chapter.) MD and EM are allelic disorders linked to the e-sarcoglycan gene on chromosome 7.
Hereditary Gcniospasm (Chin Tremor) Hereditary geniospasm is characterized by involuntary vertical movement of the tip of the chin with quivering and mouth movements. Geniospasm may be spontaneous
MOVEMENT DISORDERS
or stress induced. Trembling becomes apparent in infancy or early life. Trembling episodes last minutes. The attacks become somewhat less frequent with age. The disorder is genetically heterogeneous, with linkage to chromosome 9q 13-21 in some, but not all families (Grimes et al. 2002). Geniospasm has been suggested to be a form of hereditaty EM.
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not shown promise. Piracetam improves PHAN by an imperfectly understood mechanism that does not involve serotonin or GABA. It is available in Europe and Canada, though not in the United States. L-5-HTP administered with carbidopa may be useful, but this investigational agent has limited access and gastrointestinal side effects limit its tolerability. The effects of L-5-HTP may be enhanced by concomitant use of a selective serotonin reuptake inhibitot.
Posthypoxic Myoclonus (Lance-Adams Syndrome) The first cases of posthypoxic myoclonus (PHM) were described in 1963 by Lance and Adams. P H M is a generalized myoclonus that occurs with recovery from the acute effects of severe brain hypoxia. The most common etiologies of the hypoxia are respiratory arrest (especially asthmatic), anesthetic and surgical accidents, cardiac disease, and drug overdose. The typical patient is in coma for several days to 2 weeks. Myoclonus and seizures may be present during the comatose phase. After recovery from coma, myoclonic jerks become apparent, especially with voluntary movements, which trigger volleys of highamplitude jerks and intermittent pauses in the activated body part. The myoclonic movements typically flow to body parts not directly involved in the voluntary movements. The ampliunle ni the myoclonus is directly proportional to the delicacy of the attempted task, producing extreme disability in the performance of activities of daily living. Gait is disturbed not only by positive myoclonic jerks, but also by negative myoclonus, resulting in falls. Other neurological signs are always present and include seizures, dysarthria, dysmerria, ataxia, and cognitive impairment. CSF studies have shown low levels of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin. A role for GABA in this disorder is suggested by the production of myoclonus by injecting GABA antagonists into the rat thalamus. Autopsies in patients with PHM show changes lelated to hypoxic brain damage but do not reveal any specific structural changes in brainstem raphe nuclei. Myoclonus in posthypoxic rats responds to serotonin agonists that stimulate particular subtypes of serotonin receptors (5-HT l B , .S-HT2A/2is> arid possibly 5-HTto) (Pappert et al, 1999). Other studies in rat models have suggested that basal serotonin levels are normal, but there is an abnormality in release of serotonin by potassium chloride and NMDA. There is some tendency for improvement in myoclonus over time, but most patients have significant disability related to the movements. GABAergic drugs such as valproic acid and clonazepam are usually used in the treatment of PHM. Each is associated with improvement in about 5 0 % of treated patients. Levctiracetam has been recently reported to he effective in an open-label trial in chronic myoclonus (Genton and Gelisse 2001). Other GABAergic drugs such as vigabatrin and gabapentin have
Startle and Hyperekplcxia Hypetekplexia is a startle syndrome, characterized by muscle jerks in response to unexpected stimuli. Two forms of startle have been described. Families with autosomal dominant and recessive inheritance have been described. The major form of the illness is characterized by continuous stiffness beginning in infancy, and exaggerated startle culminating in tails. Some patients have seizures and low intelligence. In the minor form, there is only excessive startle, with hypnic myoclonic jetks. Startle in patients with hyperekplcxia differs from normal startle because it has a lower threshold, is more generalized, and fails to normally habituate with tepeated stimuli. Electrophysiological studies in well-characterized cases suggest the origin of the pathological startle in the lower brainstem, possibly the medial bulbopontine reticular formation. The disorder is genetically heterogeneous, with most mutations occurring in patients with the major form of the illness. Most defined mutations involve the «i-subunit of the inhibitory glycine receptor. Symptomatic hyperekplexia has been reported to result from infarct, hemorrhage, or encephalitis. Clonazepam is the treatment of choice (Brown 2002).
Spinal Myoclonus and Propriospinal Myoclonus Spinal myoclonus (SM) is a syndrome of involuntaryrhythmic or semirhythmic myoclonic jerks in a muscle or group of muscles. The myoclonic jerks may be unilateral or bilateral. In some cases, they are stimulus sensitive. The jerks relate to spontaneous motoneuron discharge in a limited area, often a single segment of the spinal cord. Propriospinal myoclonus is a more widespread disorder in which myoclonic jerks are propagated up and down the spinal cord from a central generator. Most patients with propriospinal myoclonus have had minor spinal cord trauma with normal MRI findings, but the disorder has been reported in severe spinal eord injury, multiple sclerosis, human immunodeficiency virus, or Lyme infection, syringomyelia, spinal cord tumors, and spinal cord infarction (Nogues et al. 2000). Propriospinal myoclonus has been reported to affect particularly the transition from wake to sleep.
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NEUROLOGICAL DISEASES
Toxin- and Drug-Induced Myoclonus A number of drugs and environmental agent with central nervous system toxicity have been shown to cause myoclonus (Table 77.21). Criteria for drug- or toxininduced myoclonus include verified exposure, temporal association, and exclusion of genetic or other causes. The myoclonus produced by drugs and toxins is often multifocal or generalized, stimulus sensitive and action sensitive, and accompanied by other suggestive nervous system signs, particularly by encephalopathy signs. Metrizamide and diclofenac may cause segmental myoclonus. Treatment requires withdrawal of the causative drug and symptomatic treatment, if required with clonazepam, valproic acid, or levetiracetam.
MISCELLANEOUS MOVEMENT DISORDERS Hemifacial Spasm Data from Olmsted Comity, Minnesota, suggest that the prevalence of hemifacial spasm is 14.5 per 100,000 in women and 7.4 per 100,000 in men. Hemifacial spasm is characterized by twitching of the muscles supplied by the facial nerve. The disorder usually begins in adulthood, with an average age at onset of 45-52 yeats. Although there are some familial cases, most are sporadic. In typical cases, twitching first affects the periorbital muscles but spreads to other ipsilateral facial muscles over a period of months to years. The spasms arc synchronous in all affected muscles. In about 5% of patients, the opposite side of the face becomes affected, but when bilateral, the spasms are never synchronous on the two sides. The spasms of hemifacial spasm may be clonic or tonic, and often, a paroxysm of clonic movements culminates in a sustained tonic Tabic 77.21:
Drugs associated with myoclonus
Anesthetics
LtonmLitc, chlonilose Antibiotics, antihelminthics, antiviral drugs Penicillin, Imlpencm, quinolones, piperazinc, acyclovir Anticonvulsants Phenytoin, phenobarbital, primidone, valproic acid, carbamazepine, gabapentin, lamotngine, vigabatrin Antihistamines Sodium bicarbonate (baking soda) Benzodiazepine withdrawal Psychotropic medications Tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitor, lithium, buspirone, neuroleptics Antineoplastic drugs Chlorambucil, p red nimustine, ifosfamide Narcotics Morphine, meperidine, hydromorphone, fentanyl, sufentanil, diamorphine
contraction. Although the spasms occur spontaneously, they may be precipitated or exacerbated by facial movements or by anxiety, stress, or fatigue. The affected muscles may be weaker than their contralateral counterparts. Some patients have evidence of regional cranial neuropathy such as altered hearing or trigeminal function. Detailed neuroradiological workups using routine and specialized MRI techniques may demonstrate compressing vascular structures in most, if not all, patients with hemifacial spasm. Mm,' advanced ^canning techniques Mich as high-resolution T 1 - and T2-weighred spin-echo or gradient-echo imaging with gadolinium provides maximum visualization of the root entry zone (Port 2002). Yet, serious underlying causes are rare, and many clinicians do not toutinely image patients with typical hemifacial spasm unless the clinical picture is atypical or the patient is being considered for surgery. In cases of hemifacial spasm, the facial nerve root entry zone generally shows axonal demyehnation or nerve degeneration. Hemifacial spasm is thought to result from compression of the facial nerve at the root exit zone, usually by vascular structures. Tumors or other spaceoccupying lesions are found in about 5% of patients. Vessels commonly implicated are the posterior inferior cerebellar artery, the anterior inferior cerebellar artery, or the vertebral artery. When tumors are present, they are most commonly epidermoid, neuroma, meningioma, astrocytoma, and parotid tumors. There are two main theories of pathogenesis. The first proposes that in the area of compression-induced demyelination, an "ephapse," or false synapse, forms. Mechanical irritation or other regional changes induce ectopic activity in the region, which is then conducted antidromically within the nerve fiber. The main competing theory proposes that the aberrant signals arise from the facial nerve nucleus, which reorganized as a result of deranged afferent information. Traditionally, patients with hemifacial spasm have been treated with anticonvulsants, typically carbamazepine, and more recently gabapentin. Other agents said to be useful include baclofen, anticholinergics, halopcridol, and clonazepam. The clinical availability of borulinum toxin injections revolutionized the treatment of hemifacial spasm. Botulinum toxin injected into the periorbital subcutaneous tissue produces clinically meaningful improvement in ilmost 100% of patients and side effects are mild and transient, Botulinum toxin injections must be administered every 3-6 months. Follow-up of chronically treated patients shows the injections retain their efficacy at least 10 yeats (Defazio et al. 2002). A number of surgical techniques have been used in hemifacial spasm. These include removal of the orbicularis oris or other affected muscles, selective destruction of parts of the facial nerve, decompression of the facia) canal, or radiofrequency thermocoagulation of the netve. Intracranial microvascular decompression of the nerve is
MOVEMENT DISORDERS
successful in relieving spasms in up to 9 0 % of patients, but complications such as facial nerve injury and hearing loss occur in up to 1 5 % of patients (Samii et al. 2002).
Painful Legs-Moving Toes Syndrome Painful legs-moving toes syndrome (PLMTS) is a very rare condition characterized by pain in the legs and spontaneous movements of the foot and toes. The pain usually precedes the onset of involuntary movements and varies in constancy and intensity. In some cases, the condition is painless. The toe and foot movements arc complex, combining flexion, extension, abduction, and adduction in various sequences, at frequencies of 1-2 Hz. The movements may be precipitated or aborted by moving or repositioning the foot or toes, but they cannot be simulated voluntarily. Similar movements have been described in the arms, with or without accompanying pain. In most cases, there is an underlying cause, although there is little consistency from case to case. PLMTS has been associated with injuries to the spinal cord and cauda equina, spinal nerve roots, peripheral neuropathy, and soft tissue or bony limb trauma. EMG studies show that the movements are produced by long bursts of normal motor unit firing with normal recruitment patterns. PLMTS doubtless has a central origin. Central reorganization consequent to altered afferent information from the periphery has been proposed, but a precise location and mechanism of these changes remain unknown. Treatment of PLMTS is very difficult. Many medications have been tried, including baclofen, benzodiazepines, anticonvulsants, and antidepressants, but none has emerged as effective. Lumbar sympathetic block or epidural stimulation may give transient relief. Spontaneous resolution is very unusual.
Stiff Person Syndrome SPS is rare and no information is available about its epidemiology. SPS is a syndrome of progressive rigidity of axial and proximal appendicular muscles with muscle hypettrophy and extreme lumbar lordosis. Intense spasms are superimposed on a background of continuous symptoms. Gait is slow and stiff legged. Some authors divide SPS into three syndromes: stiff trunk syndrome, stiff limb syndrome, and rapidly progressive encephalomyelitis with rigidity (Barker el al. I99K). l'.MC! examination shows continuous firing of normal motor units. SPS is associated with autoimmune disorders, such as type I diabetes, thyroiditis, myasthenia gravis, pernicious anemia, and vitiligo. High titers of antibodies to the 65-kd fraction of GAD are present. It is thought that SPS results from dysfunction of descending suprascgmcntal pathways possibly secondary to immune-mediated inhibition of
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GABA synthesis. Paraneoplastic SPS has been reported with breast and other cancers. Untreated, SPS progresses to extteme disability. Diazepam at doses of 20-400 nig per day is the most effective symptomatic treatment. Clonazepam, baclofen, valproic acid, clomdine, vigabatrin, and tiagabine have also been reported to be effective. Plasmapheresis and immunosuppression have been reported to have variable effects on the condition. In a recent placebo-controlled crossover study of nilr.lv Pilous in in i nne j-'Juhtiliii, active [rr;i! m m ! v,as u w k / i
ated with clinical improvement and decreases in anti-GAD antibody titers (Dalakas ct al. 2001). Intrathecal baclofen and local intramuscular injections of botulinum toxin have been lielpti:) :n Mime cases.
Psychogenic Movement Disorders Psychogenic movement disorders (PMDs) make up a small part of any clinical movement disorders practice. The most common PMD is tremor, but dystonia, myoclonus, and parkinsonism are also seen. In many cases, the symptoms are abrupt in onset and associated with a specific trigger. Clinically, distractibiliry is common, as ate stimulus sensitivity and entrainment with voluntary activities. Other psychogenic symptoms are often present. About 2 5 % of patients have a comorbid organic movement disorder. About half have an Axis 1 psychiatric disorder, most often depression. The long-term outcome of patients with PMDs is unknown. In a series of 88 subjects with documented PMD, interviews were conducted an average of 3 years after diagnosis; 52.5% of survivors were interviewed, and 9 5 % had active or remote primary psychiatric illness (major depression and anxiery or both). Nearly half had personality disorders. In only 10% had the PMD remitted, but half of these patients had new psychogenic symptoms. Patients with PMD did not acknowledge the psychiatric origin of their PMD (Feinstein et al. 2001). No specific information is available about treatment.
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l 9 , •:.4 Port, J, D. 2002, "Advanced magnetic resonance imaging techniques for patients with hemifacial spasm," Ophthal Plast Reconstr Surg, vol. 18, no, 1, pp. 72-74 Rampoldi, L., Danek, A., & Monaco, A. P. 2002, "Clinical features and molecular basis of neuroacanthocytosis," / Mol Med, vol. 80, no. 8, pp. 475-491 Rascol, O., Brooks, D. J., Korczyn, A. D., et al. 2000, "A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or
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Swohoda, K. J., Hytand, K., Goldstein, D. S., ct al. 1999, "Clinical and therapeutic observations in aromatic L,-amino acid decarboxylase deficiency," Neurology, vol. 5 3 , no. 6, pp. 1205-1211 Tan, E. K., Khajavi, M. et al. 2000, "Variability and validity of polymorphism association studies in Parkinson's disease," Neurology, vol. 55, no. 4, pp. 533-538 Tanner, C. M., Ottman, R., Goldman, S. M., ct al. 1999, "Parkinson disease in twins. An etiologic study," JAMA, vol. 281, no. 4, pp. 342-346 Taylor, J. P., 1 lardy, J,, & I'ischbeck, K. H. 2002, "Toxic proteins in neurodegenerative disease," Science, vol. 296, no. 5575, pp. 1991-1995 Trost, M., Carbon, M., et a I. 2002, "Primary dystonia: is abnormal functional brain architecture linked to genotype?" Ann Neurol, vol. 52, no. 6, pp. 853-856 Trortenbcrg, T., Meissner, W,, Kabus, C, et al. 2001, "Neurostimulatiim of [he ventral intermediate thalamic nucleus in inherited myoclonus-dystonia syndrome," Mov Disord, vol. 16, no. 4, pp. 769-771 Tsai, C. H., Lo, S. K., et al. 2002, "Environmental risk factors of young onset Parkinson's disease: A case-control study," Clin Neurol Neurosurg, vol. 104, no. 4, pp. 328-333 Verhagen Metman, L., Morris, M. J., et al, 2002, "Huntington's disease: A randomized, controlled trial using the N.MDAantagonist amantadine," Neurology, vol. 53, no. 5, pp. 694-699 Vitek, J. L. 2002, "Pathophysiology of dystonia: A neuronal model," Mov Disord, vol. 17, suppl. 3, pp. S49-S62 Volkmann, J. & Benecke, R, 2002, "Deep brain stimulation for dysronia: Patient selection and evaluation," Mov Disord, vol. 17, suppl. 3, pp. S112-S115 Walsh, K. & Bennett, G. 2001, "Parkinson's disease and anxiety," Postgrad Med J, vol. 77, no. 904, pp. 89-93 Yamamoto, A., Lucas, J. J., &Z Hen, R. 2000, "Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease," Cell, vol. 101, no. 1, pp. 57-66 Yazawa, 1. 2000, "Aberrant phosphorylation of dentarorubralpallidoluysiau atrophy (DRPLA) protein complex in brain tissue," Biochem J, vol. 351, pt. 3, pp. 587-593 Yclnik, j. 2002, "Functional anatomy of the basal ganglia," Mov Disord, vol. 17, suppl. 3, pp. S15-S21 Zhang, I.., Murata, Y., et al. 2 0 0 1 , "Differentiating between progressive supranuclear palsy and corticobasal degeneration by brain perfusion SPET," Nucl Med Commun, vol. 22, no. 7, pp. 767-772 Zhou, B,, Westaway, S. K„ Levinson, B., et al. 2001, "A novel pantothenate kinase gene (PANK2) is defective in HallervordcnSpatz syndrome," Nat Genet, vol. 28, no. 4, pp. 345-349
Chapter 78 Disorders of the Cerebellum, Including the Degenerative Ataxias S. H. Subramony Acquired Ataxias Hypothyroidism loxie ' [nttvriinis Autoimmune Causes of Ataxia Inherited Ataxias Autosomal Kr.wjvi Ataxias
216? 2169 2169 2170 2171 2172 2172
Cerebellar ataxia can he the result of a variety of insults to the cerebellum and its connecting pathways. The cerebellum can be the seat of pathology in many well-recognized diseases of the central nervous system (CNS) and may be involved in such processes in isolation or in combination with other structures. Thus ataxia can he either the major feature of the disease or one of its various clinical signs. In addition, progressive degeneration of the cerebellum and its connections resulting in ataxia can result from a number of genetic abnormalities. Finally, the term sporadic ataxia or idiopathic ataxia is used for those diseases in which ataxia related to cerebellar degeneration occurs in the absence of a definite genetic or acquired etiology (Ahclc ct al. 2002). In this chapter, I briefly discuss some of the well-defined acquired causes of ataxia, summarize the current understanding of the inherited ataxias, and address the issue of sporadic ataxia.
ACQUIRED ATAXIAS In many patients, progressive ataxia results from environmental insults and other well-recognized disorders involving the nervous system. In any patient presenting with cerebellar ataxia, such disorders as ischemic or hemorrhagic stroke involving the cerebellum, previous episodes of cerebral hypoxia, primary or metastatic tumors, and demyelinating diseases such as multiple sclerosis can be diagnosed by appropriate imaging studies and other investigations. Many of these diseases tend to have an acute or subacute evolution, rather than the chronic course associated with degenerative ataxias. However, other diseases can present with ataxia in which the major imaging abnormality may be an atrophic cerebellum akin
Mitochondrial Diseases and Ataxia Autosomal Dominant Ataxias Sporadic Ataxias Sporadic Cortical Cerebellar Atrophy Spotadic Ataxia with Added Noneerehellar Deficits Clinical Approach to Patients with Degenerative Ataxias
2177 2177 2182 2183 2183 2183
to the finding in degenerative ataxias. Some of these are briefly discussed. Table 78.1 lists acquired causes of ataxia.
1 lypothyroidism Occasional patients with hypothyroidism develop a mild gait ataxia in conjunction with their systemic symptoms. Thyroid functions need to be tested in patients with progressive ataxia. Thyroid replacement can improve the neurological symptoms.
Toxic Alcohol Alcohol remains the major exogenous agent causing ataxia. A significant proportion of alcoholics have midline cerebellar degeneration at autopsy. Clinically, this disease is characterized by a progressive gait disturbance of a cerebellar type with little in the way of upper limb ataxia, speech difficulties, or eye movement abnormalities. This may reflect the relative sparing of the cerebellar hemispheres. Imaging studies typically reveal vermian atrophy, Chronic alcoholism can also produce significant cerebellar atrophy in the absence of major clinical deficits (Hillborn e t a l . 1986). Chemotherapy Some cancer chemotherapcutic agents may produce ataxia as an adverse effect. 5-Fluorouracil (5-FU), a fluorinated pyrimidine that acts by incorporating into RNA and interfering with RNA function, has been used to treat 2169
2170
NEUROLOGICAL DISEASES
Tabic 78.1:
Acquired causes of ataxia
Disorder
Diagnostic process
Vascular disease Hypoxic encephalopathy sequel Demyelinating disease
History of strokes, imaging History of hypoxic episode
Posterior fossa tumor C ra n ioverteb ra 1 junction anomaly Hypothyroidism Toxic disorders Alcohol, chemotherapy, metals Solvents, anticonvulsants Infections (see text) Acute cerehellitis, postinfectious, BickcrstafPs encephalitis, HIV, CJD Autoimmune disease Paraneoplastic
Imaging Imaging
Gluten ataxia Ann GAD ataxia
Remitting and relapsing episodes, imaging
Thyroid studies History
Imaging, CSF, serology
Anti-Hu, anti-Yo, anti-Ri, others Anti-gliadin, anti-endomysial Anti-GAD
CJD — Creutzfeldt-Jakoh disease; CSF = cerebrospinal fluid; GAD = glutamate decarboxylase; HIV = human immunodeficiency virus.
and paint thinners are the usual sources. Cognitive deficits and pyramidal tract signs often accompany the ataxia and dysarthria. Anticonvulsants The issue of cerebellar atrophy and anticonvulsant use, especially phenytoin, is controversial. Ttansient cerebellar signs associated with supratherapeutic levels of drugs have been seen with many anticonvulsants. More persistent ataxia and documented Purkinje cell loss has been primarily seen in epileptics treated with phenytoin for prolonged periods of time. Cerebellar atrophy occurs in phenytoin-treated patients but may not always be associated with overt ataxia. The pathogenesis of this syndrome remains unclear. The various hypotheses include a direct toxic effect of phenytoin, a result of repeated hypoxia related to seizures, the effect of the seizure-related electrical discharge on cerebellar Purkinje cells, and the possibility that both the seizures and the cerebellar pathology are secondary to a unifying underlying pathology such as prenatal injuries. Another intriguing possibility is that both the sei/.ures and the progressive cerebellar syndrome could result from a single underlying gene mutation. It is probably best to avoid phenytoin in an epileptic patient if either ataxia or cerebellar atrophy is present.
breast and gastrointestinal cancer. Conventional doses of 5-FU may cause cerebellar ataxia if there is an abnormality of pyrimidine metabolism in the form of dihydropyrimidinc Infectious dehydrogenase deficiency. Higher doses of 5-FU can cause* a panccrcbcllar syndrome that has an acute to subacute Ataxia can be one of the features of postinfectious evolution. encephalomyelitis but usually accompanies a more diffuse cerebral process (Coyle 2000). A more restricted cerebellar When cytosine arabinoside is given in high doses (3 g/m for 8-12 doses as opposed to the conventional 100-200 syndrome has been seen in children after viral infections. mg/m for 5—7 days), a significant number of patients Connolly et al. (1994} have proposed that this diagnosis be develop a cerebellar syndrome. Pathologically, this is considered when children develop an acute ataxic disorder characterized by loss of Purkinje cells, gliosis, loss of that is not associated with a more diffuse process reflected by seizutes, meningismus, or obtundation. In most children, dentate neurons, and spongiform changes. LIIIS condition is preceded b\ a nonspeeifk viral syndrome or varicella with a peak incidence at the age of 5-6 years. A Metals similar syndrome following Epstein-Barr virus infection or Organic mercury poisoning has occurred in epidemic form vaccinations occurs in the teenage years. Cerebrospinal as a result of contamination from mercury-containing fluid (CSF) analysis may show some elevation of protein and fungicides. Mercury appears to be particularly toxic to a modest mononuclear pleocytosis and magnetic resonance cerebellar granule cells and visual cortex and causes a imaging (MRI) scans often reveal signal density changes in syndrome that includes paresthesias, ataxia, and restricted the cerebellum (Figure 78.1). Such a disorder may occur in visual fields. Manganese may cause not only parkinsonism adults as well (Klockgether et al. 1993). Prognosis for but also ataxia. Gait ataxia associated with other signs such recovery is excellent with residual dysfunction seen in a as confusion and myoclonus has also been described with distinct minority. bismuth toxicity resulting from excessive intake of bismuth subsalicylate (Pepto-Bismol). So bents Chronic solvent abuse, especially of toluene, can cause persistent neurological deficits including ataxia. Spray paint
Similarly a combination of ataxia, ophthalmoplegia, and other lower cranial nerve palsies can occur as a result of brainstem encephalitis (Bickerstaff's encephalitis). Clinically, this disorder resembles the Miller Fisher variant of GuillainBarre syndrome from which it is distinguished by the presence of high-signal lesions in the brainstem on MRI scans (Fargas et al, 1998).
DISORDERS OF THE CEREBELLUM, INCLUDING THE DEGENERATIVE ATAXIAS
2171
patients with classic CJD, close to 17% have early ataxia and more than 6 0 % have cerebellar pathology at death. Jellinger, Heiss, and Dcisenhammer (1974) noted that the ataxic variant of CJD began with minor behavior symptoms followed by ataxia. Upper motor neuron signs were common; myoclonus occurred only in 25 % and dementia evolved late. Survival among these patients was slightly longer than in typical CJD with a mean time to death of 16 months and a range of 7 weeks to 8 years. Pathologically, the cerebellum shows striking granule cell loss. Patients suspected of having CJD can be tested for the presence of the 14-3-3 protein in the CSF and for codon 129 homozygosity in the prion gene. CSF tau protein assay by enzyme-linked immunosorbent assay, already readily available in routine laboratories, has been found to have a 9 2 % positive predictive value in diagnosing CJD; 74 of 77 patients with probable CJD had tau protein levels of more than 1300 pg/mL, whereas only 2 of 28 patients with Alzheimer's disease had such high levels, and even lower percentage in other dementias (Otto et al. 2002).
FIGURE 78.1 Signal density change in the cerebellum io a child with acute cerebellar ataxia of childhood. (Courtesy Dr. V. Vedanarayanan, Department of Pediatries, University of Mississippi Medical Center.)
Interestingly, both Gerstmann-Straussler-Scheinker (CSS), an autosomal dominant form of CJD associated with codon 102 mutation, and growth hormone-related CJD have a cerebellar presentation. The new variant CJD also may have a cerebellar presentation (Will et al. 1996).
Autoimmune Causes of Ataxia Paraneoplastic Human immunodeficiency virus (HIV) infection can result in many neurological syndromes, including ataxia. Most patients with ataxia in the presence of HIV infection have discrete, well-recognized lesions such as lymphomas, chronic meningeal infection, progressive multifocal leukoencephalopathy, or toxoplasmosis. Also, approximately 3 0 % of patients with HFV dementia have an ataxic syndrome at the onset of their illness before cognitive decline begins. Other authors have described isolated progressive cerebellar ataxia that does not evolve into HIV dementia in a small number of patients (Tagliatti et al, 1998). These patients had a rapid evolution of their ataxia leading to a chair-bound status in less than a year; MRI revealed cerebellar atrophy. Pathological examination in a small number of patients has revealed marked granule cell loss. The relationship between possible human T-lymphotropic virus type II (HTLV-1I) infection and ataxia has been raised by some anecdotal experience but remains to be proven. Creutzfeldt-Jakob disease (CJD) should also be considered in the differential diagnosis of patients presenting with progressive ataxia. CJD is typically a rapidly progressive dementing illness related to the accumulation of mutant prion protein, which results from post-trans la tional modification of the normal prion protein. Among
Cerebellar
Degeneration
This is a rapidly progressive pancerebellar syndrome that reaches its nadir within a few months of onset. It produces a severe ataxic disease associated with dysarthria and oscillopsia. Diplopia and vertigo may also occur. Many patients also develop other neurological signs including dementia, extrapyramidal signs, hearing loss, and dysphagia. MRI typically shows atrophy of the cerebellum, although some high-signal density changes may occur in the deep white matter. CSF usually shows a mononuclear pleocytosis and oligoclonal bands may be present. It is believed that in many cases the syndrome results from an autoimmune process triggered by the cancer. The anti-Yo antibody is usually seen in ovarian cancer and primarily causes a cerebellar syndrome. The anti-Hu antibody is seen with small cell cancer of the lung and typically causes a multifocal disorder, the most common of which is a sensory ganglionopathy. Purkinjc cell degeneration has been noted in about 2 5 % of patients with anti-Hu antibody. The antiRi antibody has been seen in patients with truncal ataxia and opsoclonus in the setting of breast cancer. Patients who exhibit a combination of ataxia and Lambert-Raton syndrome against a background of small cell cancer of the lung usually have no demonstrable antibodies. The nomenclature of these antibodies is under debate. Thus the
2172
NEUROLOGICAL DISEASES
anti-Yo, anti-Hu, and anti-Ri antibodies may he equated with the Purkinje cell antibody type 1 (PCA-1), the antiiicuronal antibody type 1 (ANNA-1), and the antineuronal antibody type 2 {ANNA-2), respectively. Other antibodies that have been related to paraneoplastic cerebellar ataxia include the anti-Ta, anti-Ma, anti-CV2, and antiglutamate antibodies (Henzen-Logmans et al. 2000; Posner and Dalmau 2000).
there is evidence that they bind to presynaptic nerve terminals around cerebellar Purkinje cells. GAD is the enzyme that synthesizes y-aminobutyric acid (GABA) from glutamate and it is believed that the antibodies may be pathogenic because of their binding to GABA terminals. Intravenous immune globulin may cause partial remission of symptoms. Nutritional
Ataxia with
Gluten Sensitivity
Following the observation that cerebellar ataxia can often be a neurological complication of celiac disease, Hadjivassiliou et al. (1998) looked for gluten sensitivity among a group of patients with sporadic ataxia. Sixty-eight percent of these patients had antigliadin antibodies, contrary to 5% of neurological controls. Malabsorption did not appear to be the cause of the ataxia. Other studies have noted a lower prevalence of gliadin antibodies in patients with idiopathic ataxia or none at all (Pellechia et al. 1999; Combaross et al. 2000; Burk el al. 200] . Busharactal. (20:11) have reported that patients with idiopathic ataxia and those with a definite genetic form of ataxia had a similar occurrence of gluten sensitivity, taising doubts about the significance of the gliadin antibodies. Recent immunocytochemical studies, however, have supported the idea that these antibodies do indeed bind to Purkinje cells of the cerebellum (Hadjivassiliou et al. 2002). Patients with gluten sensitivity usually have slowly progressive ataxia associated with brisk tendon reflexes, peripheral neuropathy, and often, mild cognitive changes. Myoclonus and eye movement abnormalities have been desctibed as well. Nervous system pathology has been characterized by cerebellar Purkinje cell loss, infiltration by T lymphocytes, and posterior column degeneration. A variable proportion of patients have typical celiac disease on duodenal biopsy, even when there are only minor gastrointestinal symptoms; some have either normal biopsies or simply lymphocytic infiltrates. Whether a gluten-free diet or other irnmunomodutation will improve gliadin antibody-associated ataxia is unclear. Ataxia and
Antiglutamate
Acquired vitamin E deficiency occurring in the setting of fat malabsorption can cause ataxia. Examples include cystic fibrosis and cholestatic liver disease.
INHERITED ATAXIAS The initial recognition that progressive balance difficulties related to pathology in the cerebellum and its connecting pathways could have a genetic basis is attributed to Nicholas Friedreich, who published a series of papers describing siblings with such a disease, now known as Friedreich's ataxia (FA). As early as 1893, Pierre Marie noted the clinical and genetic heterogeneity among the inherited ataxias. During much of the twentieth century, inherited ataxias that did not quite fit the Friedreich mold were often labeled Marie's ataxia. Also, many patients have progressive ataxia of a degenerative nature, clinically and pathologically resembling the inherited ataxias and yet having no discernible genetic basis. Much of the last 100 years saw the detailed clinical and pathological descriptions of these patients and attempts to understand them on a clinicopathological basis. Nevertheless, the clinical, neuropathological, and genetic heterogeneity of the disorders did not allow a universally acceptable classification. Based on an extensive clinical study of many families, Harding wrote a clinical genetic classification that served as a prelude to an increasingly gene-based listing of the inherited ataxias. A classification that is based on the recent understanding of phenotype-genorype correlations is still needed. This section summarizes the current information regarding the inherited forms of ataxia.
Decarboxylase Antibodies
Recently, a number of reports have noted the presence of antibodies to glutamate decarboxylase (GAD) among a small number of patients with progressive ataxia (Honnorat et al, 1995; Said et al. 1997). The patients have been usually middle-aged women. Ataxia was occasionally associated with petipheral neuropathy, slow saccades, and in some cases stiff person syndrome. Many patients had multiple organ-specific antibodies including those directed against thyroid cells, parietal cells, and pancreatic islet cells, and insulin-dependent diabetes was an invariable accompaniment. The antibodies occut in higher titers than those found in adult-onset diabetes, and
Autosomal Recessive Ataxias Table 78.2 lists various autosomal recessive ataxias based on specific gene loci. Most of these diseases begin in childhood or early adult life; however, onset late in life is possible. Singleton patients may occur in many families. Typically, parents do not manifest any symptoms because they are heterozygous for the mutation. If the sibship size is large or when extended pedigrees are obtained, other involved persons may be found; the disotders affect both males and females. Consanguinity among the parents may be found but is not essential.
DISORDERS or THE CEREBELLUM, INCLUDING THE DEGENERATIVE ATAXIAS
Table 78.2:
2173
Autosomal recessive ataxias with known gene loci
Disease
Gene locus
Gene
Mutation
Friedreich's ataxia Ataxia-telangiectasia* Ataxia with oculomotor apraxia" A [TUSCAN-1* AVI D ARSACS Ataxia, neuropathy, high ar-femprotein IOSC A Ataxia, deafness, optic atrophy Unverricht-Lundborg disease
9ql3-21.l llq22-23 9pl3 llq21 I4q31
X2.5 ATM Aprataxin MRE11 II >!' I aTTP SACS Unknown Unknown Unknown Cystatin B
GAA expansion Point mutations/deletions Point mtirations/deletions/insertions I'oint mutations Point mutations/deletions/insertions Point mutations Point mutations Unknown Unknown Unknown Repeat expansion
H
13qll 9q33-34 10q24 6p21-23 21q
These all involve mutations in DNA repair genes. Xeroderma pigmentosum and Cockayne's syndrome are other multiple system DNA repair detects in which one may see ataxia. ARSACS = autosomal recessive spastic ataxia of Charlevoix-Saguenay; ATLD = ataxia-tclangiectasia-like disorder; AVED = ataxia with isolated vitamin E deficiency; IOSC A = infantile onset spinocerebellar ataxia; SCAN-1 = spinocerebellar ataxia with axonal neuropathy 1; TDP = tyrosyl DNA phosphodiesterase; TTP — tocopherol transfet protein.
Friedreich '$ Ataxia Clinical Features. The prevalence of FA has been estimated to be 2 x 1 0 _ s (Pandolfo 1999). Classic descriptions of the disease include an age at onset of younger than 25 years, typically early in adolescence (Harding 1981). Onset is with increasing gait difficulties and neurological examination reveals gait ataxia, loss of proprioceptive sense in the lower limbs, and absence of deep tendon reflexes, cither generalized or in the lower limbs. These findings are related to the early pathology in the dorsal root ganglion cells and the occasional patient may have symptoms that can be mistaken for a hereditary neuropathy. However, most patients exhibit signs indicating involvement of the CNS, including dysarthria, upper motor neuron findings such as extensor plantar responses and eye movement abnormalities such as square wave jerks. Rarely, patients may present with cardiac disease or .: spinal deformity and later develop neurological disease. Patients tend to lose ambulation about 9-15 years after onset. At this stage, patients have increasing ataxia of both upper and lower limbs, profound proprioceptive loss, areflexia, weakness of lower limb muscles, dystonia, flexor spasms, and increasing dysarthria and dysphagia (Hou and Jankovic 2003). Optic atrophy and hearing loss may occur in many patients. Systemic abnormalities that occut include abnormal electrocardiogram recordings, hypertrophic cardiomyopathy in about 5 0 % of the patients, and diabetes in 10%. Skeletal abnormalities such as spinal deformities and foot deformities are common. The mean age at death among patients with FA has been reported to be late in the fourth decade; however, this information comes from studies performed before the availability of FA mutation analysis. Cause of death is usually cardiac, but the respiratory compromise related to spine deformiry may also contribute.
Nerve conduction studies show early absence or reduction of sensory nerve potentials in a diffuse fashion, reflecting the loss of large sensory axons in peripheral nerves. This is correlated with loss of myelinated fibers in sural nerve biopsies. Central motor conduction studies show evolving abnormalities and may reflect the progression of the disease. MRI scans of the brain reveal no abnormalities in the cerebellum; rather, the upper cervical cord shows atrophy. Pathologically. iluTc is loss ni dorsal root ganglion cells, resultant degeneration of the dorsal columns, degeneration of spinocerebellar and corticospinal tracts, and loss of cells in the cerebellar dentate nucleus, The Friedreich's Ataxia Mutation. The mutation in FA is an unstable expansion of a repeated trinucleotide (GAA) sequence within the first intron of the gene X 25 on chromosome 9ql3-21.1 (Campuzano et al. 1996) (Figure 78,2). More than 8 0 % of the normal alleles have fewer than 10 GAA repeats. Long normal alleles with 12-40 repeats are believed to serve as a reservoir for expansion into mutations that appear restricted to Indo-Caucasian populations (Pandolfo 1999). Expanded alleles have 66-1000 repeats. Because the disease is recessively inherited, both copies of the gene have to be mutated to produce disease. In nearly 9 5 % of the affected persons, the GAA expansion occurs in both alleles (homozygous expansion), although the size of the expansion can be different in the two alleles. Patients with clinical findings compatible with FA but with only a heterozygous expansion of the GAA repeats constitute the remaining 5 % ; such patients are found to have point mutations in the unexpanded allele. Commercially available FA mutation analysis cannot distinguish between such compound heterozygotcs and unaffected carriers of the disease. Homozygous point
2174
NEUROLOGICAL DISEASES
FIGURE 78.2 Schematic representation of the GAA expansion in the first intron of the gene X 25 on chromosome 9 in Friedreich's ataxia. (Courtesy Dr. H. Paulson, University of Iowa.)
mutations have not been found in patients with the diagnosis of FA. Since the identification of the FA mutation, wc have realized that many patients with a phenotype very atypical for classic FA carry the FA mutation (Durr et al. 1996; Filla et al. 1996; Montcrmini et al. 1997). Approximately 1 5 % of patients with homozygous GAA expansion have neurological signs that are identical to those of classic FA hut have an age at onset of later than 25 years (late-onset FA). Other patients with the GAA expansion have the typical age at onset hut retain their tendon reflexes or even have exaggerated reflexes (FA with retained reflexes). There are patients who combine a later onset with retained reflexes ;'.-, well; in addition, vcr\ Life unset ol mild gail ataxia, spastic paraparesis, and even chorea has been rarely associated with the FA GAA expansion (Hon and Jankovic 2003). As with other trinucleotide repeat diseases, there is an inverse correlation between the size of the GAA repeat and the age at onset; this correlation is better with the smaller of the two expanded alleles. Cardiomyopathy and diabetes also tend to occur in patients with larger (>700) GAA repeats. However, not all of the variation in age at onset and severity of disease can be cortelated with the GAA size alone. Other genetic and possibly environmental factors may contribute to this variation. We already know that the size of the GAA expansion exhibits somatic mosaicism, so the severity of pathology in a particular tissue may depend to some extent on the repeat size in that tissue. Point Mutations. Approximately 5% of patients with FA have heterozygous GAA expansion in one copy of the gene and a point mutation m the second copy. Both missense and truncating mutations located in the carboxy terminal half of the frataxin gene appear to be associated with typical FA phenotype (Cossee et al. 1999). Missense mutations in the amino terminal half such as the G130V mutation appear to result in a milder phenotype with less ataxia, greater spasticity, and absence of d\ sartbria. Pathogenesis. The presence of the expanded GAA sequence in the first intron of the gene results in reduced
transcriptional and translations) efficiency, leading to a partial deficienc) ol the protein frataxin (I'uccio and Koenig 2000; Lodi, Taylor, and Schapira 2001; Pandolfo 2001). The lack of documented homozygous point mutations causing FA suggests that the complete absence of frataxin may be incompatible with life, and this has been further supported by the inability to create transgenic animal models of the disease by complete knockout of the gene. The reduced transcriptional efficiency of the mutated gene has been attributed to an unusual "sticky DNA" configuration of the expanded repeat (Sakamoto et al. 1999). The exact role of frataxin in normal biology is still not clear, but many studies suggest that it is a mitochondrial protein. Knockout of the frataxin homologue in yeast leads to accumulation of iron in the mitochondria, a finding of interest in view of the presence of iron in the cardiac muscle in human disease. Rotig et al. (1997) have shown that activity of enzymes that contain iron-sulfur clusters is impaired in cardiac muscle biopsies of patients with FA, It has been hypothesized that this impairment is related to oxidative stress induced by the presence of excess iron that can induce such stress via the Fenton reaction. However, it is also possible that the deficiency of iron-sulfur cluster enzymes may he directly related to the reduced amounts of frataxin. Recent conditional knockout mouse models of FA, in which frataxin deficiency confined to cardiac and neural tissue has been achieved, appear to support this concept. Frataxin appears to be important in making mitochondrial iron available to such processes as synthesis of Fe-S cluster enzymes and heme synthesis. MRI has suggested excess iron in the dentate nucleus of patients with FA and there is magnetic resonance spectroscopy evidence of impaired respiratory capacity of skeletal muscle in FA. Thus FA is an example of a nuclear-encoded mitochondrial disease related to impaired respiratory activity of mitochondria.
Treatment of Friedreich's Ataxia. Based on the ability of the coenzyme Q analogue idebenone to suppress iron induced oxidative damage, early studies have shown a reproducible response of the hypertrophic cardiomyopathy of FA to idebenone treatment (Rustin et al. 1999;
DISORDERS OF THt CEREBELLUM, INCLUDING THE DEGENERATIVE ATAXIAS Hausse et al. 2002). Improved bioencrgetics of cardiac and skeletal muscle have been shown to occur in response to coenzyme Q and vitamin F. (Lodi ct al. 2001). In addition, many attempts have been made at symptomatic therapy for patients with FA with possible neurotransmitter replacements such as cholinergic, scrotoninergic, and GABAergic drugs, which have shown variable and usually less than optimal results. The supportive care of patients with FA includes adequate rehabilitation efforts aimed at mobility, using appropriate devices. Monitoring and caring for the systemic complications are also important. This includes skeletal deformities, cardiomyopathy, and diabetes. A tax ia-Telangiectasia Ataxia-telangiectasia (AT) occurs with a frequency of three per million. Typically, the disease has its onset in the first decade. Children develop progressive ataxia associated with hypotonia, areflexia, peripheral neuropathy, and choreoarhetosis. Also, they exhibit a characteristic oculomotor apraxia, requiring head thrusts for saccadic eye movements. Telangiectasias develop over the conjunctivae (Figure 78.3), ear lobes, and other areas during the second half of the first decade. MRI scan of the brain shows atrophy of the cerebellum. AT is associated with increased risk of malignancies, especially hematological and infections related to immune deficiency. Increased susceptibility to radiation damage has been shown to cause chromosomal translocations and has been used in a fibroblast survival assay as a diagnostic test. Many patients have decreased
EIGURE 78.3
2175
immunoglobulin A (IgA) levels; decreased immunoglobulin E and immunoglobulin M levels, lymphocytopenia, and skin anergy may also occur. In addition, elevation of afetoprotein in the serum is a consistent finding in AT. AT is caused by truncating mutations of the gene ATM on chromosome I 1 (Savitsky et al. 1995; Halazoncitis and Shiloh 1999). More than 300 mutations of this gene have been associated with AT, and mutation detection may not be the best way to make a definitive diagnosis. The protein product of ATM has sequence similarities to phosphatidyl3-kinase and may be involved in checkpoint responses to DNA damage, explaining many of the systemic features of the illness. The neurological illness itself is still not directly treatable; however, children with AT requite supportive rehabilitation efforts, as well as monitoring and management of the various systemic features. Ataxia with Isolated Vitamin E Deficiency The occurrence of a childhood-onset recessive ataxia associated with isolated vitamin E deficiency {AVED} is related to mutations in the gene encoding the a-tocopherol transfer protein (a-TTP) on chromosome 8 (Ouahchi et al. 1995). a-TTP is a hepatic protein involved in the processing of vitamin H for transport in the chylomicrons. The severity of the phenotype associated with a-TTP mutations depends on residual protein activity; the childhood-onset disease has considerable resemblance to FA, causing ataxia, areflexia, proprioceptive loss, and dysarthria. A recent report of 43 patients with AVED noted age at onset from 2-52 years; patients with AVED had a lower incidence of
Conjunctival telangiectasia in a patient with ataxia-telangiectasia.
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NEUROLOGICAL DISEASES
cardiomyopathy and more frequent head titubation, compared with patients with FA (C Cavalier et a I. 1998). vitamin F levels should be obtained in all persons with sporadic ataxia of childhood or young adult onset. Patients with AVED have typically less than 1.8 mg/L of vitamin E in serum. Treatment with large doses of vitamin E will elevate the levels and perhaps slow progression of the disease. A beta tip op ro teinem ia Mutations in the microsomal triglyceride transfer protein cause this rare disease (Sharp et al. 1993). The diagnosis can be established by the presence of retinopathy, malabsorption including that of vitamin E, low serum cholesterol levels, and the presence of acanthocytes. Serum lipoprotein electrophoresis can also establish the diagnosis. Autosomal
Recessive
Ataxia
of Charlevoix-Saguenay
Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a childhood-onset disease that has been described from a population isolate in the Canadian province of CharlevoixSaguenay and is characterized by spastic ataxia. Onset is in early childhood; neurological findings include spasticity, cerebellar eye movement abnormalities, and limb ataxia. Progression is v o w and MHM:I a;;;' .11 dr.ilh is in the late
fifties. The mutation causing this has been shown to involve a gene on chromosome 13, The protein product of this gene has similarities to chaperone proteins and has been named sacsin (Engert et al. 2000). Families from other parts of the wotld have been linked to the same locus. Thus the true prevalence of this disorder among childhood ataxias remains to be determined. Autosomal
Recessive Ataxia with
Oculomotor Apraxia
Autosomal recessive ataxia with oculomotor apraxia is characterized by early onset of ataxia, autosomal recessive inheritance, and some features resembling AT such as oculomotor apraxia, loss of deep tendon reflexes, and cerebellar atrophy. Setum albumin level is decreased and total cholesterol level is elevated. Other systemic features of AT such as malignancies are not seen. Two groups have identified the gene mutation involving the aprataxin gene. Aprataxin is widely expressed and shares homologies with histidine-tnad (HIT) proteins and with DNA binding C2H2 zinc-finger proteins. It may be involved in DNA repair as well (Date et al. 2001; Moreira et al. 2001). Other DNA Repair Defects Causing Ataxia An AT-like disorder (ATLD) has been recently linked to mutations in another DNA repair gene known as MRE11 {Stewart et al. 1999). Similarly, mutations in tyrosylDNA phosphodiesterase 1 (TDP-1), another DNA repair enzyme, causes spinocerebellar ataxia (SCA) with axonal
neuropathy (SCAN-1). These patients do not have any systemic features that characterize AT and ATLD (Takashima et al. 2002). Cockayne's syndrome and xeroderma pigmentosum are diseases caused by DNA repair defects in which systemic disease predominates the phenotype, but CNS features including ataxia are often present. Mutations in genes encoding components of the nucleotide excision repair pathway occur in these diseases (Chu and Maync 1996). Infantile-Onset
Olivopontocerebellar
Atrophy
Infantile-on set olivopontocerebellar atrophy has been reported from a population isolate in Finland. The disorder begins with clumsiness soon after children begin walking. Neurological signs include ataxia, peripheral neuropathy, areflexia, athetosis, and extensor plantar reflexes. Speech is impaired and hearing loss occurs. Ophthalmoplegia, optic atrophy, seizures, learning deficits, and skeletal deformities are other features. The gene has been mapped to 10q24 (Nikahet al. 1997). Other
Genetically
Defined Autosomal Recessive Ataxias
Other recessive ataxias have been genotyped in a limited number of families. These include an FA2 locus on 9p, ataxia, neuropathy, and high w-fetoprotein (9q), ataxia, deafness, and optic atrophy (6p), and ataxia with increased saccadic speed (lp) (Bemontet al. 2000; Christodoulu et al. 2001; Swartz et al. 2002). Ataxias with Defined Biochemical Errors Many childhood-onset and young adult-onset ataxias are related to metabolic errors that can be diagnosed by specific laboratory tests, rather than by gene-based tests. In many of these diseases, ataxia forms only a parr of the phenotype. Table 78.3 lists some of these diseases. Some of these are amenable to various forms of therapy including dietary manipulations. Clinically Defined but (Likely) Syndromes
Genetically Heterogeneous
Many children and young adults with progressive ataxia still have undefined genotypes. The term early onset ataxia with retained reflexes was originally used to describe a syndrome of ataxia with onset in childhood with some resemblance to FA except for the preservation of deep tendon reflexes. We now know that many of these patients carry the FA mutation; in others, however, the genotype remains unknown. Similarly, Cordon Holmes originally described the syndrome of recessive ataxia associated with hypogonadism in 1907. This may also be genetically hetetogeneous, although in some patients with such a disorder, mitochondrial mutations have been described.
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2177
Tabic 7 8 3 : Ataxias in which specific biochemical abnormalities may confirm or point to the diagnosis (some also appear in Table 78.2} Disorder
Laboratory
WHL> Abetalipoproteinemia AOA V! Cercbrotendinous xanthomatosis Ad ren o I e u k od y str o p h y Ataxia with CoQ deficiency Vanishing white matter disease Late onset G M j gangliosidoses CDG syndromes Mitochondrial diseases Sialidosis Maple syrup urine disease
Low vitamin H levels Low vitamin K levels, high cholesterol, abnormal lipoprotein electrophoresis Low albumin, high cholesterol High a-fetoprotein, low IgA High serum eholestanol Serum long chain fatty acids Low C o Q in muscle biopsy MRI, MRS Hexosaminidase in fibroblasts Transferrin isoelectric focusing Lactic acid levels, RRF in muscle Neuraminidase Urine amino a d d s Urine organic acids, ketone bodies Plasma ammonia Lactate levels
Organic acidurias
Urea cycle defects Pyruvate dehydrogenase deficiency
tests
AOA = ataxia with oculomotor apraxia; AT = ataxia-telangiectasia; AVED = ataxia with isolated vitamin E deficiency; CDG = carbohydrate-deficient glycoprotein; CoQ = coenzyme Q; M!U = magnetic resonance imaging; MRS = magnetic resonance spectroscopy; RRF = ragged red fibers. T h e term Ramsay Hunt syndrome is used for the association of ataxia and m y o c l o n u s or m y o c l o n i c epilepsy. O n e form of this, U n v e r r i c h t - L u n d b o r g s y n d r o m e , is related to m u t a t i o n s in the cystatin P> gene (Pennachio et al. 1996). O t h e r s have mitochondrial D N A m u t a t i o n s o r other disorders of intermediary metabolism such as ceroid lipofuscinosis or sialidosis (Table 78.4).
M i t o c h o n d r i a l Diseases a n d A t a x i a Progtessive ataxia is often an intrinsic feature of m a n y mitochondrial cytopathies related to m u t a t i o n s in the mitochondrial D N A ( m t D N A ) . T h e association of ataxia with m y o p a t h y , external o p h t h a l m o p l e g i a , or o t h e r features of m i t o c h o n d r i o p a t h i e s such as s h o r t s t a t u r e , endocrine deficiencies, elevated CSF p r o t e i n , and retinal pigmentary degeneration m a y suggest a m i t o c h o n d r i a l disease. Some m t D N A m u t a t i o n s have been specifically associated with a t a x i a , including the n t 8 3 4 4 m u t a t i o n tclatcd to myoclonic epilepsy with ragged red fibers (MF.RRF) a n d the n t 8 9 9 3 m u t a t i o n in t h e a d e n o s i n e triphosphatase gene associated with neurogenic w e a k n e s s , ataxia, and retinitis pigmentosa. O t h e r classic m t D N A
Table 78.4: Disorder
s y n d r o m e s such as progressive e x t e r n a l o p h t h a l m o p l e g i a , Kcarns-Sayre s y n d r o m e , a n d m i t o c h o n d r i a l , e n c e p h a l o p a thy, lactic acidosis, a n d strokclike episodes can also be associated with a t a x i a in a variable p r o p o r t i o n of patients. Because m t D N A m u t a t i o n m a y give rise to c o m p l e x tissue distribution of s y m p t o m a t o l o g y related to replicative segregation o f t h e m u t a n t m t D N A a n d t o variable tissue susceptibility to oxidative deficiency, it is possible t h a t isolated C N S s y m p t o m a t o l o g y tela ted to such m u t a t i o n s m a y be difficult to define by studies of p e r i p h e r a l tissues.
Autosomal Douiiiiani Ataxias A u t o s o m a l d o m i n a n t a t a x i a s h a v e onset usually in t h e third to fifth d e c a d e of life, a l t h o u g h there is w i d e variability in age at onset. The disease occurs in each generation of t h e pedigree; the offspring of affected p a r e n t s have a 5 0 % risk of inheriting the disease in general. M a l e - t o - m a l c transmission of t h e disease is definite evidence for a u t o s o m a l d o m i n a n t inheritance. Since the 1990s, the genetic heterogeneity a m o n g the d o m i n a n t a t a x i a s has been m o r e t h a n a m p l y d o c u m e n t e d ( S u b r a m o n y and Filla 2 0 0 1 ) (Table 7 8 . 5 ) . Progressive d o m i n a n t a t a x i a s are labeled SCA, followed by
Young-onset ataxias with some distinctive clinical features but as yet poorly understood at a genetic level Comments
Early onset ataxia with retained reflexes Some have FA or ARSACS mutation; others are genetically undefined Ataxia with hypogonadism (Holmes's ataxia} Associated hypogonadism Ataxia with myoclonus (RamsayHunrsyndro me) Heterogeneous;somemayhavemitochondr!aldisease;othcrsceroidlipofuscinosis, sialidosis, or other biochemical errors ARSACS = autosomal recessive spastic ataxia of Charlcvoix-Saguenay; FA = Friedreich's ataxia.
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NEUROLOGICAL DISEASES
Table 78.5: Autosomal dominant ataxias that have been genotypically defined Disease
Locus
Gene
Mutation
SCA-1 SCA-2 MJD (SCA-3) SCA-4 SCA-5 SCA-6 SCA-7 SCA-8 SCA-10 SCA-11 SCA-12 SCA-13 SCA-14 SCA-15 st; A- i •• SCA-1 " SCA-18 SCA-19 SCA-21 SCA-22 SCA-23 DRPLA EA-1 EA-2
6p22.3 12q24.12 14q21 16q22.1 llpll-qll 19pl3.2 3pl4.1 13q21 22ql3 Uql4-21.3 5q32 19ql3.3-13,4 19ql3.4 Reserved 8q23-24-.l 6q27 7q31-32 Reserved 7p21.3-15.1 Reserved 20pl3-12.2 12p 12p 19p
Ataxin 1 Ataxin 2 Ataxin 3 Unknown Unknown CACNA1
CAG expansion CAG expansion CAG expansion Unknown Unknown CAG expansion CAG expansion CTG expansion A T T C r expansion Unknown CAG expansion Unknown Unknown
\l.i \ir.
SCA-8 SCA-10 SCA-11 PPP2R2B SCA-13 SCA-14 SCA-15 SCA-16 TBP Unknown Unknown Unknown Unknown Unknown Atrophin KCNA1 CACNA1
Unknown CAG expansion Unknown Unknown Unknown Unknown Unknown CAG expansion Point mutations Point mutations
abnormalities related to cerebellar dysfunction are common and include abnormal pursuit and inaccurate saccades in addition to nystagmus. Many, but not all, of the disotdcrs are also associated with clinical signs referable to pathology in CNS structures other than cerebellum and its connections (Diaz et .-.'.. I1)''!); Seijuims and tioulinho P' 1 ' >; Goldfarb et al. 1996; Schols et al. 1996; Gomez et al. 1997), Oculomotor abnormalities unrelated to cerebellar dysfunction include gaze palsy, ptosis, blepharospasm, and an "ocular stare," Many patients have additional bulbar deficits such as facial atrophy, facial fasciculations, tongue atrophy and fasciculations, and poor ability to cough. Upper motor neuron signs such as brisk reflexes with or without spasticity, and Babinski's signs occur early in many dominant ataxias. Extrapyramidal signs including akineticrii',id syndromes, hypomimic fades, chorea, athetosis, and dystonia (Figure 78.4) tend to occur variably in dominant ataxia in different stages of the illness. Evidence of peripheral nerve disease occurs often and includes distal sensory loss and loss of deep tendon reflexes, as well as amyotrophy, (n selected dominant ataxias, there can be associated cerebral signs such as cognitive decline or seizures; in others, there is evidence of retinal disease with visual loss (Figure 78.5).
DRPI A = dentatoruhml-pallidoluysian atrophy; EA = episodic ataxia; MJD = Machado-Joseph disease; TBP = TATA-binding protein.
a number to denote the chromosomal locus. Dominant ataxias that are named differently include Machado-Joseph disease (MJD) (earlier known as SCA-3) and dentatorubralpallidoluysian atrophy (DRPI A), In addition, at least two gene loci are known for episodic ataxia (EA-1 and EA-2) syndromes. The absence of symptomatic disease in cither of the affected parent with autosomal dominant ataxia is rare but can occur for a number of reasons. Examples include reduced penetrance of the disease, onset of disease in a child before onset of symptoms in the affected parent because of anticipation, death of the involved parent before onset of symptoms, and wrong paternity. De novo mutations and expansion from an intermediate si/.e allele to a pathogenic allele in disorders related to repetitive nucleotide sequences may be oilier explanations. Clinical Features of Dominant Ataxias Overall, progressive dominant ataxias related to different gene mutations have ovetlapping clinical features (Subramony 1999). Gradually progressive ataxia associated with an array of cerebellar signs forms the core feature of most of these diseases. Patients exhibit progressive ataxia of gait associated with clinical signs of limb ataxia such as dysmettia and adiadokokinesia. Speech is dysarthric, often with spastic components. Eye movement
FIGURE 78.4 diseasi.
Dystonia in a patient with Machado-Joseph
DISORDERS OF THE CEREBELLUM, INCLUDING THE DEGENERATIVE ATAXIAS
2179
Table 78.6: Distinctive phenotypical features of some dominant ataxias; in general, the various genotypes resemble each other closely Phenotypical feature
Disorders
Age at onset
Young adult: SCA-1, SCA-2, MJD; older adult: SCA-6; childhood onset frequent in SCA-7/DRPLA More in SCA-7, DRPLA SCA-6
Degree of anticipation Benign course Upper motor neuron signs Akinetic-rigid/ Parkinson's signs Chorea FIGURE 78.S ataxia type 7.
Maculoparhy in a patient with spinocerebellar
The motor syndrome is inexorably progressive with loss of ambulation over 10-15 years. A faster rate of progression is correlated with earlier onset of disease. Individual gene mutations often exhibit considerable phenotypical heterogeneity. Some of the clinical heterogeneity within members of the same family is related to duration of the disease; for example, previously present nystagmus may disappear as the saccadic system gets involved or brisk deep tendon reflexes may disappear because of increasing peripheral nerve pathology. Other differences in clinical signs are related to the severity of the gene mutation itself and other intrinsic and extrinsic factors. The underlying gene mutation docs affect the clinical picture to some degree, but clinical differences between the various genotypes are not sufficient to permit confident clinical diagnosis of the genotype without the appropriate mutation analysis. Table 78.6 summarizes some clinical features that may help in the clinical differentiation of various progressive dominant ataxias. The EA syndromes cause intermittent episodes of imbalance, dysarthria, vertigo, and abnormal eye movements that last from minutes to hours. At least two different gene mutations give rise to EA. EA-1 is associated with brief episodes of ataxia and no interictal cerebellar abnormalities; however, many patients have skeletal muscle myokymia interictally. In EA-2, the ataxic episodes arc longer and may be associated with some interictal abnormalities such as nystagmus. Some patients with EA-2 also develop progressive ataxia. Imaging and Other Laboratory Studies in Dominant Ataxias MRI and computed tomographic scans of the brain are useful to exclude many disorders causing ataxia other than the inherited causes such as strokes, tumors, and multiple
Action tremor Very slow saccades Downbeat nystagmus Generalized a reflex ia Visual loss Vi/.UIYS
SCA-1, -7, -8, MJD; rare in SCA-2 MJD, SCA-2, SCA-17 Prominent in DRPI.A; late in SCA-2, -1, MJD SCA-12, 16 Early in SCA-2, -7; late in SCA-1, MJD; never in SCA-6 SCA-6, EA-2 SCA-2, SCA-4, older adult-onset MJD SCA-7 SCA-10, early onset DRPLA, SCA-7
DRPI.A = dcntatorubral-pallidoluysian atrophy; EA = episodic ataxia; MJD = Machado-Joseph disease; SCA = spinocerebellar ataxia. sclerosis. The dominant ataxias arc associated with progressive atrophy of the cerebellum; in addition, there may also be atrophy of the pons, medulla, middle cerebellar peduncles, and upper cervical cord (Klockgether et al. 1998) (Figure 78.6). There can be some hyperintensity of the middle cerebellar peduncles on T2-weighted images. Imaging studies alone are insufficient to differentiate the various genotypes. SCA-1, SCA-2, and SCA-3 are usually associated with pontocerebellar atrophy, and SCA-6 with isolated cerebellar atrophy. Experience with other disorders is limited. Many of the dominant ataxias arc also associated with evidence of an axonal polyneuropathy on nerve conduction studies :\nii abnormal hrainstem-evoked responses. Neuropathology SCA-1, SCA-2, and SCA-7 are usually associated with fairly widespread pathology in the nervous system including loss of Purkinjc cells in the cerebellum, pontine neurons, and olivary neurons (Figure 78.7). In addition, other structures such as dorsal root ganglion cells, Clarke's column cells, and cranial and lower motor neurons may be affected, together with their tracts. In MJD, cerebellar Purkinje cells are relatively spared, but there is severe involvement of pontine neurons, Clarke's column cells, and nigral cells. Spinal motoneurons and vestibular nuclei arc also involved. SCA-6 is characterized by isolated involvement of the Purkinje cells and olivary neurons (Robitailicet al. 1997) (Figure 78.8).
2180
NEUROLOGICAL DISEASES
FIGURE 78.6 Magnetic resonance imaging scan of the brain in a patient with spinocerebellar ataxia type 1, showing pontocerebellar atrophy. Gene Mutations and Phenotype—Genotype in Dominant Ataxias
Correlations
Both unstable expansions of repeated nucleotide sequences {Figure 78.9) and point mutations have been related to dominant ataxias. At least eight dominant ataxias arc related to unstable expansions of CAG repeats inherited in a heterozygous fashion (Orr ct al. 1993; Kawaguchi et al. 1994; Nagafuchi ct al. 1994; Pulst et al. 1996; Zuchenko
FIGURE 78.7 Gross features showing cerebellar and brainstem atrophy in a patient dying with spinocerebellar ataxia type 1.
FIGURE 78.8 Isolated cerebellar atrophy in a patient dying with spinocerebellar ataxia type 6.
et al. 1997; David et al. 1998; Holmes et al. 1999; Zuhlke et al. 2001); all are progressive diseases. Because CAG codes for glutamine and the protein product of the mutated gene contains excess number of gluta mines, many such diseases are examples of polyglutamine disorders. All the CAG expansion diseases are characterized bv an inverse correlation between the number of repeats in the expanded alleh and thi' age ;i( u:iscl. 1 argcr repeal sizes are also associated with more rapid progression of the disease and with more rapid atrophy of posterior fossa structures. Thus the phenotypical heterogeneity within single genotypes is related to a complex interaction between the size of the repeats in a particular individual, the duration of the disease, and additional environmental and genetic factors of unknown nature. The unstable nature of these expansions causes a change in the size of the repeats from one generation to the next, accounting for the variability in age at onset and some of the phenotypical heterogeneity. The observed anticipation in age at onset of many dominant ataxias can be at least partly explained by the expansion of these unstable repeats. Typically, paternal transmission of the disease is associated with a greater tendency for expansion. The SCA-6 CAG expansion, which involves
DISORDERS OF THE CEREBELLUM, INCLUDING THE DEGENERATIVE ATAXLAS
2181
FIGURE 78.9 Schematic representation of various repetitive nucleotide expansions in dominant ataxias. (Courtesy Dr. H. Paulson, University of Iowa.)
the wi-SLibiinit of the neuronal calcium channel gene, is exceptional in that it is transmitted in a stable fashion for the most part. The recently described SCA-8 has been related to an unstable expansion of a CTG tract in the V untranslated region of the gene on chromosome 13 (Koob et al. 1999). The primary roie of this expansion in causing ataxia has been controversial because the same CTG expansion has also been found in patients with other disorders such as stroke and Parkinson's disease and even in general population samples (Stevanin et al. 2000; Worth et al, 2000). The vertical transmission of the expansion has been extensively studied in only one family by Koob et al. (1999), in which a significant lod score was calculated; even in this family, there were several nonpenetrant individuals who had expansions of the repeat into a larger than normal but presumably nonpathogenic range. Thus the interpretation of an expanded SCA-8 CTG repeat in an individual with ataxia remains controversial, and the possibility exists that either the expansion is not fully penetrant or the real mutation is somewhere else but in linkage dysequilibrium with the expansion. The CTG tract in the SCA-8 gene is transcribed to a messenger RNA (mRNA) but not translated into a protein. Still another form of repeat expansion occurs in SCA-10, a disorder typified by progressive ataxia and epilepsy. The mutation is a large unstable expansion of a pentanucleotide repeat (A'lTCT) on chromosome 22 (Matsuura et al. 2000). The CAG expansion in the recently reported SCA-17 involves the TATA binding protein (TBP) gene (Zuhlke et al, 2001). This is of interest because TBP is a critical player in transcription, and transcriptional dysregulation may occur in many of the other polyglutamine diseases as well. The EA syndromes are related to point mutations. In EA-1, the mutation involves a potassium channel gene (KCNA1) on chromosome 12 (Browne et al, 1994). EA-2 has been related to both nonsense and missense mutations in the ai-subunit of the calcium-channel gene (CACNA1) (Ophoff et a I. 1996). Poor penetrance and phenotypical variability have been well documented in EA-2 (Danier et al, 1999). A number of dominant ataxias have been localized to specific chromosomes, but the mutations are as yet
undefined. These include SCA-4 (chromosome I6q), SCA-5 (chromosome l i p ) , SCA-11 (chromosome 15q), SCA-13 (chromosome I9q), SCA-14 (chromosome 19q), and SCA-16 (chromosome 8q), SCATS (chromosome 7q), SCA-21 (chromosome 7), and SCA-23 (chromosome 20p) (Ranum et al, 1994; Flanigan et al. 1996; Worth et al, 1999; Herman-Bert et al. 2000; Miyoshi et al. 2001; Yamashita et al. 2000; Takashima et al. 2002; Brkanac et al. 2002; Verbcck et al, 2002; Vuillaumc et al. 2002). Still others are known to be in as yet unknown loci and these include SCA-9, SCA-15, and SCA-22 (Storey et al. 2001; HUGO Web site). Pathogenesis The pathogenesis of the dominant ataxias has been the subject of intense research since the mid-1990s (Paulson 1999; Zoghbi and Orr 2000; Or 2001). The CAG expansion disorders have been particularly scrutinized by many workers. The SCA-1, SCA-2, SCA-3, and SCA-7 proteins, as well as the DRPLA protein, have all been novel proteins of unknown function and have been named ataxins 1, 2, 3, and 7, and atrophin, respectively. In all these diseases, evidence has accumulated for the gain-offunction hypothesis (Figure 78.10). This states that the disease is caused by the acquisition of a novel toxic function by the protein product of the mutated gene, rather than by the deficiency of the protein, which is typical of many recessive diseases. This idea is consistent with the fact that disease occurs from a single copy of the mutated allele. In all these diseases, the mutated allele is transcribed and translated into its respective protein product in a widespread fashion. Because CAG codes for glutamine, the mutant protein has a longer stretch of glutamines than wild type protein; thus the CAG expansion diseases have also been called polyglutamine disorders. The distribution of the protein has also been shown to be different in diseased brain. Normally, most of the proteins have a diffuse cytoplasmic localization with some additional nuclear presence. However, in diseased brain tissue, the protein has been shown to accumulate as aggregates within the nucleus in SCA-1, SCA-3, and SCA-7, as well as in DRPI.A (Orr 2001). In SCA-2,
2182
NEUROLOGICAL DISEASES
FIGURE 78.10 Diagrammatic representation of some current ideas about the pathogenesis of CAG expansion disorders. 1. The mutant gene with the CAG expansion is transcribed and translated to a mutant protein with an excess number of glutamines. 2. The mutant protein enters the nucleus where it forms aggregates (4). 3. In some situations, truncation of the mutant protein by caspases or similar enzymes might possibly create fragments of the protein containing the polyglutamine tract and such fragments may then enter the nucleus. 4. Formation of nuclear inclusions (Nls). In selected situations, aggregates may occur in the cytoplasm ;is well. 5,fi. Nls recruit a variety of other nuclear proreins including the ubiquitinproteasome system, the heat shock protein system, and transcription factors. The list of proteins associated with NI is slowly growing. 7. Secondary events may include r ra user i prion a 1 dysregulation of other critical genes or as yet unknown pathways such as depletion of critical nuclear proteins.
aggregation of the protein appears to he predominantly in the cytoplasm. Nuclear inclusions (Nls) have heen shown to contain the mutated protein in each instance, and the expanded ghitamine tract is important in the formation of the NI. The Nls also have heen shown to recruit a variety of other proteins such as members of the heat shock protein (hsp) chaperone system and the ubiquitin-proteasome pathway. These findings support the idea that the mutated protein assumes a misfolded configuration (Paulson 1999). The presence of Nl has been reproduced in many transgenic and transfection models of the CAG expansion disorders. Genetic engineering of the hsp and ubiquitin-proteasome pathway has been shown to modify the intensity of NI formation in these model systems and to alter the toxicity of the mutant protein. Also, in some model systems, such as those for MJD and DRPLA, truncated construct1; of the gene containing the CAG expansion have been more efficient in causing pathology. Whether truncation of the mutant protein occurs in human tissue in the case of the ataxias is not yet established, although many of the proteins do have caspase sites. In addition, the essential role of NI in the pathogenesis of neuronal death has been questioned. In fact, in SCA-1 transgenic mouse, genetic manipulation has been able to disassociate the NI from neuronal loss; the deletion of a self-association domain from the ataxia-1 gene prevented the formation of NI, but the pathology was not diminished. On the other hand, deletion of a nuclear localization signal preventing nuclear entry of the mutated protein was enough to prevent neurological disease, establishing the importance of nuclear entry. This has given rise to the idea that interference in essential nuclear functions by the mutated protein may be an important mechanism of disease. Such secondary events may
include binding to essential nuclear proteins including transcription factors and downregulation of other essential genes. The SCA-6 CAG expansion may cause disease by a mechanism different from the aforementioned scenario, although aggregation of the calcium-channel protein in the cytoplasm has been reported (Ishikawa et al. 1999). Expression studies of the mutated channel protein also have suggested that altered calcium-channel function may play a role (Restituito et al. 2000). This may also he true for the point mutations in the calcium-channel gene associated with EA-2.
SI'OH UMC ATAXIAS The occurrence of progressive cerebellar ataxia clinically resembling inherited ataxias but with no definite genetic etiology has been recognized for more than 100 years. The term sporadic ataxia has been used for such a process when other well-established causes of cerebellar ataxia have been excluded. Some of the common causes of ataxia such as multiple sclerosis, strokes, and tumors can be easily excluded by imaging studies. Other causes of ataxia such as alcohol and hypothyroidism have nonspecific imaging findings and can be diagnosed only by appropriate history and laboratory studies. There is little understanding of the etiopathogenesis of truly sporadic cases of ataxia. Sporadic ataxia with childhood or young adult onset may still have undefined single-gene mutations as the underlying cause. When sporadic ataxia has onset in older adults (idiopathic late-onset ataxia), it may be the result of a complex interplay of genetic and environmental factors. It should be noted that among patients with a diagnosis of sporadic
DISORDERS OF THE CEREBELLUM, INCLUDING THE DEGENERATIVE ATAXIAS ataxia, a very small percentage test positive for o n e of the k n o w n gene m u t a t i o n s . It is difficult to m a k e specific r e c o m m e n d a t i o n s regarding the gene tests t h a t need to he obtained in a patient with sporadic ataxia (Tan a n d Ashizawa 2 0 0 1 ) . T h e FA G A A e x p a n s i o n a n d the SCA-6 CAC, expansion may be the most likely to yield a positive result (Abele et al. 2 0 0 2 ) . O n e should consider s o m e of the mutation analyses in patients with sporadic ataxia if the family history is n o t very clear or the clinical picture is more typical for o n e of the genetically determined a t a x i a s . A m o n g patients with idiopathic late-onset a t a x i a , some have added n o nee rebel la r signs a n d some do n o t (Klockgcther et al. 1990).
2183
olivopontocerebellar a t r o p h y form of multiple system a t r o p h y (MSA). A m o n g patients with idiopathic progressive a t a x i a , 2 5 - 3 5 % will transition to p r o b a b l e M S A over 5 - 1 0 years (Gilman et al. 2 0 0 0 ) . T h e clinical evidence for this in m o s t will be added p a r k i n s o n i a n a n d a u t o n o m i c deficits, but in a few, only a u t o n o m i c failure develops. Such signs include o r t h o s t a t i c h y p o t e n s i o n , incontinence, erectile dysfunction, rigidity, and facial h y p o m i m i a . O l d e r age at onset and a m o r e r a p i d progression to a disabled state suggest a higher risk of such transmission. M e d i a n survival after such transition w a s only 3.5 years. Sphincter electrom y o g r a p h y and c a r d i o v a s c u l a r a u t o n o m i c testing m a y b e useful to confirm the diagnosis of M S A . Signs of a u t o n o m i c failure are u n c o m m o n in the inherited a t a x i a s , a l t h o u g h bladder dysfunction is n o t u n c o m m o n in late stages.
Sporadic Cortical Cerebellar A t r o p h y Sporadic cortical cerebellar a t r o p h y usually has onset in patients older than 50 years and results in a progressive ataxia not associated with o t h e r neurological deficits even m a n y years after onset. M R I scans and p a t h o l o g i c a l e x a m i n a t i o n usually s h o w isolated cerebellar a t r o p h y , but this correlation is not absolute. T h e disease h a s a slow progression with a median life span of m o r e than 20 years after onset.
Sporadic Ataxia with Added N o n c e r e b e l l a r Deficits Patients with sporadic ataxia with a d d e d noncerebellar deficits initially have slowly progressive a t a x i a bur s o o n develop additional signs such as u p p e r m o t o r n e u r o n signs, ophthalmoplegia, p a r k i n s o n i a n features, a n d a u t o n o m i c failure. In keeping with this, both M R I and pathological e x a m i n a t i o n s h o w cerebellar and b r a i n s t e m degeneration; the a u t o n o m i c structures m a y be affected as well. T h u s t h e L1UIIL.I1 picture of this disorder merges with t h a t of the
Tabic 7S.7: Disease FA SCA-1 SCA-2 V1JI.)
SCA-6 SCA-7 SCA-8 SCA-10 SCA-12 SCA-17 (TBP)DRPLA
CIJNTCAL A P P R O A C H T O PATIENTS W I T H DEGENERATIVE ATAXIAS A careful clinical a p p r o a c h to patients presenting with progressive a t a x i a allows a c c u r a t e diagnosis a n d a p p r o priate m a n a g e m e n t (Figure 7 8 . 1 1 ) . T h e age at onset, the t e m p o of progression, associated neurological a n d systemic signs, a n d the availability of family history all can be considered in m a k i n g a diagnosis. Imaging studies, especially MRI ol the brain, allow diagnosis of those disorders in which characteristic m o r p h o l o g i c a l a b n o r m a l ities underlie a t a x i a , such as infarcts, mass lesions, or dcmyclinating p l a q u e s . O t h e r l a b o r a t o r y studies of value include thyroid function, vitamin E and P ; _ levels, serology for syphilis, gliadin a n d a n t t - G A D a n t i b o d i e s , antibodies associated with p a r a n e o p l a s t i c s y n d t o m e s , a n d possibly CSF e x a m i n a t i o n for pleocytosis, oligoclonal b a n d s , a n d m a l i g n a n t cells. In y o u n g adults and children, specialized biochemical tests, as indicated in T a b l e 7 8 . 3 , may be indicated.
Normal and pathogenic range of repeat expansions associated with inherited ataxias Repeat •
, \ : \
CAG CAG CAG CAG CAG CTG ATTCT CAG CAG CAG
Norma! h 40 6-44 14-31 12-40 4-18 4-27 16-91 10-22 1000 39-82 33-64 54-86 19-30 37-200 107-127 2 1000-4500 66-78 50-63 44 SS
Note: In SCA-1, the normal and pathogenic ranges overlap. However, the pathogenic-ally expanded repeat can be distinguished from the normal repeat by the absence of CAT interruptions. DRPLA = dentatorubral-pallidoluysian atrophy; FA = Friedreich's ataxia; M)D = Machado-Joseph disease; TBP = TATA-hinding protein.
2184
NEUROLOGICAL DISEASES
Table 78.8:
Geographical variation in the prevalence of various genotypes among autosomal dominant ataxias
Area
SCA-1
SCA-2
MJD
5C4-6
SCA-7
United States Germany United Kingdom Prance
6 9 35 15 3 8 16 5
15 10 40 15 5 25 6 11
20 42 9 33 43 5 12 47
12 22
5
Japan India Australia China (Soong)
2 11 0 17 11
0 2 3
DRPLA
20 0 1
Unknown 42 17 9 35 18 62 47 22
Source: Data summarized with permission from Storey, E., du San, D., Shaw, J, H,, et al. 2000, "Frequency of spinocerebellar ataxia types 1, 2, 3, 6 and 7 in Australian patients with spinocerebellar ataxia," Am] Med Genet, vol. 95, pp. 351-357,
DNA testing is now available for EA, SCA-1, SCA-2, MJD, SCA-6, SCA-7, SCA-8, SCA-10, SCA-12, SCA-17, and DRPI.A (Table 78.7). Gene testing is possible for AT, autosomal recessive ataxia of Charlevoix-Saguenay, AVED, ataxia with oculomotor apraxia type 1, and EA
FIGURE 78.11
syndromes but is not readily available. Patients with features compatible with specific inherited ataxias, as discussed earlier in this chapter, are candidates for such DNA testing. Such testing is very accurate and relatively inexpensive. However, the genetic heterogeneity of the
An algorithm for a diagnostic approach to patients with progressive ataxia.
DISORDERS OF THE CEREBELLUM, INCLUDING THE DEGENERATIVE ATAXIAS ataxias, the overlapping p h e n o t y p e s , a n d the fact tliat there arc u n k n o w n genotypes all m a k e such tests less t h a n o p t i m a l . Some of the p h e n o t y p i c a l features discussed earlier can serve as guidelines to select a p p r o p r i a t e m u t a t i o n analyses. In addition, information regarding ethnic predilections a m o n g the a t a x i a s may also g u i d e the selection of tests (Tahle 78.8). T h u s FA is restricted to E u r o p e a n , Indian, and Middle I'.astem p o p u l a t i o n s . Ataxia with o c u l o m o t o r a p r a x i a is the m o s t c o m m o n recessive ataxia in J a p a n and second only to FA in Portugal. A m o n g d o m i n a n t ataxias, M J D is the m o s t c o m m o n in G e r m a n y , |ap,tn, China, and most South American countries. SCA-2 a p p e a r s co he m o r e prevalent in the United K i n g d o m , Italy, and India. SCA-6 is c o m m o n in J a p a n , DRPI.A constitutes close to 20"o oi d o m i n a n t ataxias in some parts ol J a p a n but is u n c o m m o n elsewhere. Lastly, certain p o p u l a t i o n isolates have a high incidence of certain a t a x i a s , such as SCA-1 a m o n g the Iakut in Siberia, SCA-2 in eastern C u b a , and M J D in the Azorean islands.
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DISORDERS OF THE CEREBELLUM, INCLUDING THE DEGENERATIVE ATAXIAS grandparents of President Lincoln maps to chromosome 1 1 , " Nat Genet, vol. 8, p. 280 Rcsntuito, S., Thompson, R. M., Eliet, J., et al. 2000, "The polygkitamine expansion in spinocerebellar ataxia rype 6 causes a beta subunit-specific enhanced activation of P/Q-type calcium channels in Xenopus oocytes," / Neurosci, vol. 20, no. 17, pp. 6394-6403 Robitaille, Y,, Lopes-Cendes, L, Becher, M., et al. 1997, "The neuropathology of CAG repeat diseases: Review and update of genetic and molecular features." Brain Pathol, vol. 7, no. 3, pp. 901-926 Rotig, A., de Lonlay, P., Chretien, D., et al. 1997, "Acomtase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia," Nat Genet, vol. 17, no. 2, pp. 215-217 Rustin, P., von Kleist-Rcrzow, J. C, Chantrel-Groussard, K., et al. 1999, "Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study," Lancet, vol. 354, no, 9177, pp. 477-479 Said, A., Arpa, J., Sagasta, A., et al. 1997, "Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity," Neurology, vol. 49, PP. 1026-1030 Sakamoto, N., Chastain, P, D., Pamicwski, P., et al. 1999, "Sticky DNA: Self-association properties of long GAA. TTC repeats in R.R.Y triplex structures from Friedreich's ataxia," Mol Cell, vol. 3, pp. 465^175 Savitsky, K., Bar-Slura, A,, Gilad, S., et al. 1995, "A single ataxia telangiectasia gene with a product similar to PI-3 kinase," Science, vol. 268, pp. 1749-1753 Schols, I.,, Amoroidcs, G., Buttner, T., et al. 1997, "Autosomal dominant cerebellar ataxia: phenotypic differences in genetically determined subtypes?" Ann Neurol, vol. 42, pp. 924-932 Sequiros, J, & Coutinho, P. 1993, "Epidemiology and clinical aspects of Machado-Joseph disease," in Advances in Neurology, eds A. E. Harding, & T. Duefel, Raven Press, New York Sharp, D. 1993, "Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproicmcmia," Nature, vol. 365, no. 6441, pp. 65-69 Stevanin, G., Herman, A., Durr, A., et al. 2000, "Are (CTG) expansions at the SCA 8 locus rare polymorphisms?" Nat Genet, vol. 24, p. 213 Stewart, G. S., Maser, R. S., Stankovic, T., et al. 1999, "The DNA double-strand break repair gene h M R E l l is mutated in individuals with an ataxia-telangiectasia-like disorder," Cell, vol. 99, no. 6, pp. 577-587 Storey, E., Gardner, R. J., Knight, M. A., et al. 2 0 0 1 , "A new autosomal dominant pure cerebellar ataxia," Neurology, vol. 57, no. 10, pp. 1913-1915 Storey, F., du Sart, D., Shaw, J. H., et al, 2000, "Frequency of spinocerebellar ataxia types 1, 2, 3, 6 and 7 in Australian
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patients with spinocerebellar ataxia," Am j Med Genet, vol. 95, pp.
ill
\S~
Subramony, S. H. 1999, "Dominantly inherited ataxias," Semin Neurol, vol. 19, pp. 419-425 Subramony, S. H. Sc Filla, A. 2001, "Autosomal dominant spinocerebellar ataxias ad infinitum?" Neurology, vol. 56, pp. 287-289 Swartz, B. E., Burmetstcr, M., Somers, J. T., et al. 2002, "A form of inherited cerebellar ataxia with saccadic intrusions, increased saccadic speed, sensory neuroparhy, and myoclonus," Ann N Y AcadSci, vol. 956, pp. 441-444 Tagliatti, M., Simpson, D., Morgello, S., ct al. 1998, "Cerebellar degeneration associated with human immu no-deficiency virus infection," Neurology, vol, 50, pp. 244-251 Takashima, H., Boerkoel, C. F., John, J., et al. 2002, "Mutation of TDP1, encoding a to poi some rase I-dcpendcnt DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy," Nat Genet, vol. 32, no. 2, pp. 267-272 Tan, E. K. & Ashizawa, T. 2001, "Genetic testing in spinocerebellar ataxias. Defining a clinical role," Areh Neurol, vol. 58, pp. 191-195 Vcrheck, D. S., Schelhaas, J. H., Ippcl, E. F., et al. 2002, "Identification of a novel SCA locus [SCA 19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region I p 2 1 - q 2 1 , " Hum Genet, vol. I l l , no. 4-5, pp. 388-393 Vuillaume, 1., Devos, D., Schraen-Maschke, S., ct al. 2002, "A new locus for spinocerebellar ataxia {SCA-211 maps to chromosome 7p21.3-pl5.1," Ann Neurol, vol. 52, pp. 666-670 Will, R. G., Ironside, J. W., Zeidler, M., et al. 1996, "A new variant of Creunrfeldt-Jakob disease in the UK," Lancet, vol. 347, pp. 921-925 Worth, P. F,, Giunti, P., Gardner-Thorpe, C, et al. 1999, "Autosomal domiuaui cerebellar ataxia type 1111: Linkage in a large British family to a 7.6cM region on chromosome 15ql421.3," Aw I Hum Genet, vol. 65, p. 420 Worth, P. F., Houlden, H., Guinti, P., et al. 2000, "Large expanded repeats in SCA 8 are not confined to patients with cerebellar ataxia," Hal Genet, vol. 24, p. 214 Yamashita, I,, Hidenao, S., Ichiro, Y., er al. 2000, "A novel locus for dominant cerebellar ataxia (SCA 14) maps to a 10.2cM interval flanked by D19S206 and D19S605 on chromosome 19ql3.4-qrcr," Ann Neurol, vol. 48, p. 156 Zoghbi, H. Y. & Orr, H. T. 2000, "Glutamme repeats and ncurodegeneration," Ann Rei> Neruosci, vol. 23, pp. 217-247 Zuchenko, O., Bailey, J., Bonnen, P., et al. 1997, "Autosomal dominant cerebellar ataxia (SCA 6) associated with small polygkitamine expansion in the alpha I A-voltagc-dcpendent calcium channel," Nat Genet, vol. 15, pp. 62-68 Zuhlke, C, Hellenbroich, Y., Dalski, A., et a I. 2001, "Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia," European journal of Human Genetics, vol. 9, pp. 160-164
Chapter 79 Disorders of Bones, Joints, Ligaments, and Meninges Richard B. Rosenbaum and David P. Ciaverella Congenital and Inherited Spinal Disorders Craniocervical Deformities Arnold-Chiari Malformation and Syringomyelia Abnormalities of the Cervjcomedullary Junction Achondroplasia Spinal Dysraphism Spinal Deformities and Metabolic Bone Disease Osteoporosis Osteogenesis Imperfecta Osteomalacia and Rickets Osteopetrosis Pager's Disease Juvenile Kyphosis Scoliosis Diffuse Idiopathic Skeletal Hyperostosis Ossification of the Posterior Longitudinal Ligaments Lii^imentum Flavum Degenerative Disease of the Spine Spinal Osteoarthritis and Spondylosis
2189 2189 2192 : 19$ 11 'tf,
2196 2199 2)99 2201 2201 2201 2202 2203 2203 2203 2203 2204 2204
Because of their proximity to the nervous system, disorders of the bones, joints, ligaments, and meninges can cause several myelopathic and radiculopathy syndromes and can affect the cranial nerves and intracranial contents. This chapter considers many of these disotders, both congenital and acquired. Chapters of overlapping interest include Chapters 27, 56C, 57b, and 66.
CONGENITAL AND INHERITED SPINAL DISORDERS Disorders of the craniocervical junction include bony abnormalities of the occiput and foramen magnum, dysfunction of connecting ligaments, hindbrain malformations, upper cervical skeletal deformities, and syringomyelia or syringobulbia (Mcnzes 1997). Many of these are congenital; their embryogenesis is discussed in Chapter 66, Magnetic resonance imaging (MRI) and computed tomogtaphic (CT) scanning have improved the detection, understanding, and treatment of these anomalies.
2205 Cervical Spondylosis 2205 Cervical Radiculopathy 2207 Cervical Spondylotic Myelopathy Vertebral Artery Stroke Caused by Cervical 2207 Osteoarthritis 2207 Thoracic Spondylosis Lumbar Spondylosis 2207 2212 Lumbar Canal Stenosis 2213 Infectious Diseases of the Spine Pyogenic Vertebral Osteomyelitis and Epidural Abscess 2213 2214 Granulomatous Vertebral Osteomyelitis Inflammatory Joint Disease 2215 2218 Epidural Lipomatosis 2219 Chronic Meningitis 22 1 9 Chronic Adhesive Arachnoiditis 2220 Recurrent Meningitis Uveomeningitis Syndromes 2220 Superficial Hemosiderosis 2220 2220 Fibromyalgia
Craniocervical Deformities Occipitalization
of the Atlas
Occipitalization ot assimilation of the atlas refers to congenital partial or complete fusion of the atlas (first cervical vertebra) to the occiput (Figute 79.1). The anterior arch of the atlas may fuse to the lower end of the clivus or the posterior arch of the atlas may fuse to the occiput. The anomaly is often asymptomatic until early adult life and may become symptomatic after trauma. Unilateral occipitalization of the atlas is one cause of torticollis in young children. The loss of movement between the occiput and atlas increases the stresses at the atlantoaxial joint, predisposing it to gradual degeneration or traumatic dislocation. Patients with occipitalization of the atlas may have associated anomalies, such as the Klippel-Feil anomaly, basilar impression, or Chiari malformation. Basilar
Impression
Basilar impression or invagination refers to abnormal cephalad position of the fotamen magnum (Goel et al. 1998). 2189
2190
NEUROLOGICAL DISEASES Several radiological lines (Chamberlain's, McGregor's, McRae's, digastric) (Figure 79.2) and measurements can be used to make the diagnosis. Congenital basilar impression may occur in isolarion or may be associated with conditions such as achondroplasia, occipital dysplasia, Down syndrome, Hurler's syndrome, Klippel-Feil anomaly, and cleidocranial dysplasia. Some instances of basilar impression are familial. The skeletal anomaly is often accompanied by anomalies of the neuraxis, including Chiari 1 or II malformation and syringomyelia. Basilar impression can cause compression of the brainstem (Figure 79.3) or cerebellum, or rarely vertebral artery compression, leading to vertebrobasilar ischemia. It is often asymptomatic, particularly when mild and unaccompanied by other anomalies. Platybasia or flattening of the skull refers to straightening of the angle between the clivus and the floor of the anterior fossa. It infrequently accompanies basilar impression; it can occur also as an isolated radiographic finding without any adverse neurological consequences. Klippel-Feil
FIGURE 79.1 Occipitalization of the atlas. Radiograph shows fusion of the lamina of the atlas to the occiput (open arrow). The lamina contains the circular arcuate foramina [arrow), through which the vertebral arteries pass. The spinous process of the atlas {curved arroiv) has fused with C2, making this a partial incorporation of CI into the skull base. There is a broad spectrum of variations in this congenital anomaly. (Courtesy Erik Gaensler.)
Anomaly
Patients with the Klippel-Feil anomaly (congenital synostosis of the cervical vertebrae) (Figure 79.4) have short necks, low haitlines, and limitation of cervical motion. The diagnosis is confirmed by radiographic demonstration of fused cervical vertebrae. The condition is congenital, caused by failure of normal segmentation of the cetvical vettebrae between the third and eighth weeks of fetal development. Although familial instances oecut, most cases ate isolated and idiopathic. The anomaly can cause direct nerve root, cetvical spinal cord, or vcrrebtal or spinal artety compression, Neck pain is common. Hearing loss is the most common symptom of cranial neuropathy. Mitror
FIGURE 79.2 Chamberlain's line (dashes) extends from the roof of the hard palate to the posterior lip of the foramen magnum; McGregor's line (solid) extends from the roof of the hard palate to the most caudal portion of the occipital bone; McRae's line [dots] extends from the anterior lip of the foramen magnum ro the posterior lip of the foramen magnum. The tip of the odoiitoid is normally not more than 5 mm above McGregor's line and not above Chamberlain's or McRae's line. (Modified with permission from Roscnhaum, R. B, Campbell, S. M., &c Roscnhaum, J. T. 1996, Clinical Neurology of Rheumatic Diseases, BurtcrworthHeinemann, Boston.)
DISORDERS OP BONES, JOINTS, LIGAMENTS, AND MENINGES
2191
abnormalities of brain, spinal cord, or skeletal development, especially congenital scoliosis ot Sprengel's deformity with unilateral shoulder elevation. Patients may develop hydrocephalus, syringomyelia, or syringobulbia. However, most patients with Klippel-Feil anomaly have no neurological symptoms or signs. Atlantoaxial
FIGURE 79.3 Magnetic resonance image of a patient with basilar impression showing angulation of the brainstem. movements of the hands may occur in children with Klippel-Feil anomaly and are attributed to incomplete decussation of the pyramidal tracts. Patients with KlippelFeil anomaly can have a wide variety of associated
Dislocation
Various congenital or acquired conditions can disrupt the integrity of the atlantoaxial joint, leading to its dislocation (Table 79.1). In horizontal subluxation, CI usually moves anteriorly to C2. The movement can be assessed by measuring the separation between the dens and the anterior arch of CI on flexion radiographs; in adults, the separation should not exceed 3.5 mm. Patients with horizontal atlantoaxial joint subluxation are likely to compress their spinal cords if the diameter of the spinal canal at the level of the dens is less than 14 mm, and they are unlikely to if the diameter is more than 17 mm. The actual relationship between the cord and the subluxing bones is best imaged wiili MRI or CI myelography, which should include I iix i< >n and extension views. In some patients, particularly those with acquired inflammatory disease, such as rheumatoid arthritis (RA), inflamed adjacent soft tissue contributing to cord compression is best characterized by MRI. Patients with congenital atlantoaxial dislocation may have associated abnormalities such as Chiari I malformation or diastcmatomyelia. They can develop secondary syringomyelia. Atlantoaxial subluxation in patients with long-standing RA is a prime example of acquired Table 79.1:
FIGURE 79.4 Patient with Klippel-Feil syndrome showing short neck,
Mechanisms of atlantoaxial dislocation
[. Congenital A. Os odontoideum (failure of the odontoid to fuse with the body of the axis) 1. Isolated 2, With connective tissue dysplasias (e.g., Down syndrome, pscudoacbondroplasia, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, Morquio's disease, Klippel-Feil anomaly, Conradi's syndrome) B. Hypoplastic dens 1. With connective tissue dysplasia 2. With incomplete segmentation (e.g., occipital assimilation of atlas, basilar invagination, incomplete segmentation of C2, C3, and so forth) C. Other anomalies of C2 (e.g., bifid dens, tripartite dens with os apieale, agenesis of all or part of dens) D. Laxity of the transverse arlantal ligament (e.g., Down syndrome) II. Acquired E. Traumatic, acute or chronic un-united dens fracture F. Infectious G. Neoplastic (e.g., neurofibroma) H. Arthritic (e.g., in rheumatoid arthritis, ankylosing spondylitis, renal amyloidosis) I. Bone disease (e.g., vitamin D-resistant rickets and others associated with basilar invagination)
2192
NEUROLOGICAL DISEASES
abnormality of the atlantoaxial joint and is discussed in more detail later in this chapter. Patients with atlantoaxial subluxation may be asymptomatic, particularly if their spinal canal diameter is generous. However, they are vulnerable to spinal cord trauma during intubation or other neck motion under anesthesia, or in relation to a whiplash injury. Patients at risk of atlantoaxial dislocation, such as those with Down syndrome or chronic RA, should have lateral flexion and extension cervical spine radiography performed before general anesthesia so the anesthesiologist can plan appropriate care during intubation.
Arnold-Chiari Malformation and Syringomyelia Arnold-Cbiari Mai format ion Chiari (1891, 1896) described four types of malformations with cerebellar tonsillar displacement. Cleland (1883) had previously written about them. Arnold (1894) reported a
case of Chiari II malformation. In current usage, the terms Arnold-Cbiari and Chiari malformation are often used interchangeably for all four types. Chiari 1 malformation (Figure 79.5) is characterized by abnormal extension of the cerebellar tonsils below the foramen magnum and is sometimes accompanied by rostral displacement or extension of the medulla. Slight extension of the tonsils below the foramen is normal in childhood, and normal values decrease with increasing age (Table 79.2). Cerebellar tonsillar displacement below the foramen magnum results from downward herniation of the brain caused by mass lesions or sagging of the brain in patients with low intracranial pressure. Patients with Chiari malformations of all types often have hydrocephalus, syringomyelia, or syringobulbia. Patients may have associated bony abnormalities such as basilar impression, occipitalization of the atlas, or CI-level spina bifida. Chiari I malformations can be asymptomatic (Meadows et al. 2000). Clinical manifestations, which typically begin in young adulthood, can include headaches, visual
FIGURE 79.5 (A) Sagittal magnetic resonance imaging (MRI) scan of a patient with an Arnold-Chiari type I malformation. This midline Tl-wcighted image demonstrates low cerebellar tonsils, 8 mm below the foramen magnum. (Id VI RI ferebrospirial fluid (CSI;) flow study of the same patient demonstrates diminished flow signal at the cerebellar tonsils, indicative of CSF flow propagation abnormality. Notice the normal CSF flow signal below the tonsils and anterior to the brainstem. (C) Sagittal MRI of a patient with lowlying cerebellar tonsils at 6 mm below the foramen magnum, and (D) CSF flow study demonstrating normal flow signal ar the level of the cerebellar tonsils. This is indicative of normal propagation of CSF flow through the foramen magnum.
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2193
Tabic 79.2: Suggested upper limits of normal for position of the cerebellar tonsils below the foramen magnum Decade of life
Distance below the foramen magnum {nun)
First Second or third Fourth to eighth Ninth
6 5 4 3
Source: Data used with permission from Mikulis, D. J., Diaz, O., Egglin, T. K., et al. 1992, "Variance of the position of the cerebellar tonsils with age: Preliminary report," Radiology, vol. 183, pp, 725-728. disturbances, neurootologica! complaints, cranial nerve dysfunction, and sleep apnea (Milhorat et al. 1999). Motor, sensory, sphincter, and reflex disturbances suggestive of myelopathy can occur whether or not a syrinx is present. Despite speculation and public interest, there is no scientific confirmation of an association between Chiari I malformation and fibromyalgia or chronic fatigue syndrome (Garland and Robertson 2001). The malformation is best seen on sagittal MRI scans of the brain and cervical spine, which allows assessment of the shape of the posterior fossa, search for any accompanying syrinx, and extent, if any, of brainstem compression. Magnetic resonance cerebrospinal fluid (CSF) flow imaging of CS! pulsation at tin.' for .inu-n magnum in both systole and diastole may provide further information about the significance of tonsillar ectopia, the potential for development of syringohydromyelia, and value of decompressive surgery. Surgical treatment of Chiari I malformation is aimed at brainstem decompression; any associated syrinx will often improve after improvement in CSF flow. Chiari II malformation combines the features of Chiari I with caudal displacement of the medulla and fourth ventricle. The brainstem is elongated and distorted at the foramen magnum. Usually, patients have a lumbar myelomeningocele. In Chiari III malformation, the displaced cerebellar and brainstem tissue extends into an infra tentorial meningocneephalocele. Chiari IV malformation is characterized by cerebellar and brainstem 1npi>pl;w:i i . i ; k r ih.in dn-p aivneni and is probably a variant of the Dandy-Walker malformation. Hydromyelia,
Syringomyelia,
and Syringobulbia
Hydromyelia is an abnormal dilatation of the central spinal canal, which almost always communicates with the fourth ventricle. A syrinx is a cavity in the spinal cord (syringomyelia) or brainstem (syringobulbia) (Figures 79.6 through 79.8). The cavity may be connected with a dilatated central spinal canal or may be separate from the central canal. There are several causes of syringomyelia. Clinical Presentation. The prototypical presentation of a syrinx is the combination of lower motor neuron signs at
FIGURE 79.6
Diagrammatic representation of persistent central
i anal extending throughout the length of the spinal cord.
the level of the lesion (usually in the arms or lower cranial nerves), a dissociated suspended sensory loss (impaired pain and temperature sensation but preserved light touch, vibration, and position sense in a cape or hem i-cape distribution on the arms and upper trunk), and spinal long tract dysfunction below the level of the lesion. However, few patients show this total picture, and the clinical features vary with the size, location, and shape of the cavity and with associated neurological conditions. Fain is a prominent symptom in most patients with syringomyelia. Common complaints include neck ache, headache, back pain, radicular pain, and areas of segmental dysesthesia. Some patients have trophic changes corresponding to the segmental dysesthesia. Sytingomyelia can cause neuropathic monoarthritis (Charcot's joints), most commonly in a shoulder or elbow. Most syringes are in the cervical spinal cord. Those developing from hydromyelia of the central canal are usually associated with Chiari I or II malformations,
2194
NEUROLOGICAL DISEASES
FIGURE 79.8 Magnetic resonance image demonstrates a large syringomyelic cavity in the cervical cord. communicating hydrocephalus, or abnormalities at the craniocerebral junction. Hydromyelia and these associated syringes may be noted as asymptomatic abnormalities on MRI scans obtained to study the cranial problems. When the syrinx enlarges as an asymmetrical localized paracentral outpouching from the hydromyelia, particularly at its cranial or caudal ends or at its level of greatest axial cross section, the paracentral extensions often lead to local segmental signs such as cranial nerve dysfunction in patients with syringobulbia, as well as segmental lower motor neuron signs and dissociated sensory changes at the level of spinal involvement. Patients with eccentric cavities have some combination of long tract and segmental signs depending on the location of the cavity and of any associated cord pathology such as tumor, ischemia, or contusion. A syrinx associated with a spinal cord tumor can occur at any level of the spinal cord.
FIGURE 79.7 (A) Sagittal T2-weighted magnetic resonance imaging demonstrates intramedullary signal abnormality posterior to the T1-T3 level of rhe spinal cord. Possible causes include edema, myelomalacia, or syringohydromyelia. (B) Axial computed tomographic myelogram performed at a 3-hour delay demonstrates filling of the area of signal abnormality with myelography contrast that had been injected into the lumbar subarachnoid space. The filling of the cavity with contrast is consistent with syringohydromydia but would not be expected in cases of cord edema or myelomalacia.
Although either CT or MRI can demonstrate a syrinx, MRI is more sensitive for complete evaluation of the cord and surrounding soft tissues. CT myelography can be useful in discerning syringohydromyelia, which will commonly fill with contrast on delayed images, because of communication with the CSF through the central canal of the spinal cord (see Figure 79.7A and B}. Causes Communicating and Noncommunicating Syringes. The terms communicating and noncommunicating syringes indicate whether the syrinx is in communication with the CSF pathways. However, it is often difficult to determine this, even at autopsy, and hence these terms are mainly of use in discussions of etiology. It is better to classify syringomyelia according to its associations.
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2195
Abnormalities of the Cervicomedullary Junction The exact mechanism of production of the syrinx m patients with abnormalities of the cervicomedullary junction and posterior fossa is controversial (Oldfield 2001). The central canal of the spinal cord is normally widely open during embryonic life and becomes atretic after birth. It can be found occasionally to be patent in the adult (see Figure 79,6). It is more commonly dilatated (hydromyelia) when associated with abnormalities of the cervicomedullary junction, including Chiari anomalies types I and 11 and the Dandy-Walker malformation. Syringes often arise in association with hydromyelia and are formed as outpouchings of the dilatated central canal (see Figures 79.7 and 79.8). One hypothesis is that the posterior fossa abnormalities interfere with the passage of CSF from the fourth ventricle through the foramina of Luschka and Magendic into the subarachnoid space. The consequence is transmission of bulk flow and the various pressure waves of the CSF (arterial, venous, respiratory, and so forth) down the central canal of the spinal cord, leading to dissection of a syrinx into the substance of the spinal cord. Noncongenital abnormalities at the cervicomedullary junction that sometimes cause syringomyelia include arachnoiditis and meningiomas. Syrinx Associated with Spinal Cord Tumors Syringomyelia accompanies 2 5 - 6 0 % of intramedullary spinal tumors; conversely, 8-16% of syringes are caused by tumors (Figure 79.9). Intramedullary tumors in von Hippel-Lindau syndrome or neurofibromatosis are particularly likely to be accompanied by syringes. The syrinx extends from the tumor, more often rostrally than caudally. Syrinx Associated with Spinal Cord Trauma Syringes develop as late sequelae in perhaps 3% of cases of serious spinal cord trauma. Symptoms of usually ascending long tract or segmental spinal cord dysfunction develop months or years after the acute traumatic myelopathy has stabilized, improved, or even become asymptomatic. Pain is often a prominent symptom. Findings usually evolve gradually but occasionally worsen suddenly after events such as a cough or Valsalva maneuver. The cavity is usually eccentric, arising from an area of post-traumatic myelomalacia, then spreading rostrally or caudally.
FIGURE 79.9 Magnetic resonance image demonstrates syrinx associated wirh spinal cord tumor (hcmangioblastoma). (A) Tl-weighted image shows enlargement has a nodule on the upper cervical cord caused by a low-signal central mass suggestive of a cyst. The upper border of the cyst has a nodular component. (B) Postgadolimum image shows that the nodule intensely enhances, which is classic for hcmangioblastoma. (Courtesy Erik Ciaensler.)
Syrinx Associated with Other Focal Spinal Cord Pathologies
myelography with oil-based dyes, and spinal surgery, but many cases of focal arachnoiditis are idiopathic. Syringes can develop as a complication of various intramedullary pathologies including trauma and tumors (see previous discussion), spinal ischemic or hemorrhagic strokes, radiation necrosis, or transverse myelitis.
Any illness causing arachnoid inflammation can lead to formation of a noncommiinicating syrinx. Reported causes include meningitis, subarachnoid hemorrhage, spinal trauma, epidural infections, epidural anesthesia,
Treatment. Indications for and approaches to surgical therapy for syringes are far from standardized (Goel and Desai 2000). The cavity may be drained by simple myelotomy or by shunting to the subarachnoid, peritoneal,
2196
NITUO! OC;iCAI DISF.ASES
or pleural cavity. In patients with Chiari I malformations, the syrinx may improve after decompression of the malformation with suboccipital craniectomy, tipper cervical laminectomy, and dural grafting. When the syrinx extends from an intramedullary tumor, resection of the tumor often leads to regression of the syrinx, so no specific surgical drainage of the cavity is needed. When the syrinx extends from an area of localized arachnoiditis, some surgeons report satisfactory results after resection of the arachnoiditis without shunting or entering the cavity.
Spina
Bifida
Occulta
Spinal bifida occulta is usually asymptomatic. It is most common at posterior elements of L5-S1 and is usually noted as an incidental finding on spinal plain radiography (Figure 79.10). Cutaneous abnormalities may be associated (Table 79.4). Orthopedic foot deformities, urinary or rectal sphincter dysfunction, or focal neurological abnormalities can indicate that the spina bifida occulta is associated with compression or malformation of neural tissues or with spinal cord tethering.
Achondroplasia Achondroplasia, the most common cause of abnormally sin in stature, is ,m autosomal dominant disorder of endochondral bone formation caused by a specific mutation of a fibroblast growth factor receptor gene. The mutant genotype has complete penetrance, and approximately three fourths of cases occur because of spontaneous mutation. The diagnosis can be confirmed by pathognomonic radiographic changes or by DNA testing. Neurological complications of achondroplasia are common (Table 79.3). Young achondroplasia children should be observed for complications such as hydrocephalus, compression at the foramen magnum, thoracolumbar kyphosis, and sleep apnea. Neurological complications of spinal stenosis tend to occur later in life.
Spinal Dysraphism Spinal dysraphism is congenital failure of the neural tube to close during fetal development (Botto et al. 1999). In spina bifida occulta the vertebral elements fail to fuse, but the thecal and neural elements remain within the spinal canal. In spina bifida cystica {also called spina bifida aperta), the meninges protrude out of the spinal canal through the bony defect; neural elements may be contained within the protruding sac. Tabic 79,3:
Neurological complications of achondroplasia
Macrocrania, with or without hydrocephalus Foramen magnum abnormalities with cervicomedullary compression Respiratory disturbances, including sleep apnea and sudden infant death syndrome Syringomyelia, diastematomyelia Spinal stenosis with spinal cord or nerve root compression Infantile hypotonia Cortical atrophy Atlantoaxial subluxation Psychomotor delay (most have normal intelligence) Source; Adapted with permission from Ruiz-Garcia, M., TovarBaudin, A„ Del Castillo-Ruiz, V., et al. 1997, "F.arly detection of neurologic:)! manifestations in achondroplasia," Child Nerve Syst, vol. 13, p. 208.
FIGURE 79.10 occulta.
Lumbar spine radiograph shows spina bifida
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2197
table "9.4: l)urs.il midlife skir findings associated with spina bifida occulta W m n K l l k . ' l l I'JllU.ll I'dlii
Dermal sinus or dimple Hairy tuft Hemangioma Lipoma Nevus Pilonidal sinus kiuiiMi/iu.m lail Spinal aplasia cutis
Myelomeningocele Myelomeningocele and meningocele (spina bifida cystica) are congenital defects of spinal closure that when present are often visible on examination of the back of the newborn (Figures 79.12 and 79.13). When the skin and vertebral canal are unclosed, a sac of meninges is directly visible. The defect is most common in the lumbar region. If it contains nerve roots or spinal cord, it is a myelomeningocele; if neural elements are absent from the sac, it is a meningocele. It is often accompanied by hydrocephalus and may be accompanied by cerebellar tonsillar herniation (Chiari II malformation), syringomyelia, or cerebral malformations such as poly microgyria. Initial surgical treatment in utero or in the neonatal period can provide cosmetic repair and decrease the risk of infection; hydrocephalus can be shunted. Any existing myelopathic or radiculopathic neurological deficit is likely to persist after surgery. The infants are at risk for later development of tethered cord syndrome (sec Tethered Cord Syndromes, later in this chapter) or of spinal dermoid or epidermoid inclusion cysts. Myelomeningocele is the most common major birth defect. An impottant cause is maternal folate deficiency, and most cases would be prevented if women with childbearing potential routinely took 0.4 tng of folic acid daily. Other risk factors include family history of neural closure defects, and maternal treatment with antiepilcptic drugs such as valproic acid. Pregnant women can be screened for serum cr-fetoprotein levels, which are elevated when the fetus has neural closure defects. The defects also can iv delected by fetal ultrasound. Tethered
Cord Syndromes
Congenital abnormalities of the spinal cord or cauda equina can prevent normal cephaiad movement of the conus mcdullaris during early life (McLone and La Marca 1997) (Table 79.5). A child or even an adult with these abnormalities can develop progressive neurological dysfunction due to traction on the cord or nerve roots. The most common neurological finding is unilateral lower motor neuron dysfunction in one leg, but patients can also have sensory, upper motor neuron, or sphincter
FIGURE 79.11 Sagittal T]-weighted magnetic resonance image demonstrates several findings. The conus medullaris is low lying; there are lipomas of the filum terminale (bright signals within the central canal); and there is spina bifida with protruding lipomyelomeningocele through the defect (arrowheads).
dysfunction. Children also may present with orthopedic foot deformities or scoliosis. Diastematomyelia (Figure 79,14) is a congenital malformation of the spinal cord characterized by sagittal division of a portion of the cord into two hemicords. In most instances, the division is located in the lower thoracic or lumbar regions. Diastematomyelia is often accompanied by skin abnormalities, such as a tuft of hair at the level of the lesion. If each hemicord is enclosed in its own arachnoid sheath, the sheaths are usually separated by a bony, cartilaginous, or fibrous spur and by dura in the cleft between the two portions of the cord. The spinal cord is usually tethered by the spur, leading to progressive neurological dysfunction as the spinal cord attempts to move upwards upon the spur during growth. The diagnosis can often be suspected on plain radiography, which shows widening of the interpeduncular distance and a posterior bony bridge at the level of the lesion. MRI scans or CT myelography can confirm the diagnosis (see Figure 79.14), Surgical therapy consists of attempts to free all structures tethering the cotd by removing the spurs and dura in the cleft and cutting the filum terminale if abnormal.
2198
NEUROLOGICAL DISEASES
FIGURE 79.12 ningocele.
Diagrammatical representation of myelomeFIGURE 79.13
Clinical Correlations. A single patient often has more than one of the conditions discussed {Figure 79.15). Thus a patient with one of the Chiari hindbrain malformations also may have some combination of bony abnormalities of the foramen magnum or cervical spine, syringomyelia, and meningomyelocele. The clinical manifestations of craniocervical deformities are protean depending on which neural structures and associated anomalies are involved. When a patient has these problems, diagnosis and treatment starts by analyzing each component. MRI and CT scans have greatly eased the analytical ptocess. Many patients arc asymptomatic or first present with neurological complaints in adult life. Patients may have short necks or abnormal neck posture or movement, particularly if there is an element of skeletal deformity (e.g., Klippel-Fcil anomaly and occipitalization of the atlas). Findings attributable to the brainstem or cerebellum may occur with Chiari malformations, compression of the brainstem (e.g., basilar impression or vertical displacement of the dens), or syringobulbia. Uncommonly, atlantoaxial disease or basilar invagination can cause compromise of vertebrobasilar circulation, causing posterior circulation strokes or transient ischemic
Diagrammatical representation of meningocele.
attacks. Specific findings suggestive of disease at the foramen magnum include downbeat nystagmus or the combination of long tract signs with lowet motor neuron dysfunction in the lower cervical spinal cord; the lower Table 79.5:
Causes of tethered spinal cord
Primary causes Dermal sinus tract Dias tenia romyclia Dural hands Intraspinal lipoma or tumor Meningocele, myelomeningocele, anterior sacral meningocele Neuroenteric cyst Sacral agnesis Tight filum terminale Secondary causes Arachnoiditis Dermoid Re-tethered spinal cord Suture granuloma 1 r:iiiin I
Source; Adapted with permission from McLonc, D. G. He La Marca, F. 1997, "The tethered spinal cord: Diagnosis, significance, and management," Sem'm Pediatr Neurol, vol. 4, pp. 192-208.
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2199
FIGURE 79.14 Magnetic resonance image of a patient with diastematomyelia. (A) Sagittal Tl-weighted image shows severe scoliosis and division of the spinal cord into right [arrow) and left (curved arrow) hemicords. (B) Axial Tl-weighted image confirms the presence of two hemicords. (C) Axial gradient-echo image demonstrates two separate subarachnoid spaces divided by a central fibrous spur (arrow). (Courtesy Erik Gaensler.)
motor neuron dysfunction has been attributed to impaired spinal venous drainage at the foramen magnum. Spinal cord syndromes can be caused by syringomyelia or by extramedullar}' cord compression (e.g., by the dens with atlantoaxial dislocation or by spinal stenosis in Klippel-Eeil anomaly). Additional neurological dysfunction can occur when the anomalies form part of more widespread developmental failure (e.g., lumbar effects of myelomeningocele in Chiari II malformation or accompanying cerebral malformations in Klippel-Feil anomaly).
SPINAL DEFORMITIES AND METABOLIC BONE DISEASE Osteoporosis Osteoporotic vertebral compression fractutes occur most commonly in the thoracic and thoracolumbar spine (Figure 79.16). Most occur in postmenopausal women. By age 75 years, nearly one fourth of women have vertebral compression fractures; although these may lead to kyphosis and loss of body height, most are painless. In younget men and
2200
NEUROLOGICAL DISEASES FIGURE 79.15 Venn diagrams show the overlap of various craniospinal abnormalities from patients seen at a center specializing in syringomyelia. (A) Findings in 346 patients with syringomyelia and 304 patients with Chian malformations (hindbrain hernia). (B) Findings in patients with dysraphism syndromes compared with patients with syringomyelia or Chiari malformations. (C) Findings in KlippelFeil anomaly or basilar impression compared with patients with syringomyelia {ovals) or Chiari malformations {round rectangle). (Reprinted with permission from Williams, B. 199], "Pathogenesis of syringomyelia," in Syringomyelia; Current Concepts in Diagnosis and Treatment, ed U. Batzdorf, Willi a ins & Wilkins, Baltimore.)
DISORDERS OF BONES, JOINTS, LIGAMENTS, AND MENINGES
2201
FIGURE 79.16 Spinal magnetic resonance image of patient with vertebral compression fracture secondary to osteoporosis. T1-weighted images of the lumbar spine show 70-80% loss of height of the midportion of the II vertebral body with relative preservation of the height of the posterior portion of the vertebral body. The bright appearance of the vertebra indicates preservation of the fat within the marrow compartment, which would be dark if replaced by tumor. t .on: ley I r.k ( ..ICII-.IIT. •
women, acute post-traumatic compression fractures arc more likely to be painful. The pain usually is centered at the level of the compression and is accompanied by loss of spinal range of motion. Pain increases with activity, decreases with bed rest, and resolves slowly, sometimes incompletely. Percutaneous vertebroplasty with polyiru-t/iyliiiciii.kTyl.iir
c.i:i
decrease
the
duration
"I
pain
(Mathis et al. 2001). Transient radiculopathic pain or spinal cord compression are uncommon complications of this procedure. Compression fractures not due to metastases infrequently lead to spinal cord or nerve root compression, so if a compression fracture is accompanied by a focal neurological compression syndrome, the possibility of a metastatic vertebral lesion should be considered. MRI features that favor a malignant cause of the compression fracture include decreased Tl-weighted and increased T2-weighted signal in the vertebral body, pedicle involvement, and associated epidural or paravertebral mass (Do 2000}.
short stature, blue sclera, bearing loss, scoliosis, and skeletal abnormalities. Potential neurological complications of osteogenesis imperfecta include communicating hydrocephalus, basilar invagination, macrocephaly, skull fractures, and seizure disorder. The basilar invagination can lead to brainstem compression (Hayes et al. 1999). Spinal cord compression, syringomyelia, Chiari I malformation, Dandy-Walker cysts, leptomeningeal cysts, microcephalus, or central nervous system tumors are rarer associations.
Osteomalacia and Rickets Osteomalacia and rickets are conditions of deficient bone mineralization. Usually long bones arc more involved than the spine. Spinal pain, kyphosis, and compression fractures can occur in osteomalacia, bui compression ot -.pina. cord or nerve roots is rare. Basilar impression can occur in patients with osteomalacia. The neuromuscular complications of osteomalacia are discussed in Chapter H5.
Osteogenesis Imperfecta Osteopetrosis The various types of osteogenesis imperfecta are inherited connective tissue disorders manifested by brittle osteopenic bones and recurrent fractures. Four types are known, with variations in severity and in associated findings such as
Osteopetrosis is a rare disease characterized by increased bone density caused by impaired bone resorption (Figure 79.17). It may be inherited as an autosomal dominant or
2202
NEUROLOGICAL DISEASES
FIGURE 79.17 Radiograph of patient with osteopetrosis. The skull is extremely dense. The radiograph is slightly overexposed; note the darkness of the central areas {arrow). The bone of the petrous apex {curvedarrow) is particularly dense. (Courtesy Erik Gaensler.)
recessive disorder. Osteopetrosis of the skull can cause cranial neuropathies, basilar impression, hydrocephalus, or syringomyelia. Osteopetrosis of the spine can contribute to spinal canal stenosis with secondary compressive myelopathy.
Pager's Disease Paget's disease is a focal metabolic bone disease of excessive osteoclastic bony destruction coupled with reactive osteoblastic activity (Poncelet 1999) (Figure 79.18). The incidence increases with age and varies among ethnic groups, with a high incidence (nearly 5%) in elderly whites of Northern European descent. Men are slightly more commonly affected. The current leading pathogenic hypothesis is that a chronic viral infection of osteoclasts causes the illness and genetic factors affect susceptibility. The condition is usually asymptomatic and discovered only because of laboratory or radiographic abnormalities. However, it may cause symptoms by bone or joint distortion, fractures, compression of neurological tissue by calcification, hemorrhage, or focal ischemia caused by a vascular steal by the metabolically hyperactive bony tissue. It may also cause hypercalcemia, especially if the patient becomes bed bound. Uncommonly, neoplasms, especially osteogenic sarcoma, can develop in pagetic bone.
FIGURE 79.18 Radiograph of patient with Paget's disease of the skull. Note the thickening of the calvaria {white arrows) and the bony sclerosis with a cotton-wool appearance {curved arrows). The patient has basilar invagination; note the high position of the dens with respect to the clivus. (Courtesy Erik Gaensler.)
Osteoblastic activity can lead to thickening of cortical bone and then to a general increase in bone density, often with distortion of normal organization. Osteolytic and nsicnNastic findings arc often present together, Although most patients with Paget's disease have elevation of serum bone alkaline phosphatase and of markers of bone resorption, focal skeletal disease with neurological complications may occur in patients without laboratory abnormalities. Alkaline phosphatase levels, when elevated, are helpful not only in making the diagnosis but also in following response to treatment. Cranial
Neurological
Complications
Paget's disease of the skull can lead to head enlargement, Patients often complain of headache. The most common focal neurological manifestation is hearing loss. Paget's disease of the cribriform plate can disrupt olfaction. Other cranial mononeuropathies, including optic neuropathy, trigeminal neuralgia, and hemifacial spasm, can occur. Distortion of the posterior fossa or basilar invagination can lead to brainstem or cerebellar compression, hydrocephalus, or syringomyelia. Patients with Paget's disease of the skull occasionally develop seizures. The pagetic skull is m o r e • Li 11 IL- : ,i 1>I L t;> b k n L i u ; l i o i n :i 1:01 I: • i m i , ; , w h i c h can
lead to epidural hematoma.
Diagnosis
Spinal
Pager's disease usually can be diagnosed by characteristic findings on radiography. Osteolytic activity can cause well-demarcated round patches of low bone density.
Symptomatic Paget's disease of the spine occurs most often in the lumbar region, where it can cause monoradiculopathies or a cauda equina syndrome. The disease may
Neurological
Complications
DISORDERS OP BONES, JOINTS, LIGAMENTS, AND MENINGES
involve adjacent vertebra) bodies and the intervening discspace or may cause root compression by extension from a single vertebral body. The differential diagnosis in patients with Paget's disease and neurological dysfunction in a single limb includes peripheral nerve entrapment by pagetic bone. Paget's disease of the spine leading to myelopathy is more often thoracic than cervical. A variety of mechanisms arc reported, including extradural extension of pagetic bone, distortion of the spinal canal by vertebral compression fractures, spinal epidural hematoma, or sarcomatous degeneration leading to epidural tumor. In a few cases of myelopathy, imaging shows no evident cord compression, and vascular steal from the cord by hypermetabolie bone in the vertebral body is suggested. In support of this hypothesis, drug treatment of Paget's disease in these patients can lead- to improved spinal cord tunction. Treatment. The potent bisphosphonates are the drugs of first choice for treatment of Paget's disease. Other treatment options include calcitonin, plicamycin, ipriflavone, or gallium nitrate. Within 1-2 weeks of treatment, bone pain may improve, and serum alkaline phosphatase levels may decrease. Some patients experience significant neurological improvement after treatment, but improvement is often delayed 1-3 months. In cases with severe cord compression, surgical decompression is indicated, but drug treatment before surgery decreases the risk of operative bone hemorrhage. Patients with cranial neuropathy have less impressive responses to drug therapy. Patients with hydrocephalus may benefit from ventricular shunting.
Juvenile Kyphosis Juvenile kyphosis (Scheuermann's disease) manifests as thoracic or thoracolumbar 1-. •-•hnM-. m .idolcM-i-nK. Spinal pain is more likely to accompany lumbar than thoracic disease. Spinal radiography shows anterior vertebral wedging. Neurological abnormalities are uncommon, but spinal cord compression can occur from thoracic disc herniation or direct effects of severe kyphosis.
Scoliosis Scoliosis, with or without kyphosis, which develops as an idiopathic painless condition in childhood and adolescence, is usually not accompanied by neurological abnormalities. Most cases are idiopathic, but a minority have an accompanying tumor, spondylolisthesis, syrinx, or Chiari I malformation. Indications for spinal MRI include pain, progression suddenly or after spinal maturity, thoracic curvature to the right, or abnormal neurological examination (Oestreich, Young, Young Poussaint 1998). Spinal cord compression is a rare complication of idiopathic scoliosis and is particularly rare if no kyphosis is present.
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In each patient presenting with scoliosis and myelopathy, an important consideration is whether the myelopathy caused, rather than resulted from, the scoliosis. Patients with congenital scoliosis, unlike those with idiopathic scoliosis, usually have anomalous vertebrae and may have other associated developmental problems such as Klippel-Feil anomaly or diastematomyelia. Scoliosis caused by skeletal disease, such as achondroplasia, is more likely than idiopathic scoliosis to lead to spinal cord compromise. Myelopathy can result also from spinal cord distraction during treatment of scoliosis with traction or surgery. Scoliosis can be caused by various neurological diseases including cerebral palsy, spinocerebellar degenerations (e.g., Friedreich's ataxia), inherited neuropathies (e.g., CharcotMarie-Tooth disease), myelopathies (e.g., syringomyelia), paralytic poliomyelitis, spinal muscular atrophy, dysautonomia (e.g., Riley-Day syndrome), and myopathies (e.g., Duchcnne's muscular dystrophy). Scoliosis is the most common skeletal complication of neurofibromatosis type 1. Scoliosis that develops in adulthood can often be traced to an underlying cause such as trauma, osteoporotic fracture, degenerative spondylosis, or ankylosing spondylitis; it can result in local back pain, nerve root compression, or spinal canal stenosis.
Diffuse Idiopathic Skeletal Hyperostosis Diffuse idiopathic skeletal hyperostosis (DISH) (Forestier disease, ankylosing hyperostosis) is a syndrome of excessive calcification that develops with aging, more often in men than in women. The diagnosis is made by spinal radiographs that show "flowing" calcifications along the anterior and lateral portion of at least four contiguous vertebral bodies without loss of disc height and without typical radiographic findings of ankylosing spondylitis (Figure 79.19). Patients are often asymptomatic but may have spinal pain or limited spinal motion. Large anterior cervical calcifications can contribute to dysphagia, hoarseness, sleep apnea, or difficulty with intubation. A rare complication is myelopathy caused by spinal stenosis if the calcifications are present also within the spinal canal. Like patients with ankylosing spondylitis, patients with diffuse idiopathic skeletal hyperostosis can develop spinal fractures after relatively minor trauma.
Ossification of the Posterior Longitudinal Ligaments or Ligamcntum I'lavum Ossification of the posterior longitudinal ligament anterior to the spinal canal (Figure 79.20) and ossification of the ligamcntum flavum posterior to the spinal canal are uncommon syndromes of acquired calcification. The posterior longitudinal ligament extends the length of the spine, scpatating the posterior aspects of the discs and
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NEUROLOGICAL DISEASES It may be visible on lateral spinal radiography but is usually asymptomatic. It is better seen by CT scan, in which it is distinguished from osteophytes by favoring the middle of the vertebral bodies rather than concentrating at the endplates. Thickness of the calcification can range from 3-15 mm. Ossification of the posterior longitudinal ligament is most likely to be symptomatic in the cervical spine where it can contribute to cord compression if it is rhiek or it the canal is lunbr- narrowed K congenital md degenerative changes. The ligamentum flavum can contribute by hypertrophy or ossification to spinal stenosis, most often in the lower thoracic or lumbar spine, affecting the cord or cauda equina. Risk factors for development ot ossification of the ligamentum flavum include trauma, hemochromatosis, calcium pyrophosphate deposition disease, diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, or ossification of the posterior longitudinal ligament.
DEGENERATIVE DISEASE OF THE SPINE Spinal Osteoarthritis and Spondylosis Osteoarthritis of the spinal facet joints manifests radiographically as joint narrowing, sclerosis, and osteophyte formation. Spondylosis refers to degenerative disease of the intervertebral discs, visible on radiography as disc space narrowing, vertebral endplate sclerosis, and osteophyte development. Spinal osteoarthritis and spondylosis are inevitable consequences of aging that are visible on routine spinal radiography in more than 9 0 % of people by age 60 years. They are usually asymptomatic but cause compression of the spinal cord or nerve roots in a minority of people. Nonetheless, they are the most common cause of compressive myelopathy or radiculopathy, accounting for far more neurological disease than all the other conditions discussed in this chapter combined, FIGURE 79.19 Lateral thoracic spinal radiograph shows diffuse idiopathic skeletal hyperostosis. Note the flowing calcification of the anterior osteophytes with preservation of disc heights. (Reprinted with permission from Roscnbaum, R. B., Campbell, S. M., & Rosenbaum, J. T. 1996, Clinical Neurology of Rheumatic Disease, Butterworth-1 ieineinann, Boston.)
vertebral bodies from the thecal sac. The ligamentum flavum is in the dorsal portion of the spinal canal, attaching the laminae and extending to the capsules of the facet joints and the posterior aspects of the neural foramina. Either ligament can ossify in later life, apparently independently of the usual processes of spondylosis and degenerative arthritis. Ossification of the posterior longitudinal ligament occurs more commonly in Orientals than in non-Orientals.
In youth, the intervertebral discs consist of a gelatinous central nucleus pulposus and a firm collagenous annulus fibrosus. The disc herniation syndromes occur when the nucleus pulposus bursts through a tear in the annulus fibrosus. This herniation can compress the nerve roots or spinal cord, depending on the spinal level involved. Rarely, disc material breaks into the thecal sac or a fragment ruptures into an epidural vein. Disc herniation is most likely to occur in young adults. By age 40 years, most adults have some disc degeneration with dehydration and shrinkage of the nucleus pulposus, necrosis and fibrosis of the annulus fibrosus, and sclerosis and microfractures of the subchondral bone at the vertebral endplate. Compression of neurological tissue can develop from a combination of disc herniation, osteophyte formation, ligament hypertrophy, congenital stenosis of the spinal canal, low-grade synovitis, and deformity and misalignment of the spine.
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FIGURE 79.20 Computed tomographic scan of a patient with ossification of the posterior longitudinal ligament. Note the continuous bony ridge that is present at every level, nor just at the disc space. In contrast to calcified degenerative spurs, these ligamentous calcifications are not connected to the vertebral bodies. (Courtesy Erik Gaensler.)
Cervical Spondylosis
Cervical Radiculopathy Clinical
The cervical spinal column includes 37 joints that are continually in motion throughout life. Cervical osteoarthritis and spondylosis are ubiquitous with increasing age (Figure 79,21), These disorders can be attributed only rarely to specific activities or injuries. Patients with dystonia and other cervical movement disorders may be predisposed to premature cervical spinal degeneration. Because cervical osteoarthritis and spondylosis are so commonplace, it is usually difficult to ascertain their role in contributing to the pathogenesis of chronic neck pain or headache. Cervical spine surgery is rarely, if ever, indicated for treatment of headache or neck ache in the absence of cervical radiculopathy or myelopathy.
Presentation
The symptoms of cervical radiculopathy often appear suddenly. Although disc herniation or nerve root contusion can be caused by acute trauma, many cases become symptomatic without an identifiable preceding traumatic event. Disc herniation is more likely to be the cause in patients younger than 45 years; neural foraminal stenosis by degenerative changes becomes more likely with increasing age. Pain is usually in the neck with radiation to an arm; patients may also have headache. Radiculopathic arm pain may increase with coughing or with the Valsalva maneuver. Arm pain may increase with neck rotation and flexion or extension to the side of the pain (Spurliug's sign).
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NEUROLOGICAL DISEASES
FIGURE 79.22 Computed tomographic scan of the cervical spine with intrathecal contrast shows herniated cervical disc. The spinal cord {gray) and thecal sac (white) arc distorted on the left by the disc. (Reprinted with permission from Rosenbaum, R. B,, Campbell, S. M., & Rosenbaum, J. T. 1996, Clinical Neurology of Rheumatic Disease, Buttcrworth-Heinemann, Boston.)
FIGURE 79.21 Lateral radiograph of the cervical spine shows typical changes of spondylosis and osteoarthritis. (Reprinted with permission from Rosenbaum, R. B., Campbell, S. M., Sc Rosenbaum, J. T. 1996, Clinical Neurology of Rheumatic Disease, Buttcrworth-Heinemarin, Boston.)
Spondylosis, osteophytes, and disc herniations at the C4C5 level can affect the C5 root, causing pain, paresthesias, and sometimes loss of sensation over the shoulder, with weakness of the deltoid, biceps, and brachioradialis muscles. The biceps and supinator reflexes may be lost. Spread of the biceps reflex to the finger flexors, an increased triceps reflex, or an inverted biceps reflex (absent or reduced biceps reflex with reflex contraction of the finger flexors, or rarely the triceps) suggest the presence of a myelopathy at the C6 level. Spondylotic lesions at the C5-C6 level can affect the C6 cervical root and cause paresthesias in the thumb or lateral distal forearm and weakness in the brachioradialis, biceps, or triceps. The biceps and brachioradialis reflexes may be diminished or inverted. Lesions at the C6-C7 level, compressing the C7 root, cause paresthesias, usually in the index, middle, or ring fingers, and weakness in C7-inncrvated muscles, such as the triceps and pronators. The triceps tendon reflex may be diminished. The C5, C6j and C7 roots are the ones most commonly involved in cervical spondylosis, because they are at
the level of greatest mobility, where disc degeneration is greatest in the cervical spine. The relative frequency of root lesions in cervical spondylosis varies in different series. Clinically evident compression of the C8 root or of roots above CS is more rare. Cervical radiography is of little value in diagnosing or excluding cervical radiculopathy. MRI scanning of the cervical spine is usually helpful in identifying nerve root compression in patients with cervical radiculopathy. Cervical myelography followed by CT scanning is sometimes more sensitive than MRI (Figure 79.22). However, MRI may show nerve root compression, particularly in the neural foramina, which is invisible by CT. CT myelography is also better than MRI for distinguishing disc herniation from osteophytes. However, cervical MRI or CT myelography must be interpreted with caution because degenerative abnormalities are so commonly seen in the asymptomatic spine. Electromyography and nerve conduction studies can be useful in difficult diagnostic cases, both by identifying an affected motor nerve root and myotome and by helping to exclude other diagnoses, such as brachial plexopathy or peripheral neuropathy (Nardin et al. 1999). Treatment Most instances of cervical radiculopathy improve significantly over 4-8 weeks, regardless of treatment. Various treatments such as nonsteroidal anti-inflammatory drugs, use of a soft cervical collar, physical therapy, or cervical
DISORDERS OF BONES, JOINTS, LIGAMENTS, AND MENINGES
traction give similar results. Patients with a typical clinical presentation and little or no neurological deficit usually can he managed with these noninvasive approaches without radiography or electrodiagnostic studies. When patients have intractahlc weakness or pain or have not improved with nonoperative therapy, surgical nerve root decompression is usually successful; however, there is little randomized, controlled comparison of nonoperative therapy and surgery (Fouyas, Statham, and Sandercock 2002). Anterior cervical discectomy is used more widely than posterior cervical laminectomy.
Cervical Spondylotic Myelopathy Myelopathy caused by compression of the cervical spinal cord by the changes of spondylosis and osteoarthritis usually develops insidiously, but it may be precipitated by trauma or progress in stepwise fashion. Typical findings are a combination of leg spasticity, upper extremity weakness or clumsiness, and sensory changes in the arms, legs, or trunk. Either spinothalamic tract-mediated or posterior column-mediated sensory modalities may be impaired. Sphincter dysfunction, if it occurs, usually is preceded by motor or sensory findings. Neck pain is often not a prominent symptom, and neck range of motion may or may not be impaired. Some patients experience leg or trunk paresthesia induced by neck flexion (Lhermitte's sign). The anterior-posterior diameter of the cervical spinal cord is usually 10 mm or less. Patients rarely develop cervical spondylotic myelopathy if the congenital diameter of their spinal canal exceeds 16 mm. In congenitally narrow canals, disc protrusion, osteophytes, hypertrophy of the ligamentum flavum, ossification of the posterior longitudinal ligament, and vertebral body subluxations can combine to compress the spinal cord. The relation between the spinal canal and the spinal cord can be imaged by MR I or CT myelography (Figure 79.23). MR1 provides more intramedullary detail such as secondary cord edema or gliosis. CT provides better images of calcified tissues. Even with excellent cross-sectional imaging of the spinal canal, the clinical correlation between neurological deficit and cord compression is imperfect; dynamic changes in cord compression and vascular perfusion undoubtedly contribute to the pathogenesis of cervical spondylotic myelopathy. The natural history ot cervical spondylotic myelopathy is variable. Some patients may have stable neurological deficit for many years without specific therapy, whereas other patients may have gradual or stepwise deterioration. Some patients improve with treatments such as bed rest, soft collars, or immobilizing collars, but these treatments have not been assessed in controlled trials. Many patients with cervical spondylotic myelopathy are treated by surgical decompression with variable surgical results (Figure 79,24). Surgical and nonsurgical treatment results are best when
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the neurological deficit is mild and present less than 6 months and when the patient is younger than 70 years. Anterior cervical discectomies are generally performed for spondylotic lesions at a limited number of levels, whereas posterior laminectomy, sometimes with an expanding laminoplasty, is generally performed for congenital spinal canal stenosis.
Vertebral Artery Stroke Caused by Cervical Osteoarthritis Compression of a vertebral artery by an osteophyte is a rare cause of stroke in the vertebrobasilar circulation. The vertebral arteries pass through the foramina in the transverse processes from C6-C2. Osteophytes from the uncinate joints can compress the arteries. The compression may occur only with head turning. However, the turning usually leaves the contralateral vertebral artery uncompressed, so ischemic symptoms are usually limited to those patients who have both osteophyte arterial compression on one side and a contralateral hypoplastic, absent, or occluded artery,
Thoracic Spondylosis Degenerative changes are less common in the thoracic than in the lumbar or cervical spines (Vanichkachorn and Vaccaro 2000). Thoracic osteophytes are more likely to develop on the anterior or lateral aspects of the vertebral bodies and infrequently cause clinical radiculopathy. Thoracic disc herniations arc visible on MRI in manyasymptomatic individuals. Thoracic disc herniations occur most often in the lower thoracic spine. These rarely cause cord or root compression and may regress spontaneously. Thoracic myelopathy caused by disc herniation probably has an annual incidence of approximately I case per i million. Most cases occur between ages 30 and 60 years. Symptoms often develop insidiously, without identifiable preceding trauma. Back pain may or may not be present. Patients have some combination of motor and sensory findings of myelopathy; sphincter dysfunction is present in more severe cases. Thoracic MRI, CT, or myelography can confirm the diagnosis (Figure 79.25). The treatment is surgical decompression.
Lumbar Spondylosis Low Back Pain Approximately 8 0 % of people experience episodes of acute low back pain, which usually resolve within a few days. These episodes often recur, and approximately 4% of people report chronic low back pain. Pain-sensitive structures in the lumbar region include the nerve roots,
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FIGURE 79.23 Cervical spondylotic myelopathy. (A) The sagittal T2-weighted magnetic resonance imaging scan shows maximal compression of the thecal sac and spinal cord at C5-C6. (B) The axial computed tomographic scan with intrathecal contrast at this level shows a large osteophyte arising from the posterior aspect of the vertebral hody; the spinal cord at this level is compressed, and the thecal sac is so compressed that little of the white intrathecal contrast is visible. (Reprinted with permission from Rosenbaum, R. B., Campbell, S. M., & Rosenbaum, J. T. 1996, Clinical Neurology of Rheumatic Disease, Burterworth-Heinemann, Boston.) zygapophyseal joints, sacroiliac joints, intervertebral ligaments, muscles, fascia, annulus fibrosis and circumferential portions of the discs, and vertebral periosteum. Controlled local anesthetic injection studies suggest that in some patients, the cause of low back pain can be localized to specific zygapophyseal joints or sacroiliac joints. In other patients, injection of contrast media into lumbar discs reproduces pain, suggesting that the lumbar disc is the source of pain in these patients. However, this localization cannot be achieved reliably by history or physical examination, and with current therapeutic techniques, invasive testing for localization is not valuable in planning therapy. Furthermore, localization of the source of pain is unsuccessful in many patients. Thus in clinical practice, "nonspecific lm\ h,;c \ pain" i- .1 i< minimi ly made diagnosis.
narrowing) appear gradually with increasing age and are rarely absent by age 60 years (Figure 79.26). The presence or absence of these findings does not correlate with symptoms and demonstrating them is of no diagnostic or therapeutic value. Therefore radiography of the lumbar spine is indicated only when alternative diagnoses such as compression fractures, neoplasia, or infections are being seriously considered. The Agency for Health Care Policy and Research has recommended that spinal radiography be reserved for patients with "red flags" for trauma, tumor, or infection (Table 79.6). Kven limiting radiography to patients meeting these guidelines results in many needless radiographs. For example, hack pain in a patient older than 50 years need not be an indication for imaging studies, unless other findings suggest a condition more serious than nonspecific low back pain.
The findings of osteoarthritis and lumbar spondylosis on radiography (osteophytes, endplate sclerosis, disc space
Lumbar disc disease has multifactorial etiologies, including body habitus, type and amount of physical activity,
DISORDERS OF BONES, JOINTS, LIGAMENTS, AND MENINGES
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FIGURE 79.24 Results of treatment of cervical spondylotic myelopathy. (Reprinted with permission from Rosenbaum, R. B., Campbell, S. M., £c Rosenbaum, J. T. 1996, Clinical NeurolV>gy of Rheumatic Disease, B u tter wort h -H c ine ma nn, Boston.)
acute injury, and genetic predisposition. The genetic factor is illustrated by the tendency for lumbar disc herniations to occur in families (Marini 2001). Allelic differences in collagen IX, a component of the annulus fibrosus, nucleus pulposus, and endplates, appear to affect the risk of developing symptomatic disc herniations (Paassilta et al. 2001).
Spondylolysis and Spondylolisthesis. Spondylolisthesis is displacement of one lumbar vertebral body relative to an adjacent vertebral body. Some cases are caused by spondylolysis, a discontinuity in the vertebral pars interarticularis, which disrupts the normal stabilizing effect of the facet joints. Other causes of spondylolisthesis include congenital vertebral anomalies, degenerative spondylosis, FIGURE 79.25 Thoracic magnetic resonance image of a patient with thoracic disc herniation. This large acute disc herniation at T10-T11 consists of extrusion of most of the nucleus pulposus into the spinal canal. There is secondary narrowing of the disc space. There is spinal cord edema (arrows) above and below the level of spinal cord compression. (Courtesy Erik Gaensler.)
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B
FIGURE 79.26 (A) Anteroposterior and (B) lateral radiographs of the lumbar spine showing osteophytes, disc space narrowing, and sclerosis of the vertebral body articular plates, (Reprinted with permission from Rosenbaum, R. B., Campbell, S. M., &c Rosenbaum, J. T. 1996, Clinical Neurology of Rheumatic Disease, ftuttcrworth-Heinemann, Boston.) and vertebral trauma. Spondylolysis occurs in 5 - 7 % of the population and is usually asymptomatic. Spondylolisthesis is often painless or may cause low back pain that sometimes radiates to the buttocks. Spondylolytic spondylolisthesis is a common cause of back pain in adolescents. Occasionally, spondylolisthesis can advance to the point of compressing Table 79.6: Indications for lumbar spine radiography in patients with acute low hack pain Red flags for trauma Major trauma (e.g., motor vehicle accident, fall from height) Minor trauma or even strenuous lifting in older or potentially osteoporotic patient Prolonged corticosteroid use Osteoporosis Age older than 70 years Red flags for tumor or infection Age older than 50 years or younger than 20 years History of cancer Constitiition.il symptoms (e.g., fever, chills, weight loss) Risk factors for spinal infection (e.g., recent bacterial infection, intravenous drug use, immunosuppression! Pain that is worse when supine or is severe at night Source: Adapted with permission from Agency for Health Care Policy and Research. 1994, Acute Low Back Problems in Adults. Assessrne?it and Treatment: Quick Reference Guide for Clinicians, U.S. Department of I lealth and Human Services, Roekville, Md.
nerve roots in the neural foramina or causing lumbar canal stenosis. Lumbar Radiculopathies. The back and leg neurological examination is key to decision making in patients with low back pain. Perhaps 1-2% of patients with acute low back pain have significant lumbar nerve root compression. Three syndromes merit specific diagnostic consideration. Monoradiculopathy Clinical Fresentatio?!. Patients with an acute lower lumbar or lumbosacral monoradiculopathy caused by nerve root compression present with unilateral leg pain (sciatica) radiating into the buttock, lateropostetior thigh, and distally, sometimes with paresthesia. Patients usually also have low back pain. Pain may increase with movement, coughing, sneezing, or Valsalva maneuver and decrease with rest. Pain often increases when the straightened ipsilateral leg is raised while the patient is supine (straight-leg-raising test, Laseguc's sign) or when the leg is straightened at the knee while the patient is seated. The most commonly compressed nerve roots are 1.5, usually by L4-L5 disc herniation, or SI, usually by L5-S1 disc herniation. For L5 radiculopathy, the findings are typically medial foot and hallux pain; paresthesia, especially on the medial dorsal foot; and weakness in the extensor hallucis
DISORDERS OF BONES, JOINTS, LIGAMENTS, AND MENINGES Iongus muscle, ankle dorsiflexors, and peroneal muscles. SI nerve root compression can lead to Literal foot pain and paresthesia, depressed ankle jerk, and weakness of peroneal muscles and less frequently of ankle plantar flexors. When the radiculopathy is mild, the patient may have no objective neurological deficit. Diagnostic Studies. Disc herniations, osteophytes, spondylolysis and spondylolisthesis, facet joint hypertrophy, and hypertrophy or calcification of intraspinal ligaments can compress nerve roots of the cauda equina within the spinal canal ot in the lateral recesses and neural
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foramina through which the roots exit the spinal canal. The anatomical relations between the nerve roots and the surrounding tissues are well visualized by lumbar MRI or CT myelography figure 79.27). Each technique has high sensitivity for demonstrating causes of nerve root compression. On occasion when a patient has strong clinical evidence of lumbar radiculopathy but initial imaging studies do not show the cause of the compression, a second complementary imaging study is indicated. For example, imaging with a lumbar MRI usually is sufficient for most clinical purposes, but occasionally a patient
FIGURE 79.27 (A) Lumbar magnetic resonance image (MRI) of a patient with lumbar disc herniation at L4-L5. The ventral dura is displaced {straight arrows) posteriorly. The roots of the cauda equina are compressed (curved arrows). (B) Axial Tl-weighted MRI demonstrates an intraforaminal focal disc protrusion (herniation) within the right neural foramen (arrowheads). This is well delineated because of the thin images angled to the disc space and the contrast of bright fat within the neural foramen. Notice the nerve roots as the oval structures exiting each neural foramen. (A, Courtesy Fj-ik Gacnslcr.)
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NEUROLOGICAL DISEASES
also needs CT myelography to clarify the anatomy. I nli i!iui:.;klv a I spinal imaging modalities frequently show anatomical abnormalities that are not the cause of symptomatic nerve root dysfunction; all imaging results must be interpreted carefully in clinical context. Electromyography can aid in neurological localization by demonstrating neuropathic abnormalities in specific myotomes, It is relatively insensitive because it detects only compression affecting motor roots severely enough to cause axonal interruption. However, in complex cases, it is particularly helpful in separating monoradiculopathy from other conditions such as dvsfunction ot multiple roots, plexopathies, or peripheral neuropathy. Treatment. Most sufferers of low back pain and sciatica recover within 6 weeks using simple, nonoperative therapies such as brief periods of bed rest, activity limitations as required by pain, simple analgesics, and physical or manipulative therapies. Evidence indicates that prolonged immobilization is detrimental and that early mobilization results in more rapid recovery. Many patients with acute low back pain and sciatica can be managed at this stage based on clinical examination without spinal imaging studies. Patients who have progressive weakness or sensory loss or who have severe pain that fails to improve after 6 weeks of nonoperative therapy can be considered tor surgical nerve root decompression. The patients least likely to benefit from lumbar nerve root surgery are those who lack objective neurological signs of nerve root dysfunction or who lack corresponding imaging evidence of nerve root compression. A few patients develop a chronic low back pain syndrome or have repeated exacerbations of acute low back pain. Back-strengthening exercises and the avoidance of maneuvers that put strain on the lower back, together with the judicious use of nonsteroidal anti-inflammatory drugs, generally improve such patients' pain. Workers who are off work with low back pain for longer than 6 months have a guarded prognosis for return to work. Physicians caring for patients with low back pain lasting longer than 4 weeks need, whenever possible, to emphasize exercise to avoid deconditioning and early return to graded work. When surgery is performed for lumbar nerve root compression, the surgical technique depends on the clinical details such as the cause of compression and the number of nerve roots compressed. In patients with sciatica caused by disc herniation, the most common surgical approach is microsurgical discectomy with minimal removal of the lamina. Perhaps 90% of patients reporr excellent relief of neuropathic pain after surgery. Many are able to return to physically strenuous work. However, a small proportion of patients postoperatively develop more severe chronic pain problems (failed back syndrome), which particularly occurs when patients selected for surgery have neither clinical evidence of radiculopathy nor corresponding neuroimaging evidence of nerve root compression. Patients with chronic pnMopiTa'.ive p./ I iiv.ii'v careful neurological evaluation
to consider such problems as surgery done at the wrong level, incomplete removal of extruded disc fragment or other matter compressing the nerve root, progression of spinal degeneration, postoperative arachnoiditis, and psychosocial issues interfering with recovery. Acute
Cauda Equina Syndrome
Acute cauda equina syndrome presents as low back and leg pain caused by compression of multiple lumbosacral nerve roots. Patients may have bilateral leg pain and neurological deficits in the distribution of multiple nerve roots. Particularly worrisome findings are sacral sensory loss or impaired function of the rectal and urinary sphincters. Acute Cauda equina compression occurs in fewer than 1% of all patients who have lumbar or lumbosacral disc prolapses. The cause is usually a large midline disc herniation, most often at L4-L.5 or I.5-S1. When an acute cauda equina compression occurs, the patient needs urgent spinal imaging and decompressive surgery, because the window of opportunity for restoration of neurological function is limited to perhaps 48 hours.
Lumbar Canal Stenosis Lumbar canal stenosis results from various anatomical changes that decrease the normal cross-sectional area of the spinal canal including congenitally small canal size, degenerative osteophytes, spondylolisthesis, facet joint hypertrophy, thickening of the ligamentum flavum, and disc herniation. It usually develops insidiously with aging and rarely becomes symptomatic before age 40 years. Men are more often affected than women. Stenosis is often asymptomatic. Patients often have some low back pain. The classic symptom of lumbar canal stenosis is neurogenic intermittent claudication: leg discomfort elicited by walking or by certain postures such as standing straight, which is relieved within minutes by stopping walking or changing posture. This is to be contrasted with the relief within seconds of stopping walking m vascular claudication. The pain may be anywhere in the legs or buttocks and may include numbness or paresthesia. Patients sometimes can decrease their discomfort by bending forward while they walk and may be able to bicycle without difficulty. They may develop leg symptoms with sustained erect posture or after lying with their back straight. In contrast, vasogenic intermittent claudication may be elicited by almost any leg exercise and is not elicited or relieved by any specific postures. Most patients with neurogenic intermittent claudication do not have objective signs of nerve root dysfunction. However, occasionally a patient manifests progressive neurological deficits from chronic cauda equina compression. Some patients develop leg weakness or other abnormal neurological signs following exercise, and neurological
DISORDERS OF BONES, JOINTS, LIGAMENTS, AND MENINGES
examination before and after precipitation of the pain is a helpful part of the evaluation of neurogenic claudication. Patients with congenital lumbar canal stenosis are more likely to have congenital stenosis of the cervical canal and may have signs of a cervical myeloradiculopathy. Diagnostic
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be treated with wide laminectomy of the stenosed spinal canal, which usually improves claudication. Back pain is much less likely TO improve after surgery. Those with severe or multilevel stenosis ate least likely to benefit from surgery.
Studies
Spinal canal stenosis can be studied by MRI, CT, and myelography (Figure 79.28). MRI is best at demonstrating sagittal relationships, such as the role of spondylolisthesis in narrowing the canal. CT is best at studying calcified tissues and distinguishing disc from osteophyte, especially within the neural foramina. No imaging modality quantifies the extent of nerve root comptession, and clinical correlations between symptoms and apparent reduction in size of the spinal canal are imperfect. In choosing which patients would benefit from decompressive surgery, one should rely more heavily on clinical findings than on the appearance of the canal in imaging studies. Treatment Patients who have neurogenic intermittent claudication may have stable symptoms for many years without developing progressive neurological deficit. Some even note regression of symptoms aftct months of recurrent claudication. These patients may be managed with mild analgesics. Some describe decreased discomfort if they walk with a slight stoop or using a cane. Those patients with intractable leg pain or progressive neurological deficit can
INFECTIOUS DISEASES OF THE SPINE Pyogenic Vertebral Osteomyelitis and Epidural Abscess Vertebral osteomyelitis and spinal epidural abscess (see Chapter 59) are uncommon conditions that present with focal spinal pain and tenderness. Epidural abscesses in the anterior spinal canal are more likely than those in the posterior canal to be associated with osteomyelitis; in cither location, they can cause radiculopathic pain, compromise of nerve root function, or spinal cord compression. Some patients with spinal epidural abscess or with vertebral osteomyelitis are afebrile at presentation, but nearly all have an elevated sedimentation rate. Early in the infection, routine spinal radiography may be norma). If the diagnosis is being considered, an MRI scan (Figure 79.29) of the involved area is sensitive for detecting vertebral body abnormalities and is particularly helpful to assess for epidural or paravertebral infection. Spinal CT is useful if MRI is unavailable or contraindicated. Osteomyelitis may involve any vertebral body but is least common in the cervical vertebrae. Often in pyogenic, but infrequently in granulomatous, osteomyelitis, the MRI shows involvement of the adjacent disc space. The most common causative
FIGURE 79.28 Magnetic resonance image of patient with lumbar spinal stenosis. (A) Midline and (B) parasagittal images of the lumbar spine show narrow anteroposterior dimensions of the spinal canal consistent with spinal canal stenosis (see normal dimensions in Figure 79.27). The 1.4-1,5 disc herniation (arrows) that fills the entire spinal canal is actually much smaller than the herniation shown in Figure 79.27. (Courtesy Erik Gaensler.) •
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FIGURE 79.29 Magnetic resonance image of a patient with pyogenic vertebral osteomyelitis. (A) Tl-weighted sagittal image shows replacement of the normal marrow fat of the C4 and C5 vertebrae with low-signal intensity edema, with narrowing of the disc space {arrow) and thickening of the epidural soft tissue (small arrows). (B) T2-weighted image shows mild spinal cord compression [arrow] and hype nn ten sin- of the anterior longitudinal ligament, consistent with superior extension of the infectious process (small arrows). (Courtesy Erik Gaensler.) organism is Staphylococcus aureus, but a wide variety of other bacteria can be responsible. Polymicrobial infection is uncommon after hematogenous infection but can occur when the source is open trauma or contiguous spread from other tissues. Osteomyelitis and spinal epidural abscess usually occur by hematogenous spread and arc more likely following septicemia. Diabetes, alcoholism, acquired immunodeficiency syndrome (AIDS), and other forms of immunosuppression increase the risk of its development. Other risk factors are intravenous drug use or spinal trauma. Cases may be iatrogenic following spinal surgery. When cases are diagnosed before development of spinal instability or compression of the spinal cord or nerve roots, long-term antibiotic therapy can be curative. Spinal instability may require surgical stabilization. Neurological compression is an indication for emergent surgical decompression.
Granulomatous Vertebral Osteomyelitis Tuberculosis (TB) of the spine (Pott's disease) is one of the more common forms of nonpulmonary TB and by far the
most common gtanulomatous spinal infection. The risk is highest in regions or populations where TB is endemic. In the United States high-risk factors are immigration from an endemic area, AIDS, homelessness, and drug or alcohol abuse. Other organisms capable of causing granulomatous osteomyelitis include brucellosis, a variety of fungi, Nocardia, and Actinomyces. Granulomatous spinal infection typically presents with insidious progression of back pain. The patient often has symptoms of systemic infection such as weight loss, fever, night sweats, or malaise. Pott's disease classically presents with destruction of vertebral bodies. Routine spine radiography results are usually abnormal by the time the diagnosis is made, and spinal deformity is a common complication. MRI or CT is needed to assess for contiguous abscess in the epidural or paraspinal spaces and to evaluate possible nerve root or spinal cord compression when the spine is deformed (higure 79.30). Compression of spinal cord or nerve roots can occur in vertebral TB by vertebral deformity or collapse, epidural abscess, granulation tissue, or bony sequestrum. Patients may develop delayed neurological complications after apparently successful treatment of the infection.
DISORDERS OF BONES, JOINTS, LIGAMENTS, AND MENTNCES
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FIGURE 79.30 Magnetic resonance image of a patient with tuberculous vertebral osteomyelitis. T2-weighted images show destruction of rhe posterior inferior portion of the TI2 vertebra, with a soft tissue mass projecting posteriorly into the spinal canal, compressing the conus medullars {arrows). Note that the T12 and LI discs (curved arrows) are relatively well preserved, which is a distinguishing feature of spinal tuberculosis. (Courtesy Erik Gaensler.)
This may be caused by infarction from endarteritis obliterans, delayed degenerative bony changes, or reactivation of infection. Neurological compression is most common with thoracic vertebral disease, hence the eponym Pott's paraplegia- cauda equina compression is uncommon in TB. Treatment of vertebral TE requires long-term multiple-drug antituberculous therapy. Spinal surgery may be needed depending on the degree of spinal destruction or deformity and is often required in cases of neurological compression.
Inflammatory Joint Disease Rheumatoid
Arthritis
Systemic Presentation. RA is a chtonic, inflammatory, symmetrical destructive immune-mediated polyarthritis. In population studies, 0.2-2.0% of the population is affected, women twice as often as men. The cause of RA is unknown, but genetic factors are evident in familial cases and susceptibility is linked to some human leukocyte antigen-DR (HLA-DR) types. The most commonly affected joints are the small joints of the hands and feet. The diagnosis is based primarily on characteristic clinical findings. Serological testing for rheumatoid factor can support the diagnosis. However, many patients have seronegative RA, and, conversely, there are numerous other causes for elevation of rheumatoid factor. Radiography shows juxta-articular demitieralization or characteristic joint erosions in advanced cases. Pathogenesis. The immimopathogenesis of RA includes T- and B-cell activation, angiogencsis and cellular proliferation in the synovium, inflammation in soft tissue, and eventual destruction of cartilage and bone. Cytokine release, immune complex deposition, and vasculitis can all contribute to the inflammatory process. The inflamed
proliferative rheumatoid synovium is called pannus. In the spine, pannus can disrupt stabilizing ligaments, particularly of the atlantoaxial joint, and thick pannus can add to compression of nervous tissue. Rheumatoid inflammatory tissue can form nodules in soft tissue; on the rare occasions that these nodules form in the dura, they can conttibutc to rheumatoid pachymeningitis. Neurological Manifestations. Common neurological complications of RA are carpal tunnel syndrome and other nerve en trap men ts, peripheral neuropathy, and myopathy; these are discussed in Chapters 55, 82, 84, and 85. RA can evolve to a rheumatoid vasculitis that like other mediumsized vessel vasculitides has the potential to cause ischemic mononeuritis, mononeuritis multiplex, or, rarely, stroke. Headache and neck ache are common in patients with RA. These are often caused by rheumatoid disease of rhe cervical spine. Focal neurological dysfunction is a rarer and later manifestation of spinal RA. Patients with RA, of course, develop the ubiquitous changes of spinal osteoarthritis and spondylosis. In addition, early in RA, cervical radiography may show rheumatoid changes such as erosions and sclerosis at vertebral endplates and apophyseal joints. Patients may have cervical subluxations. Disc space narrowing may occur at upper cervical discs, without associated osteophytosis. Patients with progressive RA can develop subluxation at the atlantoaxial joint. Lateral atlantoaxial joint subluxation rarely causes focal neurological dysfunction but can contribute to neck ache and headache. Horizontal atlantoaxial joint subluxation, often combined with adjoining soft tissue pannus, can cause myelopathy, especially in patients with a smaller congenital canal diameter (Figure 79.31). The earliest neurological sign is usually hyperreflexia; assessment of gait and strength in patients with advanced RA is often difficult because of their peripheral
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NEUROLOGICAL DISEASES FIGURE 79.31 Lateral radiographs of the flexed neck of a patient with rheumatoid arthritis and anterior atlantoaxial subluxation. The odontoid and pedicle of C2 and the elements of the ring of CI are outlined. The atlantoaxial separation {double arrow) is also shown. (Reprinted with permission from Rosenbaum, R. B., Campbell, S. M., & Rosenbaum, J. T. 1996, Clinical Neurology of Rheumatic Disease, Bultcrworth-Heinemann, Boston.)
joint pain and deformity. Vertical subluxation can lead to spinal cord or brainstem compression or rarely to vertebral artery compression or injury. Choosing which patients will benefit from surgical stabilization of the subluxed joint is a clinical challenge. Findings of progressive myelopathy or brainstem dysfunction are usually indications for surgery if the general health of the patient permits. Neurological dysfunction caused by atlantoaxial subluxation usually occurs in patients who are already severely debilitated by their disease. Many patients do not regain neurological function after surgical stabilization of the subluxation; goals arc limited to preventing deterioration. The 5-year survival of patients at this late stage of RA is perhaps 5 0 % .
sacroiliitis and spondylitis (Figure 79.32). The clinical symptoms of inflammatory lumbosacral spine disease are insidious onset of low back (and sometimes buttock) pain, lasting more than 3 months, prominent morning stiffness, and improvement with activity. Most patients become symptomatic before age 40 years, and men are affected more commonly than women. Other organ systems are affected commonly in patients with inflammatory spondyloarthropathies; manifestations include uveitis, mucocutaneous lesions, peripheral arthritis, gastrointestinal disease, cardiac disease, and enthesopathy (entheses are sites of
Patients with RA may also develop spinal subluxations, usually in the cervical spine, at levels caudal to the atlantoaxial joint. These subluxations can lead to spinal cord compression. Subaxial subluxations may progress after surgical stabilization of the atlantoaxial joint. A rare late manifestation of RA is rheumatoid pachymeningitis. The dura may develop either focal rheumatoid nodules or diffuse infiltration by inflammatory cells. In rare instances, toed ilin.il disease can lead to spinal cord, cauda equina, or cranial nerve compression or to focal cerebral complications such as seizures.
I}iflammatory
Spondyloarthropathies
Clinical Presentation. The inflammatory spondyloarthropathies include ankylosing spondylitis, reactive arthritis, FIGURE 79,32 The anteroposterior radiograph of the sacroiliac psoriatic arthritis, and the arthritis of inflammatory bowel joint shows sacroiliitis with some preservation of the left sacroiliac disease. Ankylosing spondylitis is characterized by inflam- joint. (Reprinted with permission from Rosenbaum, R. B., matory low back pain, loss of spinal range of motion, Campbell, S. M., & Rosenbaum, J. T. 1996, Clinical Neurology sacroiliitis, and, as it advances, radiographic evidence of of Rheumatic Disease, Butte r worth-He in emaun, Boston.
DISORDERS OF BONF.S. JOINTS. LIGAMENTS, AND MENINGES
insertion of ligament or tendon to bone). The syndesmophytes that form where spinal ligaments join vertebral bodies arc one form of enthesopathy. Examples of other sites of enthesopathy are the foor (Achilles tendinitis, plantar fasciitis, heel pain}, fingers or toes (dactylitis or sausage digits), and symphysis pubis, clavicle, and ribs. Reactive arthritis (formerly called Reiter's syndrome) is classically preceded by venereal or gastrointestinal tract infection. The triad of reactive arthritis is arthritis, conjunctivitis, and urethritis, but many patients do not have all thtee manifestations. Inflammatory low back pain is common in patients with reactive arthritis, and up to one fourth of patients develop radiological evidence of sacroiliitis ot spondylitis. Pathogenesis. The inflammatory spondyloarthropathies are generated by" a combination of genetic and environmental factors. In ankylosing spondylitis, the genetic factor is clearest, with perhaps 9 0 % of patients expressing the gene fot HLA-B27. However, only approximately 5% of people expressing this gene develop ankylosing spondylitis. In the other spondyloarthropathies, the prevalence of HI.A1127 positiviiy is lower. In reactive arthritis, the environmental factors arc clearest, with many patients experiencing a preceding gastrointestinal or genitourinary tract infection with organisms such as Shigella, Salmonella, Yersinia, Campylobacter, or Chlamydia. The inflammatory process is presumably mediated by autoimmune T cells with tissue specificity leading to inflammation at such sites as joints, entheses, and the eye. Spinal Neurological Complications. The neurological complications of the inflammatory spondyloarthropathies generally do not occur until spinal disease is clinically advanced with loss of spinal range of motion and kyphosis and radiologieally evident with vertebral body squaring and syndesmophytes. Spinal complications include atlantoaxial joint subluxation, spinal fractures and pseudoarthroses, disco vertebral destruction, spinal canal stenosis, and cauda equina syndrome caused by lumbar arachnoid diverticula (Table 79.7). Table 79.7: Spinal complications of ankylosing spondylitis based on 105 hospitalized patients Anatomically abnormal Spinal fracture 13 Disco vertebral destruction 4 Atlantoaxial subluxation 1 Spinal canal stenosis 2
Neuro logically abnormal 7 0 (1 2
Source: Data used with permission from We in stein, P., Karpman, R. R., Gall, E. P., et a). 1982, "Spinal injury, spinal fracture, and spinal stenosis in ankylosing spondylitis," J Ncurosurg, vol. 37, pp. 609-616. (Reprinted from Roscnbaum, R. B., Campbell, S. M., &r Rosenbaum, J. T. 1996, Clinical Neurology of Rheumatic Disease, Butterworth-Heinemann, Boston.)
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Subluxation of the atlantoaxial joint is a late and uncommon complication of inflammatory spondyloarthropathy. Diagnosis and management issues are the same as those for patients who develop atlantoaxial disease as part of RA. The fused spondylitic spine is particularly susceptible to fracture, especially in the midecrvical region. The most common fracture site is C6, followed by C5 and C7. After even minor trauma, the patient with advanced spondylitis needs radiographic assessment of the cervical spine to detect fractures if possible before myelopathic complications. Much more rarely, patients with spondylitic rigid spines develop post-traumatic myelopathy caused by epidural hematomas or cord contusions. Destruction of a disc, particularly in the low lumbar or high thoracic region, is a late complication of spondylitis (Figure 79.33). The adjacent vertebral bodies also may be involved. An initiating trauma is not always identified. The destruction may be asymptomatic or painful. The pain increases with movement and decreases at rest, in contrast to typical inflammatory low back pain. An epidural inflammatory response leading to cord compression can occur. Cauda equina syndrome with insidious evolution of leg pain, sensory loss, leg weakness, and sphincter dysfunction is a late complication of inflammatory spondyloarthropathy. Imaging studies (MRI, CT, myelogtaphy) show posterior lumbosacral arachnoid diverticula (Figure 79.34). Although arachnoiditis may play a role in development of this syndrome, the presence of the diverticula distinguishes it from most cases of chtonic adhesive arachnoiditis. Other unusual complications of spondyloarthropathy include lumbar monoradiculopathy secondary to disc herniation or osteophytes, spinal canal stenosis, and from the era when spinal radiation was used to treat spondylitis, radiation-induced cauda equina sarcoma. Nonspinal Neurological Complications. Rare nonspinal complications of inflammatory spondyloarthropathies include brachial plexopathy or tarsal tunnel syndrome. Proximal weakness and atrophy, sometimes with mild elevations of serum creatine kinase level, often occur in advanced cases of spondylitis, suggesting an inflammatory myopathy. In patients with psoriatic arthritis, the myopathy is occasionally painful. A number of case reports detail unusual neurological sequelae in patients with reactive arthritis (Table 79.8). Laboratory Abnormalities. Patients with inflammatory spondyloarthropathies sometimes have mild elevations of CSF protein levels with normal glucose and cell counts. They can have unexplained abnormalities of visual, auditory, and somatosensory evoked responses. Possible Associations with Multiple Sclerosis. Case reports and small series link the occurrence of multiple sclerosis and ankylosing spondylitis in the same patient,
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NEUROLOGICAL DISEASES FIGURE 79.33 Magnetic resonance image shows disco vertebra I destruction {arrows) in a patient with ankylosing spondylitis. There is a chronic fracture in the lower thoracic spine, which is otherwise rigid because of bony fusion. Chronic hypcrmobility at this single nonfused segment has occurred, leading to exuberant fibrous tissue development. The fibrous tissue enhances on this postgadolinium-enhanced Tl -weighted image. This appearance can be mistaken for infectious spondylitis (see Figure 79.29) if the presence of a bamboo spine on plain films is overlooked. (Courtesy Erik Gaensler.)
FIGURE 79.34 Magnetic resonance image of the lumbar spine shows a posterior lumbar arachnoid diverticulum in a patient with ankylosing spondylitis. The spinal canal is expanded at T12T.1 by a mass that shows signal intensity equivalent to cerebrospinal fluid on these Tl-weighted images. Isointensity to cerebrospinal fluid suggests an arachnoid cyst, and the small arrows outline the internal margins of the cyst. The curved arrows show the nerves of the cauda equina, which have been displaced anteriorly. (Courtesy Erik Gaensler.)
Table 79.8: arthritis
f:\iiiiiplcs (>1 neurological complications of reactive
Acute transverse myelitis Brainstem dysfunction Encephalitis Neuralgic amyotrophy Personality change Seizures Unilateral ascending motor neuropathy Source: Reprinted with permission from Rosenbaum, R. B., Campbell, S. M. ; & Rosenbaum, J. T. 1996, Clinical Neurology of Rheumatic Diseases, Butterworth-Hememann, Boston.
b u t insufficient data exist to determine w h e t h e r a true association exists between the t w o illnesses. E v a l u a t i o n is complicated because either condition might c a u s e a m y e l o p a t h y , transient vision loss (iritis versus optic neuritis), or evoked response a b n o r m a l i t i e s .
Epidural Lipomatosis E p i d u r a l lipomatosis is a non-neoplastic a c c u m u l a t i o n of fatty tissue in the thoracic or l u m b a r epidural space t h a t can occur idiopathically but is m o r e c o m m o n l y a
DISORDERS OF BONES, JOINTS, LIGAMENTS, AND MENINGES
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FIGURE 79.35 Magnetic resonance image shows epidural lipomatosis. T1weighted axial images show markedly increased fat {arrows) within the spinal canal compressing the thecal sac, which is quite small. Note that the patient is quite obese, with large amounts of fat in the retroperitoneutn and posterior paraspinous tissues [open arrows). (Courtesy Erik Gaensler.)
complication of chronic corticosteroid excess, obesity, or hypothyroidism (Koch et al. 2000). A typical patient has been on corticosteroids for more than 6 months and is obese and cushingoid; spinal radiography typically shows diffuse osteoporosis. Criteria for the diagnosis include (1) history consistent with segmental spinal cord compression or nerve root compression, (2) epidural fat thickness of more than 7 mm in the region of compression, and (3) a body mass index of more than 27.5 kg/m 2 (Figure 79.35), The compressive tissue can regress when corticosteroid doses are decreased, but the compression of neurological tissue may be severe enough to require laminectomy.
Chronic Meningitis Most cases of chronic meningitis arc caused by infection (see Chaptet 59), neoplasia (see Chapter 58), or sarcoidosis (see Chapter 55). Behcet's syndrome, isolated central nervous system angiitis (sec Chapter 57), systemic lupus erythematosus, Sjogren's syndrome, or Wegener's granulomatosis are included in a comprehensive differential diagnosis. Some other chronic or recurring meningitic syndromes merit discussion.
Chronic Adhesive Arachnoiditis Chronic focal or diffuse inflammation of the spinal theca can cause neurological symptoms caused by inflammation, adhesion, and distortion of nerve roots or spinal cord. This condition is termed chronic spinal arachnoiditis or chronic adhesive arachnoiditis. However, the process usually involves all layers of the meninges and in its chronic stages may be fibrotic rather than inflammatory. Calcification of the meninges (arachnoiditis ossificans) is an occasional late finding. The clinical manifestations are of a gradually
ascending painful cauda equina syndrome, followed by an ascending myelopathy as the arachnoiditis spreads up the spinal cord. Death may result in 3-10 years from decubiti, urosepsis, and other complications of severe paraplegia. Adhesive arachnoiditis occasionally complicates a variety of surgical or medical violations of the thecal sac {Table 79.9). Focal arachnoiditis is most common in the cauda equina following lumbar disc surgery or myelography, particularly if oil-based contrast has been used for the latter. The symptoms can include local or radicular pain, radicular paresthesia, and less commonly more severe findings of oligoradiculopathy such as motor loss or sphincter dysfunction. The diagnosis can usually be made by spinal MRI, which may show clumping of nerve roots, nodules in the subarachnoid space, loculation of spinal fluid, and local areas of enhancement. The nerve roots may clump at the periphery of the thecal sac, usually adjacent to an area of previous surgery, or in the center of the sac, usually in areas of spinal stenosis. The extent of the MRI findings correlates poorly with the severity of the clinical nerve root dysfunction. Spinal fluid may show increased CSF protein levels and mild to moderate mononuclear pleocytosis. Surgical debridement of the arachnoiditis is sometimes attempted but is usually unsuccessful and may lead to increased neurological deficit. Epidural or intrathecal corticosteroids arc sometimes tried, but there is no proof of their efficacy, and there are reports of arachnoiditis
Table 79.9:
Causes of adhesive arachnoiditis
Myelography, especially with oil-based dyes Spinal surgery Ankylosing spondylitis Intrathecal or epidural chemical exposure, e.g., spinal anesthesia, corticosteroids Granulomatous infection, e.g., tuberculosis Ruptured dermoid or epidermoid cyst
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NEUROLOGICAL DISEASES
caused by their use. Therefore most treatment is aimed at symptomatic pain control, except in the unusual patient with progressive neurological deficits. Arachnoiditis of the spinal cord is less common than arachnoiditis of the cauda equina. It can occur after apparently successful treatment of granulomatous meningitis or of epidural or vertebral infection and can lead to myelopathy. Arachnoiditis, especially at the craniocervical junction, can cause syringomyelia.
Recurrent Meningitis Patients with recurrent attacks of acute bacterial meningitis need to be screened for dural CSF leaks or fistulas, parameningcal infections, and immunodeficiency (see Chaptet 59). Recurrent meningitis also can be caused by chemical irritation from leaking dermoid tumors or craniopharyngiomas. Drug-induced meningitis, most c o m m o n as an idiosv ncralii reaction to noiiMcniidn
.inii
inflammatory drugs, can recur with repeated drug exposures. Rarely, recurrent meningitis can complicate systemic inflammatory diseases such as systemic lupus erythematosus, Sjogren's syndrome, Behcet's disease, Lyme disease, familial Mediterranean fever, or sarcoidosis. Mollaret's meningitis is another form of recurrent aseptic meningitis. Attacks are self-limited, lasting a few days. The spinal fluid shows a mixed pleocytosis; sometimes large macrophagc-like cells (Mollaret's cells) arc present as well. Some cases are caused by herpes virus infections, but a causative organism is not always identified.
Uveomeningitis Syndromes The combination of chronic or recurrent meningitis and uveitis has a specific differential diagnosis (Table 79.10). Often ophthahnological chatacterization of the uveitis can further limit the differential diagnosis. For example, the
Tabic 79.10:
Causes of combined uveitis and meningitis
Acute multifocal placoid pigmentary epithelioparhy Acute retinal necrosis Behcet's syndrome Human T-lymphotropic virus type 1 infection Infection in immunocompromised host Isolated central nervous system angiitis Lyme disease Primary central nervous system lymphoma Sarcoid Syphilis Systemic lupus erythematosus Vopt-Koyanagi-Harada syndrome Source: Reprinted with permission from Rosenbaum, R. B., Campbell, S. M., & Rosenbaum, J. T. 1996, Clinical Neurology of Rheumatic Diseases, Butterworth-Heinemann, Boston.
uveitis of Vogt-Koyanagi-Harada syndrome is bilateral and often causes retinal elevations and retinal pigmentary changes. Vogt-Koyanagi-Harada syndrome also causes skin and hair findings such as vitiligo, poliosis, or focal alopecia.
Superficial Hemosiderosis Superficial hemosiderosis is a rare disorder that causes slowly progressive cerebellar ataxia, mainly of gait, and sensorineural deafness, often combined with manifestations of myelopathy, such as spasticity, brisk reflexes, and extensor plantar responses, bladder disturbance, or sensory signs. Less common features include dementia, anosmia, or anisocoria, and more rarely extraocular motor palsies, neck or backache, bilateral sciatica, or lower motor neuron signs (5-10% each). Men are more often affected than women (3:1). The diagnosis may not be suspected clinically, but the neuroraetiological abnormalities arc striking. MR1 shows a black rim around the posterior fossa structures and spinal cord and less often the cerebral hemispheres on T2-weighted images (Figure 79.36). These paramagnetic signal changes represent encrustation of the brain surfaces with hemosiderin. The adjacent neural tissue atrophies, with accumulation of ferritin in microglia and Rergmami's cells in the cerebellum. Superficial siderosis is presumably secondary to chronic or recurrent blood leakage into the subarachnoid space. It has been described after hemispherectomy, head or spine trauma, and in association with chronically or recurrently bleeding intracranial aneurysms, arteriovenous malformations, and spinal tumors. However, the CSF analysis may be normal, and not all patients have an identifiable source of bleeding. Treatment relies on identifying and arresting the source of bleeding; chelation therapy does not appear to be effective.
Fibromyalgia Fibromyalgia, a syndrome defined by widespread musculoskeletal or soft tissue pain and multiple tender points, is part of the differential diagnosis of many patients with spinal pain. The American College of Rheumatology classification criteria for the diagnosis define pain as widespread when it is bilateral, above and below the waist, and axial. To meet the classification criteria, a patient must have tenderness to palpation at 11 or more of 18 specific points (Figure 79.37), but the validity of these tender points as diagnostic criteria has been cogently questioned. Typically, patients have multiple symptoms including fatigue, stiffness, nonrcstorative sleep, headaches, and mood disorders. Patients may have many symptoms of neurological import such as weakness, paresthesia, and dizziness. Nonetheless, theit neurological examinations ate normal, unless they have a separate neurological Illness.
DISORDERS Or BONES, JOINTS, l.IGAMEN IS, AND MENINGES
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FIGURE 79.36 (A, B) Axial T2-weighted magnetic resonance images demonstrate a thin ring of hypointensity surrounding the medulla and midbrain, indicating hemosiderin deposition along the leptomeninges. (Courtesy Jim Anderson, Oregon Health Sciences University, Portland, Oregon.)
FIGURE 79.37 The tender point location of fibromyalgia. The nine paired tender points recommended by the 1990 American College of Rheumatology Criteria Committee for establishing a diagnosis of fibromyalgia are (1} insertion of the nuchal muscles into occiput; (2) upper border of the trapezius, midportion; (3) muscle attachments to upper medial border of scapula; (4) anterior aspects of the C5, C7 intenransverse spaces; (5) second rib space approximately 3 cm lateral to the sternal border; (6) muscle attachments to lateral epicondyle, approximately 2 cm below the bony prominence; (7) upper outer quadrant of gluteal muscles; (8) muscle attachments just posterior to the greater trochanter; and (9) medial fat pad of knee proximal to joint line. A total of 11 or more tender points in conjunction with a history of widespread pain is characteristic of the fibromyalgia syndrome. (Reprinted with permission from Bennett, K, M, 1997, "The fibromyalgia syndrome: Myofascial pain and the chronic fatigue syndrome," in Textbook of Rheumatology, 5th ed, eds W. N. Kelley, E. D. Harris, Jr., S. Ruddy, et al., WB Saunders, Philadelphia.)
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NEUROLOGICAL DISEASES
Diagnostic neurological investigations, such as brain imaging, muscle biopsy, or electrodiagnostic studies, a r e n o r m a ! or s h o w minor nonspecific a b n o r m a l i t i e s . T h e cause of most cases of fibromyalgia is u n k n o w n . Behavioral a n d biological factors b o t h c o n t r i b u t e to t h e clinical presentation of the s y n d r o m e ( O o f ford a n d C l a u w 2002). Neuroscientific research on the pathogenesis of fibromyalgia has examined muscle, sleep, n e u r o e n d o c r i n e function, and central pain processing, including studies using functional brain imaging (Bradley et al. 2 0 0 2 ) . Symptoms a n d signs of fibromyalgia can occur in association with an a u t o i m m u n e disease, such as systemic lupus erythematosus, or other systemic illness, such as h y p o t h y roidism. Focal t r a u m a can cause localized, self-limited soft tissue myofascial pain. T h e pathogenic role of t r a u m a , on-the-job injury, or w o r k p l a c e stress is controversial. T r e a t m e n t includes a supportive d o c t o r - p a t i e n t relationship, tricyclic antidepressants, aerobic exercise, and avoiding inactivity.
REFERENCES Botto, L. D., Moore, C. A,, Khoury, M. J., & Erickson, J, D. 1999, "Neural-tube defects," N Engl J Med, vol. 341, pp. 1509-1519 Bradley, L. A. et al 2002, "Is fibromyalgia a neurologic disease?" Curr Pain Headache Rep, vol. 6, pp. 106-1 14 Crofford, L. &c Clauw, D. 2002, "Fibromyalgia: Where are we a decade after the American College of Rheumatology classification criteria were developed?" Arthritis Rheum, vol. 46, pp, 1136-1138 Do, H. M. 2000, "Magnetic resonance imaging in the evaluation of patients for percutaneous vcrtebroplasty," Topics Magn Reson imaging, vol. 11, pp. 234-244 Fouyas, I. P., Statham, P. F. X., & Sandercock, P. A. G. 2002, "Cochrane review on the role of surgery in cervical spondylotie radiculomyeloparhy," Spine, vol. 27, pp. 736-747 Garland, F.. M. & Robertson, D. 2001, "Chiari 1 malformations a cause of orthostatic intolerance symptoms: A media myth?" Am } Med, vol. I l l , pp. 546-552 Goel, A. & Dcsai, K. 2000, "Surgery for syringomyelia: An analysis based on 163 surgical cases," Acta Neurochir (Wien), vol. 142, pp. 293-302
Goel, A. et al. 1998, "Basilar invagination: A study based on 190 surgically treated patients," J Neurosurg, vol. 88, pp. 962-968 Hayes, M., Parker, G., Ell, J., & Sillence, D. 1999, "Basilar impression complicating osteogenesis imperfecta type IV: The clinical and neuroradiological findings in four cases," / Neurol Neurosurg Psychiatry, vol. 66, pp. 357-364 Koch, C. A. ct al. 2000, "Do glucocorticoids cause spinal epidural lipomatosis? When endocrinology and spinal surgery meet," Trends Endocrinol Me tab, vol. 11, pp. 86-90 Marini, J. C. 2001, "Genetic risk factors for lumbar disk disease," JAMA, vol. 285, pp. 1886-1888 Mathis, J. M., Barr, J. D., Belkoff, S. -VI., ct al, 2001, "Percutaneous vcrrcbroplasty: A developing srandard of care for vertebral compression fractures," AjNR Am J Neuroradioi, vol. 22, pp. 373-381 McLone, D. G. & La Marca, F. 1997, "The tethered spinal cord: Diagnosis, significance, and management," Semin Pediatr Neurol, vol. 4, pp. 192-208 Meadows, J. et al. 2000, "Asymptomatic Chiari type 1 malformations identified on magnetic resonance imaging," / Neurosurg, vol. 92, pp. 920-926 Menzes, A. H. 1997, "Craniovertebral junction anomalies; Diagnosis and treatment," Semin Pediatr Neurol, vol. 4, pp. 209-223 Milhorat, T. H., Chou, VI. W., Trinidad, K. M„ et al. 1999, "Chiari I malformation redefined: Clinical and radiologic findings for 364 symptomatic patients," Neurosurgery, vol. 44, pp. 1005-1017 Nardin, R. A., Paid, M. R., Gudas, T. F., ct al. 1999, "Electromyography and magnetic resonance imaging in rhe evaluation of radiculopathy," Muscle Nerre, vol. 22, pp. 151-155 Oestreicb, A. E,, Young, L. W., & Young Poussaint, T. 1998, "Scoliosis circa 2000: Radiologic imaging perspective. 1. Diagnosis and pre treatment evaluation," Skeletal Radiol, vol. 27, pp. 591-605 Oldfield, E. FI. 2001, "Syringomyelia," / Neurosurg, vol. 95, suppl. 1, pp. 153-155 Paassilta, P. et al. 2001, "Identification of a novel common genetic risk factor for lumber disc disease," JAMA, vol. 285, pp. 1843-1849 Poncelet, A. 1999, "The neurologic complications of Paget's disease," / Bone Miner Res, vol. 14, suppl. 2, pp. 88-91 Vanichkachorn, J. S. Sc Vaccaro, A. R. 2000, "Thoracic disk disease: Diagnosis and treatment," / Am Acad Orthop Surg, vol. 8, pp. 159-169
Chapter 80 Disorders of Upper and Lower Motor Neurons Brian Murray and Hiroshi Mitsumoto
Disorders of Upper Motor Neurons Neuroanatomy of Upper Motor Neurons Signs and Symptoms of Upper Motor Neuron Involvement Laboratory Evidence of Upper Motor Neuron Involvement Primary Lateral Sclerosis Hereditary Spastic Paraplegia Human T-Lymphotropic Virus Type [-Associated Myelopathy or Tropical Spastic Paraparesis Adrenomycloncuropathy Plant F.xcitotoxins Disorders of Lower Motor Neurons Neuroanatomy of Lower Motor Neurons Signs and Symptoms of Lower Motor Neuron Involvement Laboratory Evidence of Lower Motor Neuron Involvement Acute Poliomyelitis Progressive Postpoliomyelitis Muscular Atrophy Multifocal Motor Neuropathy Benign Focal Amyotrophy Infantile and Juvenile Spinal Muscular Atrophy Adult-Onset Spinal Muscular Atrophy (Spinal Muscular Atrophy Type 4) Kennedy's Disease (X-Linked Recessive Bulbospinal Neuronopathy)
2223 2223 2224 2225 2226 2227 2227 2 22W 222H 2229 : .'.."' 2229 2230 2231 2232 2234 2236 2237 2241
Progressive Muscular Arrophy 2245 Subacute Motor Neuronopathy in Lymphoprol iterative Disorders 2246 Postirradiation Lower Motor Neuron Syndrome 2246 Disorders of Both Upper and Lower Motor Neurons 2246 Amyotrophic Lateral Sclerosis 2246 Familial Amyotrophic Lateral Sclerosis 2258 Autosomal Dominanr Familial Amyotrophic Lateral Sclerosis 2258 Autosomal-Reeessive and X-Linked Mutations 2259 Amyotrophic Lateral Sclerosis-Parkinsonism-Dcmentia Complex (Western Pacific Amyotrophic Lateral Sclerosis} 2260 Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease) 2260 (OMIM 109150) Adult Hexosamimdase-A Deficiency (OMIM 606869) 2260 2261 Triple-A Syndrome (OMIM 231550) Disinhibition -Dementia-Park insonism-Amyorrophy Complex (Wilhelmsen-Lynch disease) (OMIM 600274} 2261 Autosomal Dominant Fronro temporal Dementia with 2261 Motor Neuron Disease Adult Polyglucosan Body Disease 2261 Paraneoplastic Motor Neuron Disease 2262 Viral Hypothesis and Human Immunodeficiency Virus Type 1-Associated Motor Neuron Disorder 2262
2243
The marriage of clinical nenroscience and molecular biology has greatly advanced our understanding of motor neuron disorders over the last decade. Through cellular, animal, and Inn nan research, there has been a veritable explosion in new information relating to the pathogenesis of both hereditary and acquired disorders of the motor system as it extends from the brain to the anterior horn cell. In addition, a host of prospective, controlled trials are yielding new treatment options for several disorders that were hitherto unbeatable. In this chapter, we review the causes, diagnosis, and treatment of the motor neuron diseases according to whether the disorder affects upper motor neurons (UMNs), the lower motor neurons (LMNs}, or both UMNs and LMNs.
DISORDERS Ol UPPER M O T O R NEURONS Neuroanatomy of Upper Motor Neurons The UMN is the motor neuron, the cell of which lies within the motor cortex of the cerebrum, and the axon of which
forms the corticobulhar and corticospinal tracts. It is distinguished from the LMNs lying in the brainstem motor nuclei and the anterior horns of the spinal cord that directly innervate skeletal museles. The UMNs are rostral to the LMNs and exert direct or indirect supranuclear control over the LMNs (Mitsumoto, Chad, and Pioro 1997) (Table 80.1). Motor
Cortex
In the cerebral cortex, UMNs are located in the prtmary motor cortex (Brodmann's area 4) and the premotor areas (brodmann's area 6), which are subdivided into the supplementary motor area (sometimes called the secondary motor cortex) and the premotor cortex, respectively. The somarotopic organization and topographic specificity of the corticospinal projection appear to be far more complex and broader than was previously thought, Betz's cells (giant pyramidal neurons) are a distinct group of large motor neurons in layer 5 of the primary motor cortex and represent only a small portion of all primary motor neurons 2223
2224
NEUROLOGICAL DISEASES
Table 80.1:
Upper motor neurons and their descending tracts
The motor areas The primary motor neurons (Betz's giant pyramidal cells and surrounding motor neurons) The premotor areas (the supplementary motor area and ptemotor cortex) Corticospinal and corticobulbar tracts Lateral pyramidal tracts Ventral (uncrossed) pyramidal tracts Brainstem control Vestibulospinal tracts Reticulospinal tracts Tectospinal tracts Limbic motor control
with axons in the corticospinal tracts. Individual motor neurons in the primary motot cortex initiate and control the contraction of small groups of skeletal muscles subserving individual movements. The entire motot area of the cerebral cortex controls the highest levels of voluntary muscle movement, including motor planning and programming of muscle movement. Corticospinal and Corticobulbar Tracts. Axons from the motor areas form the corticospinal and corticobulbar tracts. Axons arising from neurons in the primary motor cortex constitute only one third of all the corticospinal and corticobulbar tracts. Among these, Betz's cell axons make up 3 - 5 % of the tract, and the remaining fibers from the primary motor cortex arise from other neurons in layer 5 of :1K- pnman mom:- concx. Another one iln:\: ol the axons in these tracts arc detived from Brodmann's area 6, which includes the supplementary motor and the lateral premoror cortex. The remaining third is derived from the somatic sensory cortex (areas 1, 2, and 3) and the adjacent temporal lobe region. The corticobulbar tract projects bilaterally to the motot neurons of cranial nerves V, VII, IX, X, and XII. Most corticospinal fibers (75-90%) decussate in the lower medulla (pyramidal decussation) and form the lateral corticospinal tract in the spinal cord (the pyramidal tracts). The remaining fibers descend in the ipsilateral ventral corticospinal tract. The lateral corticospinal tract projects to ipsilateral motor neurons and their interneurons that control extremity muscle contraction, whereas the anterior corticospinal tract ends bilaterally on ventromedial motor neurons and interneurons, which control the axial and postural muscles. These corticospinal axons provide direct glutamatergic excitatory input to alpha motoneurons. Brainstem Control. In a broad sense, several brainstem nuclei can be considered part of the UMN system because they exert supranuclear influence on the LMN population in the spinal cord. The projections from the brainstem to spinal cord LMNs are highly complex. The fibers originating in the medial and inferior vestibular nuclei in the medulla descend in the medial vestibulospinal tract and
terminate both on medial cervical and thoracic motor neurons and on interneurons. They excite ipsilateral motor neurons but inhibit contralateral neurons. The lateral vestibulospinal tracts originating in the lateral vestibular nucleus (Dciter's nucleus) activate the extensor motor neurons and inhibit the flexor motor neurons in both the upper and the lower extremity. The brainstem reticular formation also sttongly influences the spinal motor neurons, exerting widespread polysynaptic inhibitory input on extensor motor neurons and excitatory input on flexor motor neurons. The reticulospinal tracts modulate various reflex actions during ongoing movements. The brainstem reticular formation receives supranuclear control from the motor cortex via the cortical reticulospinal pathway, to act as a major inhibitot of spinal reflexes and activity. Therefore a lesion of the corticoreticular pathway can disinhibit reticulospinal control of the LMNs. The tectospinal tract originates in the superior colliculus and controls eye and head movement. Muscle tone is altered by variations in the balance between inhibitory input (mediated by the dorsal reticulospinal tract) and faeilitatory input (mediated by the medial reticulospinal tract and to some extent by the vestibulospinal tract) upon muscle stretch receptors. Limbic Motor Control. The limbic system is involved in emotional experience and expression and is associated with a wide variety of autonomic, viscetal, and endocrine functions. It strongly influences the somatic motor neurons: The emotional status and experience of an individual determines overall spinal cord activity and the limbic motor system also influences respiration, vomiting, swallowing, chewing, and licking (at least in animal studies). Furthermore, the generation of pseudobulbar signs in amyotrophic latctal scletosis (ALS) is closely related to an abnormal limbic motor control, particularly in the periaqueductal gray and nucleus retroambiguus. The latter nuclei project to the somatic motor neurons that innervate pharyngeal, soft paiatal, intercostal, diaphragmatic, abdominal, and probably laryngeal muscles. Pseudobulbar symptoms may appear when UMN control over these motor nuclei is impaired, and thus limbic motot control is disinhibited. There appears to be some degree of emotional regulation by the cerebellum: The recently described "cerebellar cognitive affective syndrome" can arise when stroke, tumor, or infection interrupts connections between the cerebellum and cerebral association and paralimbic regions (Schmahmann and Sherman 1998).
Signs and Symptoms of Upper Motor Neuron Involvement Loss
of Dexterity
Loss of dexterity is one of the most characteristic signs of UMN impairment. Voluntary skillful movements require
DISORDERS OF UPPER AND LOWER MOTOR NEURONS Table 80.2:
Signs and symptoms of upper motor neuron
l!l\ i i[\ C I I M I I
Loss -.-i tk-xii -MILOSS of muscle strength (weakness! Spasticity Pathological hyper-reflexia Pathological reflexes Increased redeyes in an atrophic limb Pseudobulbar (spastic bulbar) palsy
Pathological
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Hyper-reflexia and Pathological Reflexes
Pathological hyper-reflexia is another crucial manifestation of UMN disease. The Babinski sign (extensor plantar response) is the most important sign in the clinical neurological examination and is characterized by extension of the great toe (often accompanied by fanning of the other toes) in response to stroking the outer edge of the ipsilatcral sole upward from the heel with a blunt object. Pseudobulbar (Spastic Bulbar) Palsy
the integrated activation of many interneuron circuits in the spinal cord; such integration is ultimately controlled by the corticospinal tract and thus by UMNs. Loss of dexterity may be expressed as stiffness, slowness, and clumsiness in performing any skillful motor actions; in particular, rapid repetitive motions, such as foot or finger tapping, are impaired (Table 80.2). Loss of Muscle Strength (Weakness) Although muscle strength is reduced, the degree n\ muscleweakness resulting from UMN dysfunction is generally mild. Extensor muscles of the upper extremities and flexor muscles of lower extremities may become weaker than their antagonist muscles because the UMN lesion disinhibits brainstem control of the vestibulospinal and reticulospinal tracts. Spasticity Spasticity is the hallmatk of UMN disease. The pathophysiology of spasticity is complex and controversial: It seems to reflect altered firing of alpha motoneurons and interneurons within the spinal cord, together with increased activity of group II nerve fibers derived from muscle spindles. There is an excess level of excitatory input to gamma motoneutons via excess synaptic levels of excitatory neurotransmitters such as serotonin, noradrenaline, and glutamate. In addition, there is reduced inhibitory glycinergic and y-aminobutyric acid (GABAergic) neurotransmission. The result is a state of sustained increase in muscle tension when the muscle is lengthened. Clinically, muscles exhibit a sudden resistive "catch," midway during passive movement of the limb. However, when a sustained passive stretch is continued, spastic muscles quickly release the tension and relax, an event often described as the "clasp-knife phenomenon." In muscles that are severely spastic, passive movement becomes more difficult and even impossible. Sustained increases in muscle tone lead to a slowing in motor activities, which may be clinically demonstrated by asking a patient with spasticity to carry out rapid repetitive motor activities such as finger or foot tapping. In some patients with UMN degenerations, the increase in tone may be minimal.
Pseudobulbar palsy (or spastic bulbar palsy) develops when there is disease involvement of the corticobulbar tracts that exert supranuclear control over those motor nuclei that control speech, mastication, and deglutition. The prefix "pseudo-" is used to distinguish this condition from "true" bulbar palsy that results from pure I.MN involvement in brainstem motor nuclei. Articulation, mastication, and deglutition are affected in both pseudobulbar and bulbar palsies, but the degree of impairment in pseudobulbar palsy is generally milder. Spontaneous or unmotivated ctyiug and laughter uniquely characterize pseudobulbar palsy. This is also termed emotional lability, labile affect, or emotional incontinence and is often a source of great embarrassment to the patient.
Laboratory Evidence of Upper Motor Neuron Involvement Nettroimagmg Brain magnetic resonance imaging (MRI) sometimes shows abnormal signal intensity in the corticospinal and corticobulbar tracts as they descend from the motor strip via the internal capsules to the cerebral peduncles. In AI.S, a disorder of UMNs (and LMNs), these signal changes are best appreciated on T2-weighted (increased signal in the internal capsules) and proton density (low signal in the preccntral cortex) images and probably represent wallerian degeneration. However, theses changes do not appear to be sufficiently sensitive or specific, and efforts continue to evaluate other potential MRI techniques, such as diffusion tensor and volumetric MRI, which may serve as markers of UMN disease (Ellis et al. 2001; Smith 2002). Magnetic
Resonance
Spectroscopy
Imaging
Proton density magnetic resonance spectroscopy ('H-MRS) is a noninvasive nuclear magnetic resonance technique that combines the advantages of MRI with in vivo biochemical information. N-acery(aspartate, a neuronal marker, is significantly reduced relative to creatine:phosphocreatine level (used as an internal standard because all cells, including glial cells, contain creatine and phosphocreatine),
2226
NEUROLOGICAL DISEASES
Table 80.3:
Disorders of upper motor neurons and their key characteristics
Disorders
Key characteristics
Primary lateral sclerosis Hereditary spastic paraplegia HTLV-1-associated myelopathy HTLV-2-associated myelopathy Adrenomyeloneuropathy Lathyrism Konzo
A diagnosis i1:40,000) should prompt an investigation for an IgM monoclonal gammopathy. CSF protein concentration is usually normal but may he modestly etc va led to less tii.m Kill ni(',.AU.. Differential
Diagnosis
Although focal asymmetrical muscle weakness and atrophy occur both in ALS and in M M N , the former is characterized by the additional presence or later development of prominent UMN and pseudobulbar findings. It is thus crucial to perform follow-up examinations to distinguish between these disorders. PMA is a rare pure LMN syndrome that often presents with focal and asymmetrical weaknesses in distal extremity muscles, thus closely mimicking MMN. However, the weakness in PMA is regional rather than in the distribution of major motor nerves (as seen in the earlier stages of MMN). PMA is associated with neither conduction blocks nor high titers of anti-GM! antibodies and does not respond to immunomodulatory treatment. One of the useful clinical clues is that weakness exceeds atrophy. The combined electro diagnostic and serological criteria that support MMN serve to differentiate it from other predominantly motor disorders such as adult-onset SMA, benign focal amyotrophy/monomelic amyotrophy, and acute neuralgic amyotrophy (Parsonage-Turner syndrome). The classic anti-Hu antibody-associated paraneoplastic syndrome is a subacute sensory neuronopathy, but a recent retrospective analysis of 20 patients revealed that 5% of presentations were pure motor in nature and 10% were multifocal in distribution (Camdessanche et al. 2002). Furthermore, a subacute paraneoplastic pure motor neuropathy has been described in the setting of an underlying lymphoproliferative disorder. There are many similarities between M M N and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Both are characterized by the presence of dcmyclination-range motor conduction slowing and/or conduction block. However, there are significant differences. M M N characteristically involves distal upper extremity muscles in an asymmetrical fashion, whereas CIDP typically involves proximal muscles in a symmetrical fashion. A remitting and relapsing course is uncommon in MMN but common in CIDP. Although CIDP can manifest as a predominantly LMN syndrome, clinical and electrodiagnostic sensory abnormalities arc the rule, which is in stark contrast to MMN. Reflexes are characteristically absent in CIDP, whereas they are usually present but diminished in MMN. CSF protein levels do not exceed 100 mg/dL in MMN and are usually normal, but very high CSF protein levels are not uncommon in CIDP. CIDP responds
2235
well to corticosteroids and plasma exchange, whereas these treatments are generally not effective in M M N . M M N must also be clearly differentiated from multifocal acquired demyelinating sensory and motor neuropathy (MADSAM or Lewis-Sumner syndrome). This disorder may very closely mimic M M N . It presents in the same agegroup and in the same tippet limb-predominant asymmetrical fashion in the distribution of multiple different distal peripheral nerves. Reflexes are usually diminished rather than absent. However, clinical examination and EDX typically reveal sensory abnormalities, which distinguish this unusual disorder from M M N . MADSAM may respond to intravenous immune globulin (IVIG) therapy or prednisone. Other immune-mediated demyelinating neuropathies, such as a nti-myel in -associated glycoprotein (antiMAG) antibodies or polyneuropathy with monoclonal gammopathy, cause not only severe muscle weakness but also prominent sensory loss and often other systemic signs. There has been a report of a small series of patients (n = 9) with a slowly progressive or nonprogressive pure axonal M M N in the absence of anti-GM, antibodies. No electrodiagnostic features of demyelination were detected, but there was evidence of a "relatively indolent axonal process." This condition, referred to as multifocal acquired motor axonopatby, may respond to corticosteroids or IVIG infusions (Katz et al. 2002). Treatment Although MMN is considered an immune-mediated disease, neither plasma exchange nor corticosteroids are effective and may even worsen the condition. The treatment of choice is IVIG prepared from pooled human immunoglobulin G (IgG) (Van den Berg-Vos et al. 2000). To date, four separate randomized placebo-controlled trials have shown the benefit of this therapy in M M N . Clinical improvement may be noticed within a matter of hours, but generally one may expect a benefit within 15 days. It appears that those patients who ate younger, who are anti-GMi antibody positive, have conduction blocks, and who are clinically milder at onset have the best response. In general, conduction blocks are not altered by this therapy despite improvements in clinical motor function. Similarly, treatment does not appear to reduce anti-GM i antibody titers. A total dose of 2 g/kg given as a slow intravenous infusion in divided doses over 2-5 days can improve strength in more than 5 0 % of patients. The duration of benefit varies between patients, ranging from 2 weeks to 6 months or more. It is usually necessary to tailor the particular schedule on a case-by-case basis depending on how the individual responds and how long the effect lasts. A typical maintenance schedule is 400-600 mg/kg once every 3-8 weeks. Serum immunoglobulin A (IgA) should be checked before treatment: Those who have congenital IgA deficiencymay suffer an anaphylactic reaction to second and later infusions because of the presence of a small amount of IgA
2236
NEUROLOGICAL DISEASES
contamination in the pooled IgG infusion. Side effects of iVIG include headaches, aseptic meningitis, allergic reactions {including acute renal failure), strokes, myocardial infarctions, and fluid overload. IVIG treatment is expensive; therefore objective documentation of improvement, including quantitative muscle strength testing and quantitative motor function testing, is important to prove efficacy. Apart from IVIG, there have been no prospective, double-blind, randomized, placebo-controlled treatment trials completed to assess the value of alternative immunomodulatory treatments for M M N (Umapathi et al. 2002). However, several small scries and case reports show that cyclophosphamide treatment is also effective, ft is the only immunosuppressive treatment that may induce a long-term benefit and it does so in more than 5 0 % of patients with MMN. I f i >", I • cunuiLime lilt-lime i.l< >,:.-, (>7\i g) increase the risk of neoplasia, especially of the bladdet. Thus cyclophosphamide is reserved for more severe cases that cannot tolerate or do not respond to IVIG. Six monthly treatments with intravenous cyclophosphamide (1 g/M 2 ), each preceded by two plasma exchanges, are the recommended regimens. This regimen not only produces a sustained motor improvement but also a sustained 6 0 - 8 0 % reduction in serum anri-GM, antibody liter in two thirds of patients. One or two more additional treatments may be given if the patient is not improving and anti-GM, antibody titers do not decline. There is often a 3-6-month delay in improvement after starting cyclophosphamide therapy, and remission usually lasts for 1-3 years, after which time antibody titers often rise and weakness recurs. Retreatment may then be necessary. Several small case series have recently reported beneficial effects of interferon-/Ma in refractory cases of M M N . In addition, rituximab, a chimeric monoclonal antibody directed against the B-cell CD20 epitope, was effective in improving motor outcome in four patients with MMN. Clearly, further prospective controlled trials are necessary to define nie potential use ot interferon ,mtl IIKI:K>C1OI:;I1 antibody therapy in M M N .
Benign Focal Amyotrophy Most diseases affecting LMNs begin as muscle weakness in a focal area and in one extremity. In most cases, the disease steadily and relatively rapidly spreads from one extremity to another. However, there is a condition involving a limited number of myotomes in one extremity that does not spread. The terms benign focal amyotrophy, monomelic amyotrophy, or juvenile segmental muscular atrophy are used to describe this intriguing entity (Donofrio 1994). Etiology and Pathogenesis The etiology is unknown. Autopsy studies have shown thai the affected cervical spinal cord is flattened; the anterior
horn is markedly atrophied and giiotic and the numbers of both large and small motor neurons are reduced. Some researchers believe that this is a mechanically induced disease being the result of local compression of the dura and spinal cord against vertebrae during neck flexion. However, surgical decompression has not altered the course of the diseases, and this theory is no longer widely held. Another school of thought is that this is a segmental, perhaps genetically determined, SMA. Indeed, rare familial occurrence has been reported and a case of WerdnigHoffmann disease was found in a close relative of a patient who had benign focal amyotrophy. This may, of course, have been purely coincidental. Clinical Features The disease usually begins in the later teens, but many cases can present in the fourth decade. More than 6 0 % of patients are men. Although originally described in men from India and japan, the disorder is now recognized around the world. The most common presentation is one of an idiopathic, slowly progressive, painless weakness and atrophy in one hand or forearm. The distribution of muscle weakness varies markedly from case to case, but a characteristic feature is that the condition remains limited to only a few myotomes in the affected limb. Muscle stretch reflexes arc invariably hypoactive or absent in muscles innervated by the involved cord segment but are normal elsewhere. UMN signs are not present. Approximately 2 0 % have hypesthesia to pinprick and touch, usually located on the dorsum of the hand. The cranial nerves, pyramidal tracts, and the autonomic nervous system arc spared. Weakness and atrophy may progress steadily for the initial 2-3 years, but approximately 7 5 % of patients have .stabilized within 5 years. I lit arm is affected in approximately 7 5 % ol the patients, whereas the leg is affected in the remaining 2 5 % , Laboratory
Studies
There are no pathognomonic laboratory or electrodiagnostic tests for this condition. Their main purpose is to exclude alternative diagnoses. Motor nerve conduction studies are either normal or reveal only slight reduction in the CMAPs and SNAPs are modestly reduced in up to one third of patients. The needle electrode examination may show some fibrillation and fasciculation potentials and chronic neurogenic motor unit changes are prominent. The C5-to-Tl myotomes are most commonly involved when the arms arc affected. Although benign focal amyotrophy clinically presents as a unilateral disorder, it may rarely involve the opposite side to a minor extent, and careful needle electrode examination may unearth neurogenic changes on the contralateral sitle. Tin scrum creatine kinase (CK) level may be modestly elevated, but other routine laboratory test results are normal. Cervical MKI may reveal segmental spinal cord atrophy or occasionally
DISORDERS OF UPPER AND I.OWFR MOTOR NF.UKONS
an area of increased signal on T2-weighted scans of the cervical spinal cord enlargement. "Incidental" spondylosis and canal stenosis detected by MRI should be carefully evaluated before the diagnosis of benign focal amyotrophy is established. Differential
Diagnosis
Two diseases must be distinguished from benign focal amyotrophy: ALS, which is almost always a relentlessly progressive terminal disease, and M M N , which is treatable. A small proportion of ALS presents as an LMN monomelic disease albeit in an older patient population. It is only with follow-up examination that the more widespread anterior horn cell disorder becomes apparent and UMN signs appear. In classic ALS, the deep tendon reflexes will usually become abnormally brisk even in the presence of severely weak and atrophied muscles. The generalized widespread nature of motor neuron involvement, as detected on EMG, can distinguish ALS from the segmental motor neuron involvement of benign focal amyotrophy. The slowly progressive focal weakness that is distinctive of benign focal amyotrophy may also be the presenting picture of MMN, but detailed motor nerve conduction studies and serum tests for elevated titers of anti-GM! antibodies can differentiate these two conditions. Cervical or lumbosacral radiculopathy may also appear in a manner somewhat akin to benign focal amyotrophy. However, radicular pains and sensory impairment are typical of radiculopathies. Neuralgic amyotrophy/ Parsonage Turner syndrome is typically heralded by severe pain before the onset of weakness and wasting in the distribution of predominantly motor nerves derived from the brachial plexus. It may also involve selected sensory nerves. Most cases arc monophasic and do not progress over years as does benign focal amyotrophy, although hereditary neuralgic amyotrophy can present as recurrent bouts of brachial plexopathy. Cervical syringomyelia or a benign tumor involving nerve roots or the spinal cord may also cause progressive weakness in a monomelic fashion. Careful EMG studies and neuroimaging should differentiate these diseases. Treatment The term "benign" in benign focal amyotrophy is used to distinguish it from the "malignant" motor neuron disease "['able SO.7:
1U7
as seen in ALS. Although this condition is certainly not life threatening, it still seriously impairs motor function in the involved extremity. Supportive care consisting of physical and occupational therapy and effective use of assistive devices (splinting and braces) is the main treatment component. Tendon transfers can be considered in selected patients with focal weakness in a muscle group whose function is crucial for certain activities of daily living.
Infantile and Juvenile Spinal Muscular Atrophy The incidence of infantile and juvenile SMA is estimated to be I in 6000-10,000 births; SMA is one of the most common genetic causes of death and disability7 in childhood. It is inherited by autosomal recessive transmission, with a gene frequency in the general population of about 1 in 80. Autosomal dominant childhood SMA is rare and probably accounts for less than 2% of all childhood cases. X-linked SMA associated with arthrogryposis and bone fractures has also been described. Traditionally, SMA is classified as one of the three types based on the age at onset: SMA type 1 (infantile SMA or Werdnig-Hoffmann disease); SMA type 2 (intermediate SMA); and SMA type 3 (juvenile SMA or Kugel berg- Welander disease) (Nicole et al. 2002) (Table 80.7). Genetics and Etiology Al! three types of autosomal recessive childhood SMA have been mapped to chromosome .SqlL2 - 5 q l 3 . 3 , which suggests that they are allelic disorders. The normal 5q region on each chromosome contains two inversely homologous copies of the survival motor neuron (SMN) gene, termed SMN1 (t.elomeric) and $MN2 (centromcric). The 5q region also contains the neuronal apoptosis inhibitory protein (NAIP) gene, the p44 gene (encoding a subunit of the basal transcription factor, TKI1H), and the H4F5 gene. It has recently been shown that SMN1 is the SMA gene and that the severity of SMA relates to the dosage of SMN1 inherited by the patient. The SMN1 protein is functionally absent in the vast majority (95-98%) of cases of SMA, and small amounts are present m the remaining few percent. The SMN2 gene, which is unique to humans, is characteristically present in all patients (although up to 5% of the normal population may have loss of this gene). Although mutations in the .SMN/ gene
Childhood and adult spinal muscular atropines
SMA type
Age at onset
Survival/prognosis
Inheritance
Defective gene
Infantile SMA (Werdnig-Hoffmann) Intermediate SMA Juvenile (Kugel berg-We lander) Adult-onset SMA
Birth to 6 mo Before IN mo After 18 mo After 20 yt
Death by 2 yr old No walking, adulthood Adulthood Slow progression
AR AR AR AR
SMN gene SMN gene SMN gene Unknown
AR ~ autosomal recessive; SMA = spinal muscular atrophy; SMN = survival motor neuron.
223S
NEUROLOGICAL DISEASES
produce the disease, the clinical phenorype is related to the expression of SMN2. More copies of SMN2 are present in patients with milder disease than in those with severe disease. SMN is a ubiquitously expressed 38-kd polypeptide that is important in the processing of the primary transcripts of other genes. It is associated with both nuclear and cytoplasmic complexes involved in messenger RNA splicing and interacts with other proteins, such as fibrillarin, which arc important in the regulation of ribosomal RNA processing and modification, and p53, which is important in regulation of the cell cycle. Within the nucleus, SMN1 forms macTomolccular complexes with other nuclear proteins such as gemin 2, 3, and 4, which are important in the assembly of spliceosomal small nuclear ribonucleoproteins. Recent research using transgenic animal models indicates that impaired production of macromolecular complexes may lead to motor neuron degeneration. It has yet to be discovered why human spinal motor neurons are selectively vulnerable to SMN1 protein deficiency. Certainly SMN is heavily expressed in the nucleus and cytoplasm of spinal motor neurons but is also expressed in all tissues. Perhaps selective motor neuron vulnerability reflects the absence of a vital interaction with other proteins important in RNA processing that are also heavily expressed in motor neurons and axons. SMN protein is obviously vital for normal cellular function. In mice, which only have one SMN gene, complete absence of SMN protein is lethal at the embryonic stage. Humans, however, are never completely without at least one SMN copy on one chromosome. In human SMA, it is possible that SMN2 protein is able to compensate for the loss of SMN1 in all tissue types except spinal motor neurons, where only partial protection is afforded. Incomplete compensation may be due to the slight difference in coding sequence between SMN'i and 5MN2; there is a cytosine-thymine change in the coding sequence for exon 7. Because of this change, 90% of the SMN2 transcript lacks exon 7 and the resulting protein is unstable and rapidly degraded. In the complete absence of SMN1 therefore, only 10% of normal SMN2 protein may be available to bear the entire cellular burden. Thus increasing the copy number of SMN2 in the cell should reduce the severity of disease. Clinical
features
Spinal Muscular Atrophy Type 1, Infantile Form (WcrdnigHoffmann Disease). The disease begins at or before birth or within the first few months of life. By definition, children with SMA type 1 are never able to sit without support and death from respiratory failure and pneumonia usually occurs before age 2 years. About one third of mothers notice decreased fetal movements toward the end of the pregnancy. The symptoms include severe hypotonia, a weak cry, respiratory distress, and absent head control, as evidenced by an inability to lift the head when placed prone
and severe head lag when the infant is pulled from a supine to a seated position (a "floppy" baby) (Figure 80.1). The baby's posture at rest also takes a characteristic "frogleg'' position, with the thighs externally rotated and abducted and the knees flexed. Limb weakness is severe, generalized, and worse proximally. The infant is unable to sit and raise its arms or legs from the examining table, but there may be antigravity movements of the hands and flickering movements of the feet. Muscle stretch reflexes are usually absent and the sensory examination is normal. Contractures usually do not develop in the early phases but may develop after several months of immobilization. Bulbar muscle weakness makes feeding laborious, causes a continuous gurgling, and eventually leads to aspiration pneumonia. Fasciculations of the tongue are reported in about 5 0 % of affected infants. In contrast to bulbar and extremity muscles, the facial muscles are only mildly affected, if at all, giving these children an alert expression. Fxtraocular movements are always normal. Intercostal muscles are severely weakened but diaphragmatic strength is preserved. This dysequilibrium of ventilatory muscle function causes outward flaring of the lower ribeage and gives rise to a bell-shaped chest deformity. Spinal Muscular Atrophy Type 2 (Intermediate Form; Chronic .Spinal Muscular Atrophy). The signs and svmp toms of SMA type 2 usually begin before the age of 18 months. Although the symptoms may be present at birth, an insidious progressive weakness occurs during the first year of life and delayed motor milestones are often the first clue to neurological impairment. Both parents and physicians commonly observe a fine hand tremor, which also suggests the diagnosis. The distribution, pattern, and progression of weakness are similar to that found in SMA type 1, but the type 2 disease is quantitatively much milder and progression is slower than in type i. Most children eventually are able to roll over and sit unsupported, but they rarely achieve independent walking, In the sitting position, weakness of trunk muscles produces a characteristic rounded kyphosis, and as the shoulders weaken, the child becomes immobilized and wheelchair bound. Contractures of the hips and knees, clubfoot deformities, severe scoliosis, and dislocation of the hips may eventually develop. Observation of the fingers may reveal fine, small-amplitude involuntary movements called minipolymyoclonus. The long-term prognosis varies markedly; some die in childhood because of respiratory failure, but many others survive into the third or fourth decade of adulthood. Spinal Muscular Atrophy Type 3, Juvenile Form (Kugelberg-Welander Disease). The onset of the juvenile form of SMA is typically after 18 months of age (usually between 5-15 years) and usually presents with difficulty in walking. As weakness in hip-girdle muscles increases, the child develops a waddling (Trendelenburg's) gait, with an
DISORDERS OF UPPER AND LOWER MOTOR NEURONS
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FIGURE 80,1 A 6-monrh-old baby with Werdnig-Hoffmann disease. (A) The baby has a typical "frogleg" posture. The mouth is triangular, and the facial expression suggests facial weakness. (B) On sitting, the baby cannot sustain his head upright. (C) When the baby is pulled by the arms, the head falls back. (D) When the body is held supine, the head and extremities drop by force of gravity, and there is no active body motion. (Courtesy Neil Friedman, Cleveland Clinic Foundation.)
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NEUROLOGICAL DISEASES
exaggerated lumbar lordosis and trouble climbing stairs. As the weakness progresses, the patient starts using a Gowers' maneuver to arise from lying supine on the floor. Pseudohypertrophy of the calf muscles is sometimes reported, but this may be an illusion resulting from relative preservation of calf muscles as compared to thigh muscles. The disorder has an appearance not unlike a limb-girdle muscular dystrophy, but the pattern of muscle involvement is often somewhat different. Eventually, wasting and weakness of the neck, shoulders, and arms develop, but weakness in the lower extremities is nearly always more severe than in the upper extremities. Fasciculations are more prominent than in SMA-1 and SMA-2 and a fine action tremor is common. Reflexes are uniformly reduced or absent and the sensory examination is normal. The clinical course of SMA-3 is one of slowly progressive limb-girdle weakness, but there may be long periods of stability that last for years. The eventual degree of disability is difficult to predict. In general, if onset is before the age of 2 years, it is likely that the patient will be unable to walk by the age of 15 years and most patients will require a wheelchair by the time they reach their mid-thirties. However, some patients remain ambulatory for as long as 30 years after the onset of illness. Laboratory Studies. The first-line investigation is molecular genetic analysis to identify mutations in the SMN gene on chromosome 5q and no further workup is necessary if there is a mutation of SMN1 in the correct clinical setting. However, if a mutation of SMN1 is not detected in a patient with a clinical picture consistent with SMA, one can assay for the combination of a deleted SMN allele on one gene and a small mutation on the other. It should be remembered that not all SMA is related to chromosome 5cj region abnormalities; some cases are X-linked or autosomal dominant and the genes have yet to be identified. If SMA is the suspicion, it is appropriate to carry out the more traditional tests to help confirm the diagnosis. Serum CK may be elevated to 10 times normal levels in SMA-3 but is typicall; normal in the otk-r two types. i;.l)X is valuable in supporting the diagnosis, although it may be technically limited by the need to carry out the test under conscious sedation in a small infant or child. CMAPs may be reduced in amplitude, but conduction velocities and sensory nerve conduction study results are normal. The needle electrode examination may reveal evidence of acute denervation in the form of fibrillation potentials and positive sharp waves, along with fasciculation potentials and evidence of motor unit remodeling due to a chronic process of denervation and reinnervation. Reduced recruitment of large, polyphasic motor units is therefore characteristic, although full voluntary activation may be hampered by sedation. Complex repetitive discharges are an electrodiagnostic feature of SMA-3. Muscle biopsy can confirm the diagnosis of infantile SMA because the histological changes are
highly distinct: Sheets of rounded, atrophied type 1 and 2 muscle fibers are present. A highly characteristic pattern is grouped fascicular atrophy, that is, entire fascicles or groups of fascicles are atrophied, whereas neighboring fascicles (often containing almost entirely type 1 fibers) are composed of hypertrophied fibers. In SMA types 2 and 3, EMG and muscle biopsy changes are more fully developed than in type 1, showing clear evidence of acute and chronic denervation. It is important to remember that long-standing dencrvating disorders, such as childhood SMA, can he complicated by secondary myopathic changes that include fiber size variability, fiber splitting, internal nuclei, and fibrosis. Differential
Diagnosis
For SMA-1, all causes of infantile hypotonia must be excluded including Pompc's disease, centronuclear myopathy, ncmaline myopathy, congenital muscular dystrophy, central core disease, and congenital or infantile myotonic dystrophy. For older children with suspected types 2 and 3 SMA, the differential diagnoses includes myasthenia gravis, various muscular dystrophies, inflammatory myopathies, and a variety of structural, metabolic, and endocrine myopathies. Clinical, laboratory, and muscle biopsy features usually distinguish these disorders with relative ease. Treatment No disease-specific pharmacotherapy is available for SMA. Future therapies may be focused on increasing the expression of protective SMN2 gene product or stabilization of SMN1 exon 7. It may also be possible to design therapies that are based on the protein interactions of SMN1 once these have been further clarified. As with several other neurodegenerative disorders, it may even be possible to use pluripotent stem cells to replace dead or dying neurons and muscles. However, the mainstay of current treatment is focused on supportive care, including physiotherapy, respiratory care, nutritional support, orthotics, and orthopedic interventions. Typical WerdnigHoffmann disease is almost uniformly fatal by age 2 years. However, because some affected infants survive beyond infancy and live into childhood, aggtessive management including physiotherapy and respiratory therapy is essential in all cases. The management objectives in young children with the intermediate form arc twofold: (1) maintaining active mobility and independence as long as possible and (2) preventing the development of contractures and kyphoscoliosis. Any devices, even a scooter board, should be considered to maintain mobility. Because all patients invariably become wheelchair bound, they should be fitted for an electric-powered wheelchair. However, the timing of wheelchair use is critical because its use hastens the development of contractures and scoliosis. Stretching
DISORDERS OF UPPER AND LOWER MOTOR NEURONS
exercises in major joints should be part of the patient's daily routine. Patients with SMA have normal or increased intelligence. They attend school, and when they reach adulthood often work outside the home and live independently. A wellcoordinated multidisciplinary approach is essential when attempting to optimize residual function, especially during periods of disease progression. Physical therapy for stretch exercise and chest clapping, occupational therapy for maintaining activities of daily living, an evaluation at a seating clinic to obtain the best wheelchair, and orthopedic evaluation to delay or if necessary correct scoliosis are among the most important aspects of management. It is also vital to pay attention to the emotional well-being of the patient, particularly during adolescence. Maintaining an upright position delays the development of scoliosis. Therefore a specialized evaluation for wheelchair at a comprehensive seating clinic is critical. A back brace may also potentially delay the development of scoliosis, but bracing in these patients is still controversial. Bracing probably does little to retard the onset or progression of scoliosis and may actually impair function in some patients because bracing reduces spinal flexibility and tespitatory vital capacity. Potential benefits from bracing include reduced back discomfort and the ability to sit for longer periods. Progressive scoliosis eventually requires surgical correction in most patients with juvenile SMA. In general, surgery should be delayed until growth ceases. However, in some patients who have never ambulated or who lost ambulation very early, surgical intervention for severe scoliosis may be considered even before growth has ceased. Improved aesthetics, :'> il.uu •-•. aiui M;IIN:;: cu:nk>n are among the benefits; however, lack of body flexibility, reduced pulmonary function, and general decline in overall motor function may occur after surgery. Pros and cons for scoliosis surgery must he openly discussed with the patient, although for most the benefits outweigh the disadvantages. Preoperative and postoperative physiotherapy and occupational therapy assessments are critical steps for the patient who contemplates spinal fusion for progressive scoliosis in SMA (Mitsumoto et al. 1997).
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gene. However, this standard test is not absolutely accurate in the setting of genetic variations. For example, up to 3% of the population may have a duplication of the SMN1 gene on one chromosome and none on the other and it may require a hybrid technique to identify this variant. In those rare individuals, whose SMA is due to spontaneous de novo mutations in the SMN1 gene, the parents will have normal SMN1 genes. Childhood Autosomal Dominant Spinal Muscular Atrophy. Autosomal dominant SMA is exceedingly rare, accounting for less than 2% of all childhood cases. Because of the rarity of this disorder, the natural history of autosomal dominant SMA k nm WL'.I Jc--;icd. i'ypii.illv, juvenile autosomal dominant SMA is a relatively benign disease. Arypical Spinal Muscular Atrophies Fazio-Londe Disease (Progressive Bulbar Paresis of Childhood). Fazio-Londe disease is a rare form of sporadic, autosomal dominant, or autosomal recessive progressive facial and bulbar palsy. Affected children are normal at birth but develop progressive bulbar palsy (PBP) and eventual respiratory failure with little or no evidence of involvement of other motor neurons and with usually normal extraocular motility. The differential diagnosis includes a structural brainstem lesion, myasthenia gravis, and the Miller Fisher variant of Guillain-Barre syndrome. Accurate diagnosis is important because of the implications for prognosis and treatment.
Adult-Onset Spinal Muscular Atrophy (Spina) Muscular Atrophy Type 4) True adult-onset disease accounts for probably less than 10% of all cases of SMA with an estimated prevalence of 0.32 in 100,000. By definition, the symptoms of adult-onset SMA must begin in patients older than 20 years. The mean age at onset is the mid-thirties. The course is relatively benign; only a small proportion of patients become wheelchair bound over 20 years. The clinical presentation is very similar to that of SMA-3.
Genetic Counseling and Prenatal Diagnosis Inheritance and SMA is one of the most devastating diseases of childhood and the parents of affected children and their relatives should receive genetic counseling, including determination of carrier status of .SMN genes. The available carrier detection test determines the SMN I gene dosage in an individual and is best catricd out in a family where an .SMN deletion has been found previously in an affected individual or for an individual who is about to marry a known carrier with a known .S'MN deletion. Noncarriers will have a single copy of the normal SMN1 on each chromosome, whereas carriers will have only one normal and one mutated SMN
Genetic
Abnormalities
Although autosomal recessive inheritance accounts for almost all (98%) of childhood SMA cases {type 1, 2, and 3), it constitutes only 7 0 % of adult-onset SMA cases. Homozygous deletions in the 5MNJ gene responsible for childhood SMA are only rarely found in adult-onset SMA; homozygous deletions of the SMN2 gene may be more commonly identified (Moulard et al. 1998). The remaining adult-onset SMA cases are autosomal dominant and are not linked to chromosome 5. This latter group is rather heterogeneous, and in time, it may well transpire that
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NEUROLOGICAL DISEASES
it represents a series of quite separate disorders sharing certain SMA-like phcnotypical similarities.
have a distribution of weakness reminiscent of the limbgirdle i m a c u l a r dysl n o l i it's, lead hi:-, ID i'.n- oldfi term nl
pscudomyopathic SMA. Clinical Features Laboratory The characteristic clinical presentation is that of a slowly progressive limb-girdle weakness leading to difficulty in walking, climbing stairs, and rising from a chair or the floor. Fasciculations are an important finding and occur in 7 5 % of patients. Quadriceps muscle weakness is often a prominent feature. Muscle cramps may occur but are not a prominent feature. Bulbar signs and bony deformities such as scoliosis arc rare and respiratory muscles are not affected. Although the distribution of muscle weakness is usually confined to limb-girdle muscles, it can be generalized or even distal predominant (Figure 80.2). Many cases
Features
Both serum CK and aldolase arc typically elevated to levels less than 10-fold the normal values. Motor nerve conduction studies may reveal normal velocities and reduced CMAPs in the presence of normal SNAPs. Needle electrode studies show marked chronic neurogenic motor unit changes and modest, if any, evidence of acute denervation. Myopathic changes are also common. Fasciculation potentials may be found in involved muscles. Muscle biopsy typically shows evidence of a markedly chronic dencrvating disease process similar to that described in SMA-3, but with frequent changes of myopathy, with marked variation in fiber size, split fibers, necrotic fibers undergoing phagocytosis, and regeneration, Differential
Diagnosis
Limb-girdle muscular dystrophy may be difficult to distinguish from adult-onset SMA; it can be autosomal recessive, is often adult onset, and affects predominantly proximal muscles. The pattern of muscle weakness is often a pointer to the diagnosis; for instance, in adult-onset SMA, the triceps muscles may be weaker than the biceps, the opposite of the situation in iimb-girdle muscular dystrophy. Although muscle biopsy reveals a primary myopathy rather than a neurogenic process, one should be aware that some degree of secondary myopathic changes could occur in longstanding SMA. Immunohistochemistry and Western blotting can now be performed on muscle biopsy to distinguish SMA from Duchenue's and Becker's muscular dystrophy and the various limb-girdle muscular dystrophies with known protein deficiency, including sarcoglycanopathies, calpainopathies, and dysferlinopathies (Piccolo ct al. 2002). Other myopathics may also need to be considered including polymyositis and adult-onset acid maltase deficiency.
FIGURE 80.2 A patient with mild adult-onset proximal spinal muscular atrophy and marked shoulder-girdle muscle atrophy. Note subluxation at both shoulder joints and marked deltoid muscle atrophy.
CIDP may mimic SMA because of chronic proximal muscle weakness, but the tendon reflexes are usually diffusely absent in CIDP and some are preserved in SMA. Electrodiagnostic studies reveal a demyelinating polyradiculoneuropathy and CSF protein levels arc increased in CIDP. It may be very difficult to distinguish between distalpredominant adult-onset SMA and hereditary motor and sensory neuropathy type 2 (neuronal form of CharcotMaric-Tooth disease). Motor-predominant variants, such as hereditary motor neuronopathy type 5 (HMN-5), may present with a slowly progressive LMN-prcdominaut disorder affecting distal greater than proximal limb muscles. In H M N - 5 , transcranial magnetic stimulation studies may reveal prolonged central conduction times along motor pathways, a finding that is mirrored by brisk deep tendon reflexes in many cases. EDX characteristically shows
DISORDERS OF UPPER AND LOWER MOTOR NEURONS changes most consistent with a disorder of anterior horn cells, and sensory nerve studies are often normal (AuerGrumbach M et al. 2000). Hex-A deficiency in infants is well known as the cause of Tay-Sachs disease, a rapidly terminal gangliosidosis. The same enzyme deficiency in adults (although the type of missensc mutation differs from the infantile form) causes a very different disease, which can have a similar phenotype to adult-onset SMA, although later other neuronal systems often become involved. Although most reported cases have been in Ashkenazi Jews, adult forms clearly occur in other populations. In the absence of a family history of SMA, it can be most difficult to distinguish adult-onset SMA from the PMA variant of ALS. However, several features distinguish between these conditions. Adult-onset SMA progresses very slowly, whereas PMA progresses relatively rapidly (though usually slower than classic ALS). Adult-onset SMA is mainly associated with muscle biopsy and EDX evidence of a markedly chronic disease, whereas PMA findings are consistent with more acute denervation and thus more modest evidence of neurogenic motor unit remodeling. Treatment No specific pharmacotherapy is available. Treatment is supportive and symptomatic. Generally, adult-onset SMA progresses very slowly, and patients often learn how to cope with the disease quite well. For patients who engage in physical work, appropriate vocational rehabilitation may help patients accommodate themselves to their eventual physical disabilities.
Kennedy's Disease (X-I.inked Recessive Bulbospinal Neuronopathy) In 1968, Kennedy and colleagues reported a new X-linked recessive SMA with bulbar involvement and gynecomastia. The primary pathology was thought to be in the l.MNs, but sensory system involvement was later recognized, which led to a new term, bulbospinal neuronopathy. Recent progress in molecular genetics has shown Kennedy's disease to be a trinucleotide repeat disease. Though rare, it is more common than adult-onset SMA. Clinically, Kennedy's disease can be easily mistaken for ALS, and thus diagnosis of the disease is important because it has a much better prognosis than ALS (Table 80.8). Pathogenesis In 1991, La Spada and colleagues found the gene abnormality responsible for Kennedy's disease: a cytosincadenine-guanine (CAG) trinucleotide repeat expansion on the andtogen receptor gene located on the X chromosome. In normal individuals, the repeats range from 17-26 in this coding region, whereas in patients with Kennedy's disease,
Tabic 80.8:
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Characteristic features of Kennedy's disease
Pathogenesis X-linked recessive inheritance Abnormal CAG expansion in the gene encoding androgen receptor protein Neurological manifestations Slowly progressive limb-girdle muscle weakness Slowly progressive moderate bulbar dysfunction Muscle cramps and prominent faseiculan'ons Facial faseiculations S y stem i e ma n i festa ti on s Gynecomastia (60-90%) Endocrine abnormalities (testicular atrophy, feminization, infertility) Diabetes mellitus Laboratory studies Markedly abnormal sensory nerve conduction studies Hlevated serum creatine kinase Abnormal sex hormone levels Ahnormal CAG repeats in the androgen receptor gene
the repeats range from 4 0 - 6 5 . There are two independent components to the symptoms of Kennedy's disease, one androgen dependent and the other androgen independent. "Fhe gynecomastia and testicular atrophy seen in Kennedy's disease may be associated with the classic function of the androgen receptor, and thus the severity of symptoms might be related directly to the receptor's affinity for androgen. Studies of cultured scrotal skin fibroblasts found that direct high-affinity- d ihyd rotes to ste rone binding is decreased in some patients. The abnormal expansion of CAG repeats involves the first exon, an amino-terminal transactivating domain of the androgen receptor protein, The expansion of the CAG repeat in an androgen receptor causes a linear decrease in the transactivation function but does not completely eliminate androgen receptor activity. The residual androgen receptor activity is sufficient to ensure normal development of male primary and secondary sexual characteristics, as evidenced by the fact that affected men arc phenotypically male and usually fertile. The subtle decline of androgen receptor transactivation may eventually lead to the loss of integrity of certain tissues that require continuously high androgen levels. Continuous androgen activity is probably required in spinal and bulbar motor neurons; for example, androgens are crucial for normal male development of motor neurons in the rat spinal nucleus of the bulbocavetnosus and for regenerating facial motor neurons in rats and hamsters. Therefore continuous androgen receptor function may be crucial to maintain normal motor neuron function throughout life. As with most other trinucleotide repeat expansion disorders, such as Huntington's disease and several SCAs, the trinucleotide repeat expansion mutation appears to confer a toxic gain of function on the gene product rather than a loss of function. In fact, complete absence of the androgen receptor leads to an entirely different disorder
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NEUROLOGICAL DISEASES
called andmgen-insensitwity syndrome. The mutant androgen receptor Ic.uU to an altered reeeptor-DNA interaction or receptor-protein interaction that interferes with neuronal function. The CAG repeat encodes an unusually long polyglutamine tract in the androgen receptor protein, which appears to alter the normal protein moiety resulting in mutant protein aggregation. Indeed, ubiquitinated neuronal inclusions have been identified in this disorder, and it has been suggested that these mutant protein aggregates interfere with proteasomal breakdown of cellular proteins and/or interfere with tubulin mediated cellular transport. Clinical Features Being an X-linked syndrome, this is a disorder of men who remain largely asymptomatic until after age 30 years. Prominent muscle cramps, muscle twitching, difficulty walking, and limb-girdle muscle weakness are the characteristic symptoms. Dysarthria and dysphagia occur in fewer than half the patients. Muscle weakness is typically LMN in type, involving the proximal hip and shouldergirdle muscles, and is associated with decreased or absent reflexes, muscle atrophy, and occasionally, calf pseudohypertrophy. Kennedy's disease usually causes no respiratory muscle weakness. Coarse muscle fasciculations can be prominent in the extremities and trunk and hand/finger tremor is not unusual. Facial and particularly perioral fasciculations are highly characteristic, if not pathognomonic, of this disease, being present in more than 9 0 % of patients. The tongue shows chronic atrophy, often as a longitudinal midline furrow. Although weakness in the facial and tongue muscles is nearly always present, bulbar symptoms are less often reported. Neurological examination of the sensory system may reveal only modest impairment. Gynecomastia is one of the unique features of Kennedy's disease and is found in 6 0 - 9 0 % of patients (Figure 80.3). Fndocrine abnormalities include testicular atrophy, feminization, and infertility in approximately 4 0 % of patients. Diabeies mcllinis is also reported in II) 20% ot patients. It has recently been recognized that female carriers may manifest subtle neurological deficits such as late-onset btilbat dysfunction. An inverse relationship exists between the number of CAG repeats and the age at disease onset. The greater the number of the repeats, the younger the age at onset. This is an example of genetic anticipation. However, the number of repeats has no correlation with other features, such as the severity of weakness, serum CK level, and presence or absence of gynecomastia, impotence, or sensory neuronopathy. The phenotypical expression varies markedly within and among the families. The course is one of slowly progressive LMN disease. If bulbar dysfunction is severe, the prognosis becomes less favorable (Mitsumoto et al. 1997).
FIGURE 80.3 A man with X-linked recessive bulbospinal muscular atrophy (Kennedy's disease) showing gynecomastia. Laboratory
Studies
Molecular genetic testing is available to identify the abnormal expansion of the CAG repeat in the exon 1 ol the androgen receptor gene on the X chromosome. CK levels may be elevated as high as 10 times normal. Serum androgen levels are either normal or decreased, whereas estrogen levels are elevated in some patients. The estrogento-androgen ratio is also increased in some patients; however, there is no consistent finding regarding sex hormone levels. EMG is highly useful. Motor nerve conduction study results are generally normal, although one third of the patients have reduced-amplitude CMAPs. Needle electrode examination of these patients shows prominent chronic denervation changes in motor units, but evidence of acute denervation is usually only modest. One of the most unique abnormalities in Kennedy's disease is EDX evidence consistent with a sensory neuronopathy. Another unique change is the presence of prominent fasciciilation potentials in the face (especially in the perioral region) and limbs. Muscle biopsy shows modest denervation, prominent reinnervation, and fiber type grouping, that is, histological
DISORDERS OF UPPER AND LOWER MOTOR NEURONS
findings consistent with those of a chronic SMA type of denervation. Sural nerve biopsy usually reveals a marked loss of myelinated fibers and the replacement of lost nerve fibers with connective tissue. Differential
Diagnosis
The clinical features, such as progressive limb-girdle weakness, bulbar signs, muscle cramps, and prominent fasciculations, resemble those of ALS, but a careful physical examination should provide sufficient clues to distinguish one from the other. Generally, ALS progresses rapidly, whereas Kennedy's disease is a largely indolent disorder. The EDX in Kennedy's disease shows abnormal sensory nerve conduction studies, which is highly unusual for any motor neuron disease, particularly ALS. Kennedy's disease may also be easily mistaken for adult-onset SMA because of the slowly progressive limb-girdle weakness in both, but bulbar involvement is very unusual in SMA. Hereditary sensorimotor neuropathy, limb-girdle dystrophy, or facioscapulohumeral muscular dystrophy also may mimic Kennedy's disease. Careful EDX studies and muscle or nerve biopsy analyses should distinguish these disorders. Ultimately, a molecular gene study to identify the abnormal CAG repeats in the androgen receptor gene will yield the answer. Manifested Carrier The female children of an affected male patient are all obligate carriers, as is the mother, except in the rare case of a new mutation. Male children of affected individuals cannot inherit the mutant gene on the X chromosome. Female siblings of an affected patient have a 5 0 % chance of carrying the affected gene on the X chromosome. Through a process know ii .is skeined X chromosome inactwalion (lyoniziition), female carriers can present with neuromuscular symptoms, such as exertional muscle pain, cramps, and late-onset bulbar dysfunction, and the EDX may detect mild chronic denervation in both upper and lower limb muscles. Treatment Supportive and symptomatic therapy is the key to treatment, as outlined in the section on adult-onset SMA. Muscle cramps may be problematic but may he relieved by quinine sulfate, baclofen, or vitamin E. Patients with symptomatic diabetes require appropriate medical management. In Kennedy's disease, dysarthria and dysphagia may cause marked disability. Although severe loss of bulbar function is rare in Kennedy's disease, speech therapy and appropriate communicative devices should be offered when appropriate. Careful nutritional management is also important. Enteral feeding provided via gastrostomy is the most effective and practical means to meet nutritional and fluid requirements. Genetic counseling is important for patients, potential carriers, and male siblings.
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Progressive Muscular Atrophy PMA, first described by Aran in 1850, is a disease that exclusively involves LMNs during its entire clinical course and comprises approximately 8% of all adult-onset motor neuron diseases, h has been questioned whether ['MA is an independent disease or represents one end of the spectrum of ALS. However, the recent description of a rapidly progressive PMA presentation in some cases of FALS and the finding of pyramidal tract pathology in some autopsied sporadic PMA cases lends support to the conclusion that PMA is indeed an ALS variant (Cervenakova ct al. 2000). For clinical therapeutic research trials, PMA must clearly be distinguished from ALS and is nor even included in the revised El Escorial criteria. However, PMA can he considered identical to ALS in all aspects of day-to-day patient care. Etiology All hypotheses about the cause of ALS are also applicable to PMA (see Etiology, under Amyotrophic Lateral Sclerosis, later in this chapter). Clinical Features By definition, the signs and symptoms of PMA are LMN in type throughout the entire clinical course. During the early stages of the illness, however, whether the disease will evolve into the ALS phenotype is uncertain, because most such cases do eventually develop UMN signs. Thus it is generally agreed that not until 3 years after rhe onset of the disease can one conclude that the disease will not spread to involve UMNs. Although PMA occurs in both sexes, nen arc slightly more often affected than women. The age at onset of PMA is younger than that of ALS, and the disease progresses more slowly so the average survival is longer; in one study, the mean duration of disease was 159 months (Norris et al. 1993). A common presentation is that of focal asymmetrical muscle weakness in the distal extremities with gradual spread to other contiguous muscles. The weakness and muscle atrophy is purely LMN in type and eventually involves both the upper and the lower extremities. A less common presentation is that of proximal rather than distal muscle weakness. Bulbar and respiratory involvement eventually develops but is not as common in the early stages as in classic "spinal" ALS. Laboratory
Studies
The CK level can reach 10 times normal, particularly when patients are physically active. Patients with PMA do not have high titers of anti-GM[ antibodies. The EMG examination reveals findings consistent with a widespread disorder of anterior horn cells and is useful to exclude other
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NEUROLOGICAL DISEASES
diagnostic possibilities such as CIDP, M M N , or myopathy. Muscle biopsy will show denervation atrophy but is usually unnecessary unless the clinical features are unusual enough to suggest an alternative diagnosis. Differential
Diagnosis
PMA is usually a fatal disease and has no cure. Therefore the diagnosis of PMA should be made carefully after all other potentially treatable or definable diseases are excluded. In a recent review, 17 of 89 patients originally diagnosed with PMA were subsequently shown to have alternative diagnoses, including M M N , CIDP, inflammatory myopathy, and myasthenia gravis (Visscr ct al. 2002), M M N may present with focal and asymmetrical weakness in the absence of UMN signs but may be distinguished by the relative disparity between weakness and atrophy, by typical electrodiagnostic features, and by the presence of anti-ganglioside antibodies. CIDP is readily differentiated on the basis of clinical and electrodiagnostic findings of sensory involvement, high CSF protein levels, and response to immunotherapy. Important clues that should lead one to suspect inclusion body myositis (IBM) are elevated serum CK to levels more than expected in typical PMA and a selective weakness in wrist flexors, finger flexors, and quadriceps muscles. EMG in IBM should show evidence of a primary necrotizing myopathy with or without additional neurogenic changes, but quantitative EMG may be required to clearly identify the myopathic nature of this disorder (Dahby et al. 2001). Muscle biopsy characteristically reveals rimmed vacuoles. Adult-onset SMA is a far more indolent disorder than I'M A and the very chronic process of denervation and re in nervation in SMA leads to fiber type grouping in muscle biopsy, which is not a characteristic feature of the I ess-protracted PMA. It is important to carry out regular follow-up examinations on patients with PMA, to search for signs of UMN involvement that indicate the diagnosis of ALS that has a rather worse average prognosis (Mirsumoto et al. 1997), Treatment The treatment of PMA is identical to that of ALS, as summarized later in this chapter.
Subacute Motor Neuronopathy in Lymp ho proliferative Disorders A subacute, progressive, and painless motor neuron syndrome may rarely develop in patients who have Hodgkin's and non-Hodgkin's lymphoma with or without a paraproteinemia (Rudnicki and Dalmau 2000). Although UMN signs may develop in a small number of patients, an LMN syndrome is typical, with patchy, asymmetrical lower extremity predominant muscle weakness and wasting being the
most common presentation. Neuropathology shows a loss of anterior horn cells and ventral root nerve fibers; some have evidence of inflammation in the anterior horns of the spinal cord. In some patients, the disease may be relatively benign; the rate of progression of muscle weakness and atrophy tends to slow down with time, and in rare instances, the motor syndrome may respond to treatment of the underlying lymphoproliferative disorder. However, the prognosis appears to be less favorable in those who develop a combined UMN and LMN disorder. Twenty percent of all cases so far reported with motor neuron presentations in the setting of lymphoproliferative disease had myeloma or macroglobulinemia (Rowland and Shneider 2001). The pathogenesis of this ALS-likc disorder is undetermined, but an immune mechanism may be at play; small patient series and case reports reveal that some patients who develop this LMN syndrome may have various autoantibodies (such as antisulfatide antibody), paraproteinemia, increased CSF protein, and/or oligoclonal bands.
Postirradiation Lower Motor Neuron Syndrome Radiation directed to the lumbar paravertebral area for the treatment of testicular cancer can cause a pure LMN syndrome in the lower extremities that first appears many years after the irradiation. Sensory abnormalities and sphincter dysfunction are rare, and the EDX findings are consistent with a disorder of the cauda equina (the SNAPs are spared). The disease usually progresses over the first few years after symptom onset but subsequently becomes arrested (Bowen et al. 1996).
DISORDERS OF B O T H UPPER AND LOWER M O T O R NEURONS Amyotrophic Lateral Sclerosis ALS is a neurodegenerative disorder of undetermined etiology that primarily affects the motor neuron cell population. It is progressive and most patients eventually succumb to respiratory failure. The first detailed description in the literature was by Jean Martin Charcot in 1869, in which he discussed the clinical and pathological characteristics of "la sclerose laterale amyotrophique," a disorder that affected both UMNs and LMNs (Goetz 2000). ALS is known by several other names including Charcot's disease, motor neuron disease, and in the United States, "Lou Gehrig disease" in remembrance of the famous "Iron Horse" of baseball who was diagnosed with ALS in the late 1930s. The World Federation of Neurology Research Group on Neuromuscular Disorders has classified ALS as a disorder of motor neurons of undetermined cause, and several variants are recognized. Included in this group are
DISORDERS OF UPPFR AND LOWER MOTOR NEURONS
PLS and PBP. As previously mentioned, PMA is also thought to be a variant of ALS despite its exclusion from cutrcnt clinical research trial criteria. It is important to recognize that ALS is a progressive dynamic disorder. Some cases present with the classic combination of UMK and LMN signs, but others may be UMN onset, LMN onset, or bulbar onset and only later develop signs of involvement of the other parts of the motor system (Table 80.9). Between 5-10 ' . of A IS is familial rathe:" than sporadic. the most common inheritance pattern being autosomal dominant. Thus one comes across the terms, sporadic ALS (SALS) and FALS. A few other conditions have a phenotypical expression similar to that of ALS including Western Pacific ALS-parkinsonism-dementia complex (PDC) (or Guamanian ALS) and juvenile ALS. The incidence and prevalence rates for non-Western Pacific ALS are surprisingly uniform throughout the world. The incidence is estimated at 1-3 per 100,000 and the prevalence varies from 6-8 per 100,000. Several epidemiological studies have suggested that the incidence of ALS may have increased in the past two decades and that this is a disease-specific finding rather than due to factors telated to better national health care, economic prosperity, or case ascertainment. In sporadic spinal ALS, men are more often affected than women by a ratio of 1.2-1.6:1. Howe vet, several clinical papers have shown that there is a slight female predominance in the bulbar-onset variety and that there appcats to be no consistent pattern of gender predominance in familial forms of the disease. ALS is reported to occur as early as in the second decade of life, but the most common onset is in the patient's early sixties. It is notably rare in the vety oldest segment of the general population, that is, those older than 8.5 years. This has yet to be explained (Mitsumoto, Chad, and Pioro 1997). The mean disease duration from symptom onset to death is approximately 3 years, although some patients live for more than a decade, whereas others may succumb within a matter of a few months. Although no specific environmental factors have been linked with certainty to an increased tisk of ALS, epidemiological research suggested increased morralirv rates for ALS .untnis'. eledrical utility workers who were chronically exposed to electromagnetic fields (Johansen and Olson 1998), Population-based casccontrol studies have also ascertained increased risk in those with a high dietary intake of glutamatc and in smokets (Nelson et al. 2000a, 2000b). A host of environmental trace elements have been evaluated as potential causative agents for ALS including selenium, aluminum, iron, manganese, copper, zinc, cadmium, and lead, but there is no convincing evidence that any one of these plays a major part in ALS pathogenesis, Etiology Significant inroads have been made into understanding the pathogenesis of SALS and FALS. Several hypotheses have
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been put forward, including that of viral infection, activation of the immune system, exogenous toxins, and hormonal disturbances. However, there has been insufficient evidence to implicate any of these as the major cause of motor neuron degeneration in ALS. Perhaps the most significant breakthrough in understanding the cause of ALS (be it sporadic or familial) came in 1993, when Rosen et al. identified mutations in the gene encoding an enzyme called copper/zinc superoxide dismutase (SODl) in patients with FALS. SODl mutations, which can cause elevated intracellular levels of reactive oxygen species, are now identified in up to 2 0 % of all patients with FALS. Most recently, mutations in a gene encoding a novel protein called alsin have been identified in a form of recessively inherited juvenile-onset ALS of North African origin. This ptotein shares structural homology to a guanine nucleotide exchange factor, which suggests a role in altered cell signaling (Shaw 2001). A significant body of basic and clinical research lends strong support to a new theory of ALS pathogenesis, which proposes selective motor neuron damage from a complex chain of injurious events involving excitotoxins, oxidative stress, neurofilament dysfunction, altered calcium homeostasis, mitochondrial dysfunction, enhanced motot neuron apoptosis, and proinflammatory cytokines (Cleveland and Rothstcin 2001). A number of ALS susceptibility genes have also been proposed, mutations of which are known to occur in small ALS populations or individual cases but which do not appear to account for the majority of SALS cases. The focus of the following discussion is on the role of excitotoxins, free radicals, neurofilaments, immune activation, inflammation, and candidate genes as they apply to the pathogenesis of SALS. The role of SOD) mutations and mutant alsin in disease pathogenesis is discussed in more detail in the sections covering FALS and juvenile ALS. Pathogenesis
of Sporadic Amyotrophic
Lateral Sclerosis
Glutamatc Exci to toxicity and Free Radical Injury, Glutamatc, which is the most abundant ftce amino acid in the CNS, is one of the major excitatory amino acid (LAA) neurotransmitters. Glutamatc produces neuronal excitation and participates in many neuronal functions, including neuronal plasticity. In excess, however, it causes neurotoxicity. There are two types of glutamatc receptors: (I) ionotropic and (2) metabotropic. The former is an integral, cation-specific (particularly Ca + ) ion channel type, which is further grouped into two major subtypes depending on receptor characteristics: the N-methyl-Daspartate (NMDA) teceptors and the non-NMDA receptors (AMPA-kainate receptor). Metabotropic receptors are coupled to G proteins and cyclic guanosine monophosphate (cGMP), modulating the production of intracellular messengers and influencing ionotropic glutamate teceptors. In ALS, motor neurons appear to receive the glutamate excitotoxic signal through non-NMDA receptors rather than NMDA teceptors.
2248
NEUROLOGICAL DISEASES
The significance of glutamate excitotoxicity in neurodegencration is strengthened by the observation that exogenous glutamate receptor agonists result in clinically observable neurotoxicity. Lathyrism (see previous section on UMN disease) is associated with chronic neurotoxicity exerted by /3-N-oxalylamino-L-alanine (BOAA), an AMPA receptor agonist. A similar disorder, Konzo, may also be due to glutamatc-mediated damage to cortical motor neurons. An outbreak of food poisoning associated with contaminated mussels that clinically presented with chronic dementia and motor neuron disease was caused by domoic acid, another potent non-NMDA receptor agonist. In patients with ALS, a series of endogenous glutamate abnormalities have been demonstrated; for example, EAA is significantly increased in serum, plasma, and CSF. On the other hand, glutamate in CNS tissue and the glutamare-toglutamine ratio are significantly decreased in ALS. When glutamate metabolism is studied by loading with oral monosodium glutamate, plasma glutamate levels increase to a significantly greater degree in patients with ALS than in healthy patients. These studies clearly support the idea that glutamate excitotoxicity is involved in the pathogenesis of ALS, if not actually the cause. Glutamate is normally released from presynaptic axon terminals into the synaptic cleft where it binds to its receptors causing signal transduction to occur. After signal transduction, interstitial glutamate must be reabsorbed into its main reservoir, the surrounding astrocytic glial cells. This absorption process involves specific transporter proteins known as GI.T (glutamate transporter) or EAAT (excitatory amino acid transporter) proteins, which have been subclassified according to their distribution within cells of the CNS. Among these, the astrocytic glutamate transporter, termed GLT1 or EAAT2, is markedly reduced in the motor cortex and anterior horn cells of patients with ALS, which supports earlier evidence that interstitial or extracellular (including CSF and plasma) glutamate is increased in ALS. Rothstein et al. found intriguing abnormalities in the DNA encoding GLT1 in more than 60% of patients with ALS (predominantly the sporadic form). However, subsequent research suggests that GLT1 does not appear to be a candidate gene for FALS or SALS. Impaired glutamate transport reduces clearance of glutamate from the synaptic cleft, which may leave excessive amounts of free excitatory neurotransmitter to repeatedly stimulate the glutamate receptor and thus allow calcium ions enter the neuron. Excess calcium ions are usually buffered by intracellular calcium-buffering proteins, such as parvalbumin or calbindin, and by mitochondria that may also function as an extra calcium reservoir. Low levels of parvalbumin, calbindin, and altered mitochondrial function have been detected in ALS models. When calcium ion levels exceed this reduced buffering capacity, they may catalyze activity in specific destructive enzymes that are not activated under normal conditions including xanthine
oxidase, phospholipase, and nitric oxide synthase. These enzymes produce ftee radicals, including reactive oxygen and nitrogen species, which cause harmful nitration of tyrosine residues on key neuronal proteins and ultimately may also cause apoptosis. It has recently been proposed that regional differences in the levels of activity of buffering systems and in glutamate receptor subtype expression may explain the selective vulnerability of certain motor neuron pools within the CNS. Immunological and Inflammatory Abnormalities. Several pieces of evidence implicate an immune process in the pathogenesis of ALS. Immune complexes have been identified in gut and renal tissue from patients with ALS. Furthermore, up to .10% of patients with ALS may have a monoclonal gammopathy and fewer than 5% have low-level titers of anti-GMi antibody. Moreover, serum antibodies to [.-type voltage-gated calcium channels have been found in some patients with ALS but not in others. Activated spinal cord microglial cells, elevated inflammatory cytokine levels, and most recently, marked increased expression of cyclooxygcnase-2 have also been found in ALS tissue samples (Yasojima et al. 2 0 0 1 ; Aimer et al. 2002) (Figure 80.4). However, all available immunotherapies, including cyclophosphamide, IVIG, plasmapheresis, corticosteroids, and total lymphoid irradiation, have failed to alter the course of ALS (Murray and Mitsumoto 2002}. Although this might indicate that immune mechanisms are not of primary importance in the pathogenesis of ALS, there is hope that cell-targeted immune therapy and antiinftamnuinry therapy may :v usclal. Neurofilament Dysfunction. Abundant neurofilaments are present in the cytoskeleton of motor axons wrhere they are vital for bi-directional axonal transport. Abnormal axonal spheroids, consisting of neurofi lament-derived material, have been identified in tissue from patients with ALS. Subsequent research shows that abnormally slow axonal transport (referred to as "axonal strangulation") may be important in ALS, perhaps as a result of oxidative stress-induced neurofilament injury (Lamonte et al. 2002). However, it is possible that increased levels of neurofilament may actually represent a protective reaction of the cell body to harmful calcium levels or to other substances. Mutations in the genes for neurofilament subunits appear to confer increased risk for the later development of SALS (Cleveland and Rothstein 2001). The neurofilament heavy chain is thought to be important in the correct spacing of neurofilaments from each other and thus in the regulation n! axonal diameter. In rare cases of SALS (and very rarely FALS), mutations have been found in the heavy-chain gene segment that encodes an amino acid repeat motif. Over express ion of another intermediate motor neuron-specific protein called peripheric may lead to accumulation of toxic intraneuronal aggregates,
as has been demonstrated in patients with SALS and in mice with SOD1 mutations. In fact, selective motor neuron toxicity in the setting of pcriphcrin overexpression appears to occur in mice that lack light subunits, which implies that the light subunit may somehow prevent a harmful interaction between peripheral and other neurofilament subunits. Furthermore, proinflammatory cytokines appear to increase the duration of peripheral overexpression at sites of neuronal injury (Beaulicu, Kriz, and jalien 2002). Susceptibility Genes for Sporadic Amyotrophic Lateral Sclerosis. The survival motor neuron (SMN) proteins are encoded by inversely homologous genes located on chromosome 5q (see Spinal Muscular Atrophy, earlier in this chapter). In one study, no deletions in the SMNl gene were found in SALS (n = 177) or FALS (n = 66), but a pure adult-onset LMN disorder associated with homozygous deletion of the SMN2 gene was described in five cases (Moulard et al. 1998). A French study of 167 patients with ALS revealed that the SMNl gene copy number was abnormal in 16% of cases compared with only 4% of controls, which suggests that the S M N l gene may be a susceptibility factor for ALS (Corcia et al. 2002). Other rare mutations have been identified in patients with ALS, including in the APEX nuclease gene, cytochrome oxidase c subunit gene, the copper chaperone of SOD! gene, and the leukemia inhibitory factor gene. As with the genes for GLT1/EAAT2, neurofilament heavy chains, SMN protein, and the apolipoprotein H 4 genotype, there is insufficient evidence to implicate these mutations in the direct pathogenesis of all ALS, but they may act as genetically determined susceptibility factors.
Clinical Features It is widely agreed that when the clinical symptoms of ALS first appear, the biological disease must have been developing for some time and is well into its course. Electrophysiological investigations in patients in the early stages of the disease suggest that an extensive remodeling of motor units takes place by continuous denervation and reinnervation process before affected individuals can recognize muscle weakness. A study in patients with acute poliomyelitis estimated that as many as 5 0 % of the motor neurons are lost before muscle weakness is detected. Therefore an important preclinical asymptomatic stage likely precedes progressive muscle weakness in ALS. Muscle weakness in ALS usually begins in a focal area, first spreading to contiguous muscles in the same region before involvement of another region. The first presentation may appear very similar to a focal mononeuropathy; this is sometimes called the pseudo-neuritic presentation, More commonly, however, limb weakness appears to occur in muscles derived from more than one peripheral nerve and/or nerve root distribution; this is called a monomelic presentation. Onset of muscle weakness is more common in the upper than the lower extremities (classic, spinal ALS), but in approximately 2 5 % of patients, weakness begins in bulbar-innervated muscles (bulbar-onset ALS). On rare occasions ( 1 % or 2% of patients), the weakness starts in the respiratory muscles (dyspnea onset). Some patients present with weakness that is restricted to one side of the body (Mills' hemiplegic variant) and up to 1 0 % of patients appear with bilateral upper extremity wasting, which is known as the "flail arm" or flail person in the barrel variant.
2250
NEUROLOGICAL DISEASES
Symptoms of muscle weakness vary, depending on which motor function is impaired. For example, when weakens begins in the hand and fingers, patients report difficulty in turning a key, buttoning, opening a bottle cap, or turning a door knob (Figure 80.5). When weakness begins in the lower leg, footdrop may be the first symptom or the patient may complain of instability of gait, falling, or fatigue when walking (Figure 80.6). When bulbar muscles are affected, the first symptoms may be slurted speech, hoarseness, or an inability to sing or shout, which may be soon followed by progressive dysphagia (Figure SO.7). Indeed, patients with bul bar-on set ALS often initially consult car, nose, and throat specialists and not only experience progressive impairment in bulbar function but also excessive drooling (sialorrhea) and weight loss. Pseudobulbar palsy may present with inappropriate or forced crying or laughter (see Signs and Symptoms of Upper Motor Neuron Involvement, earlier in this chapter), which is often a source of great emotional distress for patients. Excessive forced yawning may also be a manifestation of pseudobulbar palsy. In the rare patient who presents with progressive respiratory muscle weakness, the first port of call may be to a pulmonologist or even to the intensive care unit; the diagnosis of ALS is then made when the patient cannot be weaned from the ventilator. Head-drop (or FIGURE NO.6 A typical left footdrop in a 45-year-old patient whose amyotrophic lateral sclerosis began 2.5 years earlier with bulbar symptoms. When she was asked to dorsiflex both feet, she was able to move her right foot only. The footdrop developed 6 months before the photo was taken, and the patient wears a left ankle-foot orthosis. droop) may be a feature in ALS and is caused by weakness of cervical and thoracic paraspinal muscles (Figure 80.8). However, weakness in these muscles is more commonly seen in myasthenia gravis and polymyositis. Fascicular ions are not commonly the presenting feature of ALS, but they develop in almost all patients soon
FIGURE 80,5 (A, B) Severe intrinsic hand muscle atrophy in a patient with amyotrophic lateral sclerosis. Note the "claw hand" and atrophy of muscles innervated by both ulnar and medial ncn i's.
FIGURE HO.7 sclerosis,
Atrophy of the tongue in amyotrophic lateral
DISORDERS OF UPPER AND LOWER MOTOR NEURONS
2251
deformities, painful pcricapsulitis, and bursitis. Sleep disturbances, in the form of increased awakenings from increased hypopneas and hypoxia, have been shown to be common in ALS and contribute to daytime sleepiness, morning headaches, and fatigue, As respiratory difficulty worsens, patients may be unable to lie supine because of worsening diaphragmatic weakness and thus compensate by using multiple pillows. In more advanced stages, patients are unable to he in bed at all. Other manifestations of ventilatory failure include dyspnea on exertion and eventually dyspnea at rest. As the disease advances, motor function is progressively impaired and activities of daily living (e.g., self-hygiene, bathing, dressing, toileting, walking, feeding, and verbal communication) become difficult. Accordingly, a patient's quality of life starts to progressively deteriorate. It may be difficult to distinguish daytime fatigue, broken sleep, affect lability, and sighing from depression, but it is vitally important to be aware of the latter. Depression is a common and underdiagnosed problem in ALS, which not only negatively affects quality of life but also shortens survival. Atypical
FIGURE 80.8 Patient with amyotrophic lateral sclerosis showing head droop caused by weakness of the thoracic and cervical pa rasp in til muscles,
after onset. In fact, absence of fasciculations should prompt one to seriously reconsider the diagnosis. In some patients, waves of fasciculations, called Lambert's waves, are seen spreading across the chest or back. Muscle cramps are one of most common symptoms in patients with ALS and often precede other symptoms by many 11 ninth-,. Although cramps arc common in health',- individuals and most commonly occur in calf muscles, in ALS they can occur in unusual muscles such as in the thigh, abdomen, hack, upper extremity, hand, neck, jaw, and even the tongue. Other signs and symptoms include exertional tatn;ue that mimics myasthenia. As dysphagia worsens, reduced caloric intake worsens fatigue and accelerates muscle weakness. Aspiration of liquids, secretions, and food becomes a risk. Patients may complain that they produce copious amounts of abnormally thick oral secretions, which may drool excessively from the mouth. This sialorrhea is made worse as perioral muscles weaken and/or head-drop develops. Weight loss is often rapidly progressive; indeed it has been suggested that this does not simply reflect poor caloric intake but represents a form of ALS cachexia. Marked loss of muscle bulk exposes joints and associated connective tissues to abnormal mechanical stresses that can lead to joint contractures, joint
Features
There arc certain clinical features that are unusual if not absent in AI.S including sensory loss, dementia, extrapyramidal dysfunction, eye movement abnormalities, autonomic disturbances, and abnormal sphincter control. When patients have these signs, the diagnosis of ALS should not be made until all possible alternative diseases are excluded. Although the sensory system is characteristically spared, some patients do report vague sensory symptoms such as numbness or aching and there is electrophysiological evidence that ascending afferent pathways may be involved despite the absence of objective sensory loss on physical examination. Overt dementia is estimated to occur in approximately 5% of non-Western Pacific ALS where it may even be the presenting feature. It is usually of the frontotemporal dementia (FTD) variety, and most commonly presents with word-finding difficulties, deficits in visual perception, and abnormal confrontation naming. Patients may exhibit poor judgment and other deficits in executive processing. There is some evidence that this form of dementia or cognitive impairment is much more common not only in bulbar-onset ALS but also in all subtypes of ALS, One needs to be cautious that language disturbances (especially anomia) may be masked by dysarthria. A prospective neuropsychological study of cognition in ALS identified deficits in up to a third of patients and a subsequent study reported an incidence of FTD in almost 5 0 % in patients with bulbar-onset ALS. Of 36 cases meeting criteria for FTD, 5 (14%) also met criteria for definite ALS (Lomen-Hoerth, Anderson, and Miller 2002). Dementia in ALS is pathologically distinct from other dementing illnesses; the most reliable pathological marker of cognitive impairment in SALS is
2252
NEUROLOGICAL DISEASES
Table 80,9; sclerosis
Practical classification of amyotrophic lateral
Sporadic ALS Classic (spina l-onscr) ALS Mills' hemiplegic variant Psendoncuritic presentation Flail arm presentation Monomelic presentation LIMN onset LMN onset Bulbar onset Dyspnea onset Progressive muscular atrophy Primary lateral sclerosis Progressive bulbar palsy Familial ALS Autosomal dominant SOD1 missense mutations Autosomal dominant linked to chromosome 9q34 (childhood) Autosomal recessive SODl (Asp90-Ala) mutation ALS linked to chromosome 2q33 [ALS1N gene) ALS linked to chromosome 15ql5 \ linked iliiiinri.uil Al S Disinbihition, dementia, parkinsonism, amyotrophy complex linked to chromosome 17q21 ALS with iron to temporal dementia linked to chromosome 9q21-22
ipsilateral lower extremity, the contralateral lower extremity, and finally the bulbar region. Onset in the lower extremity often follows a similar pattern, yet again with final involvement of the bulbar region (Brooks et al. 1994). Bulbar-onset ALS tends to spread to the distal upper extremities first, with spread to thoracic myotomes, and then the lower extremities. Overall, the pattern suggests that rostral-caudal involvement is faster than caudal-rostral spread. During the course of the disease, transient improvement, plateaus, or sudden worsening can occur, but spontaneous improvement is exceedingly rare. Prognosis
superficial linear spongiosis in neocorticai, entorhinal, and cingulate tissue (Wilson et al. 2001). The motor neurons of Onufrowicz in the sacral cord are essentially spared in ALS, and thus patients generally do not complain of significant problems with sphincter control (although some may report mild urgency of micturition). Similarly, eye movements are typically normal in ALS; it takes detailed quantitative testing to be able to identify abnormal vertical ocular saccades. Approximately 5% of patients with ALS exhibit signs of extrapyramidal tract dysfunction, usually in the form of retropulsions during attempted ambulation. Autonomic symptoms do not come to the attention of patients with ALS, although there is electrophysiological evidence of abnormal sweat production and cardiac denervation in the early stages of disease in sonic panciiis : Keck et il. 200 >).
Based on several epidemiological studies the median duration of ALS ranges from 23-52 months and the mean duration from 2 7 - 4 3 months (Mitsumoto, Chad, and Pioro 1997). About 2 5 % of patients survive 5 years and 8-16% of patients survive beyond 10 years. A number of factors influence the prognosis of ALS including the age at onset, clinical type, and duration from onset to the time of diagnosis. However, it must be emphasized that there is a wide range of rates of progression in each category of patient; the previous rate of progression in a particular patient is a better indicator of prognosis than any other feature. In general, the younger the patient, or the longet the duration between onset and diagnosis, the better the prognosis. A worse prognosis is found in those whose rate of progression is rapid within the first 6 months of diagnosis (Chio et al. 2002). Several clinical subtypes harbor a better prognosis; these include PLS, I'M A, pseudobulbar (rather than bulbar) palsy, the pseudo-neuritic presentation, and the flail-arm variant. Those who survive beyond 46 months and those who are psychologically well adjusted or not depressed have a better prognosis. Those who have low-amplitude CMAPs in the setting of notmal sensory potentials (the generalized low motor-normal sensory pattern) as revealed by nerve conduction studies appear to have a poor prognosis. Dyspnea-onset ALS has a shorter survival. Low serum chloride levels are associated with a short-term survival without ventilatory support because they reflect accumulation of bicarbonate due to respiratory failure (Stambler et al. 1998). Data on bulbar-onset AI.S vary, bur mean survival ranges between 12 and 26 months. Malnutrition is an independent risk factor for poor outcome.
Natural History of the Disease
Laboratory
It has been estimated that up to 4 0 % of anterior horn cell motor neurons are lost before the clinical detection of motor abnormalities; this suggests that a prolonged preclinical phase may be part of ALS. However, once the clinical phaseis evident, there appears to be a generally linear decline in motor function over time. There is a characteristic pattern of spread of disease. When onset is in one upper extremity, spread is often first to the contralateral side, then the
In some instances a diagnosis of definite ALS can be reached based on the history and clinical examination alone. However, often the diagnosis is not so obvious and further investigations are necessary. Because there is no single test that can make a diagnosis of ALS, all of these investigations are performed to exclude other disorders that may clinically mimic ALS and its variants. All such testing is an extension of a thorough history and physical
ALS = amyotrophic lateral sclerosis; LMN = lower motor neuron; UMN = upper motor neuron.
Studies
DISORDERS OF UPPER AND LOWER MOTOR NEURONS
examination and includes blood tests, the EDX, and neuroimaging. There is no single blood test that may objectively diagnose SALS. However, there are several blood tests that are usually performed for the evaluation of patients with suspected ALS. The list includes serum CK concentration, blood count, chemistry panel (including calcium, phosphate, and magnesium), Venereal Disease Research Laboratories test results, G M | autoantibody titers, sedimentation rate, serum pro rem unmunofixation or Immunoelectrophoresis, thyroid function studies including thyroid-stimulating hormone, and vitamin B12 levels. The CK concentration may be modestly elevated, particularly early in the disease. Patients oldet than 50 years and smokers of any age should have a chest radiograph taken. If any lesion is identified, an anti-Hu antibody level should he determined. Certain patients may have clinical features that suggest a disorder of the neuromuscular junction and may therefore benefit from testing for antibodies against the acetylcholine receptor or voltage-gated calcium channel. If there is biochemical evidence of adrenal insufficiency, it is pnnlcnl in oh lin ;i \ cry long-chain fatly acid [VI CI'A) assay to investigate for possible adrenomyeloneuropathy. Young-onset ALS with atypical clinical features should prompt the physician to obtain a Hex-A assay. If there is a positive family history, it is important to counsel the patient in preparation for SOD1 mutation analysis. There arc no specific features on muscle biopsy to distinguish ALS from other neurogenic disorders and this test should be reserved for cases that are more suggestive of a myopathy. The EDX examination is an invaluable tool in the investigation of ALS and its variants (see Chapter 36B). It serves as an adjunct to the clinical examination and is particularly useful in determining the presence or extent of LMN disease. Again, none of the EDX findings is ALS specific, but they can strongly suppott the diagnosis. Furthermore, this investigation may be repeated at intervals to more objectively monitor disease progression. Sensory nerve conduction study results are characteristically normal, unless the patient happens to have a coincidental mononcuropathy or polyneuropathy. Motor nerve conduction study results may be normal, although the conduction velocity and CMAP amplitude may be diminished in keeping with the extent of motor axon loss. There should be no evidence of conduction slowing or block, which would suggest a primarily dcmyclinating disorder. Severe motor axon loss may give rise to the "generalized low motor-normal sensory'' EDX pattern, which may portend a poorer prognosis. The needle electrode examination characteristically reveals a combination of acute (positive sharp waves and fibrillation potentials) and chronic (neurogenic firing pattern with evidence of increased amplitude and duration, polyphasic motor unit potentials) changes in a widespread distribution that is not in keeping with any single root or peripheral nerve distribution. Fasciculation potentials are usually identified; their absence should prompt an
2253
investigation for another disorder. Other common findings include moment-to-moment amplitude variation that indicates impaired motor unit stability and repetitive discharges known as doublets. Mention should be made of a special EDX finding, the split-hand phenomenon; in some patients, EDX reveals severe changes in muscles of the lateral hand (thenar eminence) but relative sparing of the medial hand (hypothenar eminence). EDX changes should be observed in a certain topographical distribution and ideally should be carried out in at least three of the four regions of the neuraxis (bulbar, cervical, thoracic, and lumbosacral). Neuroimaging studies of the brain and spinal cord are important to exclude structural, inflammatory, or infiltrative disorders that may cause UMN signs (Mitsumoto, Chad, and Pioro 1997) (see Chapter 37). Furthermore, T2-wcightcd and proton density MRI scans of btain may also reveal abnormal signal within the motor tracts as they extend from the motor cortex to the brainstem. These changes are thought to represent wallerian degeneration. Nonspecific atrophy of the frontal and patietal cortex may also be appreciated. Novel MRI techniques such as magnetization transfer ration (MTR) and diffusion tensor MRI may also reveal specific changes in the motor tracts in ALS. Research using positron emission tomography (PET) has shown increased activity in several ipsilateral and contralareral cerebral cortical regions beyond the motor cortex, which supports the current theory that ALS is not a disorder solely of motor neurons, but that this cell population is especially vulnerable to the injurious process involved. Proton density MRI data may not only support the diagnosis but also provide useful motor neuron-specific information with which to track disease progression and response to therapy. Significantly abnormal values of the ratio of N-acetylaspartate (NAA) to creatine or choline have been detected in the motor tract of patients with probable or definite ALS when compared to controls and abnormalities in these levels change over time {Chan et al. 1999; Suhy et al. 2002). Diagnosis In May 1990, at El Escorial, Spain, the World Federation nl
Neurology
established
J agnostic
criteria
for
Al S,
which were later modified at Airlie House, Virginia (1998) (wAvw.wfnals.org). These criteria include clinical, electrodiagnostic, and pathological components. The clinical criteria divide candidates into those with definite, probable, lab-supported probable, possible, and FALS based on a careful history and examination of four regions of the neuraxis: bulbar, cervical, thoracic, and lumbosacral. The purpose of establishing these criteria was to facilitate entry of appropriate candidates into clinical research trials, but they have been proven invaluable in rhe assessment of all patients with ALS. A patient is referred to as having "definite ALS" if there is clinical evidence of both UMN and LMN signs in three or
2254
NEUROLOGICAL DISEASES
more regions. "Probable ALS" is diagnosed in those with UMN and LMN signs in two regions. "Possible ALS" implies that a patient cither has UMN and LMN signs in one region only or has UMN signs alone in two regions. In addition, "possible ALS" may be applied to those with LMN signs in two regions as long as these are detected rosrmlly to the L'MN siting- " l a b supported probable ALS" refers to those patients who have clinical evidence of possible ALS but also have laboratory evidence of more widespread LMN involvement. The EDX is most valuable in providing such additional information. Follow-up examinations may be helpful in assessing patients with ALS, as disease progression may move a patient up a category, which not only may clarify the diagnosis but also may allow entry of that patient into research trials. Differential
Diagnosis
The differential diagnosis of ALS is rather extensive; motor symptoms and signs may be present in many other neurological and systemic disorders. Because there are no specific diagnostic markers for ALS, differentiating all other motor neuron diseases that may produce signs and symptoms of UMN, LMN, or both UMN and LMN involvement is essential for establishing the correct diagnosis. One may approach this task in an anatomical fashion and consider how ALS may appear similar to other disorders of the brain, brainstem, spinal cord, anterior horn cell, nerve root, peripheral nerve, neuromuscular junction, and muscle. Alternatively, one may approach this task in terms of the presentation; is it UMN only, LMN only, combined UMN-LMN, bulbar only, and so on? Are there any atypical features, such as prominent bladder or sensory involvement that suggest another diagnosis? For example, when UMN involvement is prominent, PLS, spastic paraparesis, or HAM should he considered, whereas pure LMN involvement suggests that one should also consider PMA, M M N , adult-onset SMA, or Kennedy's disease. Severe cervical spondylosis may impinge upon the cervical cord and the nerve roots and thus present with both UMN and LMN signs. Because pain, spastic bladdet, and posterior column signs are not always present, F.MG and neuroimaging may he required to distinguish it from ALS. Neuroimaging is also invaluable in assessing other disorders ol the brainstem and spinal cord that nay superficially mimic certain features of ALS such as intrinsic or extrinsic tumors, foramen magnum meningiomas, syringobulbia, and syringomyelia. Multiple sclerosis usually presents with UMN signs, but on rare occasions, LMN signs develop when ventral root exit zones are affected by demyelinating plaques. Neuroimaging and lumbar puncture studies should distinguish the two conditions. GDI 1 may manifest as a predominantly LMN disorder, hut some patients also have demyelinating lesions in the CNS that cause additional UMN signs.
It may be difficult to differentiate PBP from bulbar myasthenia gravis, as even repetitive stimulation studies and testing for serum antibodies against acetylcholine receptor may be negative in the latter. Follow-up examinations, however, usually reveal the insidiously progressive nature of the motor neuron disorder. Bulbar symptoms in ALS may be mistaken for brainstem stroke, but the progressive nature of bulbar symptoms and negative brainstem MRI will usually clarify the picture. On rare occasions, the increased tone, dysarthria, and sialorrhea of Parkinson's disease may be confused with ALS. However, the former is characteristically responsive to i.-dopa and tremor is often prominent. Multiple system atrophy may present with a combination of UMN and LMN signs, together with dysarthria and dysphagia. However, cerebellar ataxia, eye movement abnormalities, sphincter disturbance, and dysautonomia are usually prominent features. SCA types 2 and 3 (MachadoJoseph disease) are also part of the differential diagnosis. Other diseases that mimic ALS include adult Hex-A deficiency, adrenomyeloneuropathy, and certain motor paraneoplastic syndromes. Hyperthyroidism may present with prominent UMN signs, weight loss, and fasciculations but also features tremor, heat intolerance, and tachycardia. Hyperparathyroidism may present with an LMN or even myopathic disorder that mimics PMA. Both the benign fasciculation syndrome and cramp fasciculation syndrome nun- lead to rclcnaL lor [he evaluation ol ALS, hut these patients do not have any other symptoms or signs that suggest a widespread progressive disorder of motor neurons. / reatment See Table 80.10. Presentation of the Diagnosis of Amyotrophic Lateral Sclerosis. The first step in the management of ALS is to present the diagnosis in a compassionate, yet informative manner. Because many patients and their families find it difficult to absorb the information at first, a second appointment a short time later is often required. The decision-making process must include the patient and the
Table 80.10: Comprehensive care and management for patients with amyotrophic lateral sclerosis Presentation of the diagnosis oF ALS Specific pharmacotherapy Symptomatic treatment Team approach at ALS clinic Ethical and legal issues Physical rehabilitation Speech and communication management Nutritional care Respiratory care Home care and hospice care ALS = amyotrophic lateral sclerosis.
DISORDERS OF UPPER AND LOWER MOTOR NEURONS
family. At the appropriate time, it is important to bring up issues such as advance directives and issues regarding terminal care. Providing information on progress in research, newly available pharmacotherapies, and the possibility of active participation in clinical trials may increase hope for patients (Miller ct al. 1999). Specific Pharmacotherapy. In 1996, riluzole (Rilutek) was approved by the United States Food and Drug Administration (FDA) as the first specific drug for the treatment of ALS. It is believed to principally function as an antiglutamate agent, although its mechanism of action is not yet fully understood. The two studies that led to riluzole approval showed that survival was significantly longer in patients with ALS who took 50 mg of riluzole twice a day compared with those who took placebo, although this survival benefit was only modest and was disproportionately beneficial in bulbar-onset disease, A subsequent systematic meta-analysis of three randomized trials carried out in French and Belgian populations has shown a significant survival advantage at 6, 9, 12, and 15 months but not at 3 or 18 months. The median prolongation of survival was calculated at only 2 months. However, data from uncontrolled studies in other populations that were followed over longer periods have reported survival benefits of up to 20 months (Miller et al. 2002). In addition, riluzole appears to maintain patients in a milder state of disease for a longer period. Side effects are relatively uncommon and minor and include fatigue, gastrointestinal upset, and dizziness. Furthermore, there may an increase in liver function test results. To minimize side effects, we recommend 50 mg per day in the evening, and after a week or two, the patient can increase the dose to the regular dose of 50 mg twice a day. The cost of the drug (approximately S8000-S9000 per year) appears to be one of the main factors in whether patients elect to take riluzole. Several agents with antiglutamate activity have been assessed in clinical trials including lamotngine, branchedchain amino acids, topiramate, dextromethorphan, and gabapentin. None of these has been proven to be of clinical benefit, although dextromethorphan has been shown to be of benefit in the treatment of pseudobulbar affect. A series of agents with antioxidant and/or neuroproreetant properties have been studied in ALS including, Ldeprenyl, N-aeety[cysteine, and calcium-channel blockers, but so far none has been shown to be of benefit. A trial of vitamin E taken orally at a dose of 1000 ug per day also did not show a clinical benefit. Nonetheless, many patients take high doses of natural antioxidants including combinations of vitamin E, vitamin C, flavonoids, coenzvme Qm, or all of them in various combinations. Many patients are taking creatine, a naturally occurring muscle component important in mitochondrial function that is widely available as an over-the-counter supplement in health food stores. As with coenzyme QJQ, there is experimental evidence that creatine improves motor function in transgenic SOD1
22.S.S
animal models of ALS, and trials are currently under way in humans (Klivenyi et al. 1999). Neurotrophic factors are a heterogeneous group of basic peptides belonging to the cytokine family that are produced in regulated amounts from various tissues and are important in cellular proliferation, differentiation, maintenance, maturation, and repair. A number of recombinant neurotrophic factors have been studied in well-designed trials including ciliary neurotrophic factor, brain-derived neurotrophic factor, insulin-like growrh factor (IGF-1, Myotrophin), and glial cell-derived neurotrophic factor. Results from these trials have generally been disappointing, although some benefits have been noticed in certain. ALS subpopulations. It has been proposed that these negative findings may reflect poor drug delivery to target tissue and that future efforts should focus on trying to more closely mirror the natural biology of these and other neurotrophic factors: Systemic and intrathecal routes of administration do not appear to achieve adequate tissue levels and necessitate high doses that cause unpleasant side effects. The potential clinical benefits of IGF-1 are once again under investigation (Mitsumoto and Tsuzaka 1999). Another agent under clinical investigation is buspirone, an anxiolytic agent that also has neurotrophic factor-like effects. Xaliproden (Sanofi SR57746A) is a novel small nonpeptide molecule with both neurotrophic and ncuroprotcctant properties and good CNS penetration. Preliminary trials suggested that this agent might be ot benefit in ALS. Based on evidence of benefit in cell culture systems and transgenic animal models, several other new agents are being investigated for potential use in the treatment of ALS. These include novel AMPA receptor antagonists, cyclooxygenase-2 antagonists, modified catalases, copper chelators, caspase inhibitors (such as minocycline), antiapoptotic antiviral agents (indinavir), anabolic steroids (oxandrolone), and modulators of cell signaling pathways. It may also be of benefit to administer several agents in combination, such as an antiglutamate agent with one or more neuioprotecrants and neurotrophic factors. Finally, there is early evidence from animals that gene therapy and/or stem cell therapy may be effective in the trearment, maintenance, and possibly even the regeneration of the motor neuron system, although many practical and ethical issues must be addressed before such treatment becomes a reality (Murray and Mitsumoto, 2002). Aggressive Symptomatic Treatment. Although specific pharmacotherapy is still markedly limited for the treatment of ALS, symptomatic treatment can substantially improve a patient's symptoms and discomfott. Table 80.11 summarizes specific pharmacological and nonpharmacological symptomatic treatments (Miller et al. 1999). Muhidisciplinary Team Approach at Amyotrophic Lateral Sclerosis Clinic. The care of patients with ALS has become increasingly complex. As a consequence, many patients are taken care of by ;; uuihidiseiplmary •.e.un rather
22S6
NEUROLOGICAL DISEASES
Table 80.11:
Symptomatic treatment in amyotrophic lateral sclerosis
Symptoms
Pha rtna cotherapy
Other
Fatigue
Pyridostigmine bromide Antidepressants Amantadine hydrochloride
Energy conservation Work modification Assistive devices Physical therapy Rangc-of-motion exercises
Spasticity
Cramps
Fa stimulations Sialorrhea Thick mucinous saliva Pseudobulbar laughing or crying
Secretion and expectoration Aspiration
Joint pains Depression Insomnia
Respiratory failure
Constipation
Baclofen Tizanidine Dantrolene sodium Diazepam Quinine sulfate Baclofen Vitamin E Carbamazepine Anticholinergic drugs Beta blocker TCA SSR1 L-d opa/ca r bi d o pa Lithium Dextromethorphan Organ id in Cisapride
therapy
Massage Physical therapy Assurance Mechanical cleaning None
Hydration Moist air; aspiration devices; insufflator/exsufflator Modified food consistency Tracheostomy Modified laryngectomy and tracheal diversion Range-of-motion exercises Heat Counseling Support group meetings; psychiatry
Anti-inflammatory drugs Analgesics TCAs SSRI Zolpidem tartrate Lorazepam Opioids Bronchodilators Morphine sulfate Increase oral liquid Metamucil Dulucored suppositories Lactulose and other laxative
Hospital bed Nocturnal noninvasive ventilator 1PPB Noninvasive ventilation; permanent ventilation FJxercise
1PPB = intermittent positive pressure breathing; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
than by a single treating physician. The team often consists of neurologists, a nurse coordinator, physical therapists, occupational therapists, dietitians, speech pathologists, and social workers. Pulmonary specialists and other health professionals should also be available. Using this holistic approach, the aim is to maintain physical independence for as long as possible and to provide psychosocial support to patients and families {Mitsumoto, Chad, and Pioro 1997), Ethical and Legal Issues. ALS is almost invariably a relentlessly progressive and terminal disorder. Thus physicians must raise the issues of the living will and durable power of attorney for health care relatively early after the diagnosis is made to allow the patient and family to prepareahead. However, it should be emphasized that such decisions are not final and may even be reversed at any time. Furthermore, some patients either do nor wish ro or cannot make such decisions.
Physical Rehabilitation, The main goal of rehabilitation for patients with ALS is to improve their ability to carry out activities of daily living for as long as possible without causing undue physical or emotional strain. Physical therapy also prevents complications secondary to disuse of muscles and immobilization, such as a frozen shoulder. Various types of exercise are employed that maintain or enhance strength, endurance, and range of motion. There have been concerns that exercising ALS-affected muscles to the point of fatigue may actually be harmful, but this has not been borne out in the literature. The occupational therapist is another valuable member of the ALS care team. A range of assistive and adaptive devices is employed to improve mobility and comfort and to cany out activities ot daily living. For example, walkers, wheelchairs, splints, and collars are useful to manage wrist-drop, footdtop, head-drop, and gait instability. Successful rehabilitation also includes an evaluation of the
DISORDERS OF UPPER AND LOWER MOTOR NEURONS
home environment and customized home equipment can easily help preserve a patient's independence and safety [Mitsumoto, Chad, and Pioro 1997), Speech and Communication Management. Speech and communication dysfunction is probably one of the most serious factors reducing quality of life in the patient with ALS. Ideally, speech pathologists should assess speech and communication soon after the diagnosis is made so that the patient can maintain independent communication for as long as possible. To maximize communicative ability, we use a six-step approach as the disease progress: • Step 1. Maximize intelligibility strategies (e.g., teaching the patient to speak slowly and face to face) • Step 2. Introduce energy-conserving techniques • Step 3. Train the patient's main listener or communication partner • Step 4, Introduce nonverbal techniques (gestures and other body language) • Step 5. Incorporate assistive (such as a palatal prosthesis) and augmentative communication devices and techniques • Step 6. Refer for a complete augmentative and alternative communication evaluation by a speech pathologist Numerous communication devices are available that vary in sophistication and complexity, ranging from simple and relatively inexpensive mechanical devices, such as alphabet or picture hoards, to specialized electronic devices such as a voice synthesizer. Nutritional Care. Dysphagia and aspiration are distressing and dangerous complications of Al.S and are particularly prominent in the bulbar-onsct variety. As oral intake progressively declines, there is acceleration in weight loss and malnutrition, which not only aggtavates muscle weakness but also shortens survival. Therefore in every patient with Al.S, the nutritional status must be carefully evaluated at each visit. One of the best indicators of a change in nutritional status is a change in body weight. However, a detailed history of oral intake is also important, as is whether or not the patient has been coughing or choking during swallowing and whether there has been an increase in the duration of meals or an inability to finish meals. Although physicians can take such a history, evaluation by an experienced dietitian is often most helpful. Initially, patients should change the form and texture of their food and use a high-calorie food supplement, but eventually, such measures become insufficient to maintain the patient's weight, and proactive enteral tube feeding becomes imperative. Percutaneous endoscopic gastroscopy (PEG) is a standard minor surgical procedure that not only improves quality of life but also prolongs survival by several months. Although it is a relatively simple surgery for otherwise healthy patients who have dysphagia, patients with ALS pose particular
22^7
difficulties and often have impending respiratory failure that may complicate the procedure. The ALS Practice Parameters advocate placement of PEG tube in consenting patients with dysphagia, whose seated predicted forced vital capacity is more than 5 0 % (Miller ct al. 1999). However, it has recently been shown in a small series of patients that a PEG may be performed for patients with a forced vital capacity of less than 5 0 % predicted if noninvasive positive pressure ventilation is also used during the procedure (Gregory et al. 2002). It is important to emphasize that those who receive a PEG tube can continue to eat by mouth and that the purpose of enteral feeding is to provide calories and fluid and not merely to prevent aspiration. Indeed aspirarion is a continued risk to the patient even after PEG tube insertion, and if recurrent aspiration of PEG contents becomes a persistent problem, one can recommend percutaneous enteral jejunostomy (PEJ), which further reduces (but still does not eliminate) the risk. Respiratory Care. Respiratory failure is the most common cause of death in ALS. Indeed, dyspnea-onset ALS presents with obvious ventilatory difficulties and it is for this reason that it harbors a particularly poor prognosis. However, it is important to make patients and family members aware that almost all forms of ALS will eventually be complicated by ventilatory failure, although symptoms may go largely unnoticed until relatively late in the disease course. It should he made clear to the patient that although positive pressure ventilation via a tracheostomy may indefinitely prolong life, there is no effect on the disease itself. In fact, by prolonging the natural history of the disorder, there is a strong possibility that atypical symptoms may arise, such as dementia, visual changes, sensory loss, and incontinence. Most patients and their physicians opt for the noninvasive approach. One technique, bilevel positive airway pressure ventilation (BiPAP), slows the rate of pulmonary decline, improves symptoms, and prolongs survival (Kleopa et a I. 1999; Ahoussouan et al. 2001). The current recommendation is that patients be offered noninvasive ventilatory assistance at the onset of dyspnea, when the forced vital capacity falls to less than 507o predicted, or a when a rapid rate of decline in pulmonary function occurs. However, it should be remembered that progressive weakness and wasting of perioral muscles would eventually prevent adequate use of the BiPAP mask; nasal pillows can be helpful in this circumstance and are often better tolerated than the mask at all stages. Furthermore, BiPAP does not prolong life indefinitely and these patients still face the difficult decision of whether to use an invasive ventilator. When the decision has been made to withdraw from ventilatory support, or when noninvasive means of ventilatory assistance are no longer sufficient, it is imperative that all attempts should be focused on effective and compassionate palliation. Judicious amounts of opioids, oxygen, and anxiolytics should be prescribed to allow the patients to live their final days with dignity and in as much comfort as possible.
22.SS
NEUROLOGICAL DISEASES
Home Care and Hospice Care. When the patient's condition deteriorates, home care or admission to an alternative care site is required. Close collaboration among patients, their caregivers, home care nurses, and ideally the ALS clinic team will ensure effective and satisfying home care. When a patient has no caregiver, a site other than the home should he chosen for extended care. Hospice care provides highly effective palliative care to patients and their families. Just as important, hospice philosophy strongly affirms life so that patients who are in the terminal stages of their disease can maintain their independence and dignity to the gteatest degree possible.
Familial Amyotrophic Lateral Sclerosis Between 5-10% of all ALS is familial, with the majority of cases being inherited in an autosomal dominant pattern. It is quite possible that the true frequency of FALS is an underestimate; anything less than a detailed family history may fail to identify an affected family member. ALS-1 is a form of late-onset motor neuron disorder that accounts for 15-20% of all cases of FALS (and thus 1-2% of all ALS) and is associated with mutations in the gene that encode SOD1 located on chromosome 21q21 (Siddique and Lalani 2002). Most cases are inherited in an autosomal dominant pattern, but a recessive variant has also been identified. ALS-2 is a rare, recessively inherited disorder mapped to a gene on chromosome 2q33 that encodes a novel protein that one group has dubbed a I sin. Al.S-4 and ALS-5 are also recessively inherited and have been mapped to chromosomes 9q2 l-q22 and 15ql5-q22, respectively. Fheir causative genes have yet to be identified. Most recently, a large European family has been identified with adult-onset autosomal dominant ALS linked to chromosome 18q21 (Hand et al. 2002). Fhis is currently classified in the ALS-3 category, but somewhat confusingly, ALS-3 has also been assigned to denote all familial cases that have yet to be linked to a chromosomal locus or associated with an inherited genetic mutation.
Autosomal Dominant Familial Amyotrophic Lateral Sclerosis Genetics and Protein Chemistry There are three SOD isoenzymes, termed SOD1, SOD2, and SOD5. The first of these, SOD1, is A cytosolic enzyme that scavenges the free radical by-products of oxidative respiration and is known to be important in the pathogenesis of some forms of FALS. Neither mitochondrial SOD2 nor extracellular SOD3 appears to be directly pathogenic in human ALS. SOD1 is a 32-kd homodimeric protein encoded by a gene containing five exons located on chromosome 2 1 , Faeb
monomer contains one atom of copper and one of zinc. The zinc moiety maintains the dimer formation, which doubles the dismutasc activity. However, it is the copper within the active site that is important in catalyzing the conversion of 0 2 ~ to H i 0 2 and 0 2 . SODl is ubiquitously expressed in every cell of every eukaryotic organism and its sequence and structure arc highly conserved. The biological importance of this protein is also evident in its great abundance within some cells; it accounts for as much ns 1% of nil protein of the CNS. To date, more than 100 distinct point mutations have been found in all five exons of the SODl gene, the majority of which are missense mutations that usually result in the incorporation of a wrong amino acid into the gene product. Splice junction mutations, deletions, and insertions have also been detected in FALS (Siddique and Lalani 2002). Pathogenesis A simple pattern of loss of enzyme function has not been demonstrated in SODl-associatcd FALS. Mutant SODl proteins are often unstable, with activities ranging from completely normal or unaffected (aspartic acid replaced with alanine in codon 90) to entirely absent (glycine replaced with arginine in codon 85), and roral SODl enzyme activity correlates poorly with the severity of FALS. Moreover, SODl-knockout mice (animals genetically engineered to be born with no SODl proteins) are found to have no apparent motor neuron disease. The weak association between enzyme activity and disease occurrence has led to an alternative hypothesis that there is a toxic gain of function in mutated SODl. Considerable support for this theory has come from cell culture and transgenic animal studies. Toxic gamed properties in human disease may arise from one or several processes (Cleveland and Rothstein 2001): • Altered conformation of the copper-bound active site in mutant SODl protein may generate oxidative stress through an interaction with aberrant substrates such as hydrogen peroxide and peroxynitrite. Zinc-deficient mutant SODl may interact with nitric oxide to produce peroxynitrite, which in turn may cause harmful nitration of tyrosine residues on key intracellular proteins. • Mutant SODl proteins have been shown to clump together as intracellular aggregates. These aggregates may interfere with proteasomal breakdown of ubiquirinatcd proteins or imp;vr axonal transport of various substances. • SODl mutations may catalyze the inactivation of G I T I and thus cause excitotoxic cell injury via excessive influx of calcium into motor neurons. In addition, mutant SODl may also disturb calcium homeostasis through disruption of mitochondrial function.
DISORDERS OF UPPER AND LOWER MOTOR NEURONS
• Both in vitro and in vivo research shows that mutant SOD1 protein is associated with enhanced programmed cell death (apoptosis). Increased expression or proapoptotic and reduced expression of antiapoptotic members of the bcl-2 family have been demonstrated in transgenic mutant SOD] mice. Furthermore, activated caspases, the effectors of apoptosis, have been demonstrated both in the anterior horn cells of transgenic SOD1 mice and in human ALS tissue. An experimental nonselective caspase inhibitor called zVAD-fluorometbyl ketone has been shown to prolong survival and improve motor performance in mutant SOD1 mice (Murray and Mitsumoto 2002). Clinical
features
There is a large degree of phenotypical variability in the expression of SODl-associated FADS, not only between different families but also between individual members of the same family. Furthermore, penetrance is rather variable and age dependent. Generally, the diagnosis of FALS can be established only by the fact that other family members in successive generations are or were affected by ALS, Unfortunately, a reliable history is not always available. The clinical features of individual FALS patients overlap considerably with those of patients with SALS, but there may be subtle differences between the two. For example, lower-limb onset is more common in FALS, whereas bulbar onset is rare. The age at onset for FALS averages at about 46 years, which is at least 10 years earlier than that of SALS; the male-to-female ratio is 1:1 in FALS but about 1.2-1.6:1 in SALS. Neuropathological analysis in FALS shows frequent posterior column involvement, although clinical signs for this pathological change are not usually apparent. Certain clinical featutes arc often stereotypical within some families. For example, the two most common mutations, alanine replaced with valine at codon 4 in exon 1 (A4V) and histidine replaced with arginine at codon 43 in exon 2 (H43R), are associated with rapid progression, and most patients die within I year. In contrast, other mutations, such as histidine replaced with arginine at codon 46 in exon 2 (H46R) and glycine replaced with arginine at codon 37 in exon 2 (G37R), are associated with a disease duration averaging more than 15 years. SOD!-linked FALS presenting with predominantly LMN signs is associated with a mutation in which valine replaces leucine at codon 84 in exon 4 (L84V).
Auiosomal-Reeessivc and X-Linked Mutations Substitution of aspartic acid with alanine at codon 90 in exon 4 (D90A) of the SOD1 gene can result in both autosomal dominant and recessive FALS. Although encountered worldwide, D90A FALS is particularly
2259
prevalent in Scandinavian countries where a common founder effect has been identified (Andersen et al. 1996). In Scandinavian counttics, the pattern of inheritance is autosomal recessive and only homo/.ygotes are clinically affected. Patients may present with atypical features such as sensory symptoms, urinary urgency, decubitus ulcers, posterior column dysfunction, and, rarely, ataxia, Non-Scandinavian D90A families have been studied in Europe and the United States, in whom the pattern of inheritance is autosomal dominant. In these families, disease occurs in the heterozygous state, which suggests that Scandinavians may have a genetic protective factor on one or both gene copies that ensures normal cellular function until both alleles are affected. X-linked dominant ALS, featuring a combination of both UMN and LMN signs, has been reported, the gene locus being on chromosome X p l l - X q 1 2 (Hong et al. 1998). Juvenile
familial Amyotrophic
Lateral Sclerosis
An autosomal dominant form of juvenile-onset ALS has been mapped in one family to an interval of 5cM that harbors the ALS4 gene on chromosome 9q34, This autosomal dominant disorder, classified as ALS-4, typically manifests in the second decade of life (mean age is 17 years) with difficulty in walking, followed by weakness and wasting of intrinsic hand muscles and distal lower limbs. Progression is slow, so p; incuts become wheelchair bound by the sixth decade and sparing of bulbar musculature is a characteristic finding. An almost identical disorder has subsequently been described in three families diagnosed with distal H M N (spinal Charcot-Marie-Tooth disease). This disorder is also linked to the ALS4 locus. The authors have thus raised the possibility that ALS-4 and this H M N may be the same disorder (De jonghc et al. 2002). Recessive juvenile ALS has been described in families of North African origin but is also present in Europe (ALS-5). The clinical syndrome is similar to SALS except for a younger age at onset. It has been linked to chromosome 15qlS-q22, but the pathogenic gene has not been identified. Another juvenile recessive ALS syndrome, as yet unlinked to a chromosome site, has been described with a combination of both UMN and LMN signs. Symptoms and signs are more prominent in the lower extremities and bulbar function is spared, Recessive juvenile ALS has also been mapped to chromosome 2q33 (ALS-2). Although it was originally described in consanguineous families from Tunisia, it has also been discovered in families from Saudi Arabia and Kuwait. The phenotype of this disorder varies according to the family of origin; in the Tunisian family, it presents as an ALS-iikc disorder with onset in the first or second decade of life; in the Kuwaiti family, the phenotype is similar to early onset PLS. Further work identified a new ALS gene called ALS2 that encodes a protein that has been called alsin.
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NEUROLOGICAL DTSF.ASF.S
Sequence homology analysis of this protein suggests that it may function as a guanine-nucleotide exchange factor and thus be important in intracellular cell signaling and cytoskeleton organization. It appears that loss of function of this protein causes selective injury to motor neurons despite the fact that it is widely expressed in many tissue types. Furthermore, an ALS phenotype occurs when there is a onc-basc-pair deletion on exon 3, whereas a milder PLS presentation occurs in those with a rwo-base-pair deletion on exons 5 and 9. It has been proposed that the milder PLS phenotype occurs because of some residual function in a mutated longer protein product or an intact short protein product. Much has yet to he discovered about the structure and function of this protein, but the discovery of an ALS phenotype from a loss of function mutation, rather than a toxic gain of function, will likely lead to exciting new research into new models of ALS pathogenesis (Shaw 2001).
Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (Western Pacific Amyotrophic Lateral Sclerosis) In 1954, Mulder and colleagues described a disorder characterized by a combination of ALS and parkinsonism that was the most common cause of death in the adultnative Chamorro population on the Western Pacific island of Guam. A similar disorder was subsequently described in western New Guinea and the Kii peninsula of Japan, with an ALS incidence between 50 and 150 times than elsewhere. Clinically, about 5% of patients develop a predominantly ALS type of disorder, whereas 3 8 % manifest principally with a combination of parkinsonism and dementia. The pathology of tins unusual disorder bears similarities to that of Alzheimer's disease (AD), with prominent loss of CNS neurons and the presence of abundant tau-immunoreactive neurofibrillary tangles. Alpha-synuclein pathology has recently been detected in the amygdala of affected brain tissue (Forman et al. 2002). Multiple members of a single family may be affected, and it has recently been shown that fitst-degree relatives of patients with ALS-PDC have a significantly higher risk of developing the disease than controls. Despite these observations and a recent genetic association study implicating the tau gene as a susceptibility gene for ALS-PDC, accumulated epidemiological evidence MI ongb suggests that an environmental factor, rather than a genetic factor, is more important in disease pathogenesis, fhe incidence of the Guamanian ALS variant has rapidly declined over the past 50 years, a process thought to reflect the westernization of the region. Various environmental toxins have been implicated in the pathogenesis of ALS-PDC, chief among them being neurotoxins derived from the native cycad seed. This seed contains ^-methylamino [.-alanine (BMAA), an amino acid that is reversibly toxic to cortical and spina)
motor neurons. They also contain a carcinogenic substance called cycasin that may act either alone or in concert with BMAA to damage motor neurons. Toxic sterol glucosides have recently been isolated from washed cycad flour, and it has been shown that they can cause the release of glutamate (Khabazian et al. 2002). Cox and Sacks (2002) have proposed a process of biomagnification of cycad toxins through the once popular Chamorro practice of eating flying foxes, which themselves feed on cycad seeds. The decline in the incidence of ALS-PDC may reflect the dwindling flying fox population on Guam through a massive increase in commercial hunting using firearms that were introduced to the island in the decades following World War II (Cox and Sacks 2002).
Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease) (OMIM 109150) Machado-Joseph disease is an autosomal dominant syndrome with onset varying from the third to seventh decade of life. Although cerebellar ataxia is the predominant clinical feature, patients with an early onset (age 20-30 years) often present with generalized spasticity and fasciculations of the face and tongue. Other characteristic findings include extrapyramidal signs, such as dystonia and rigidity, protuberant eyes, and progressive external ophthalmoparesis. Affected patients have a twofold to threefold expansion of a CAG trinucleotide on the ataxin-3 gene on chromosome 14q32.1. The expanded triplet repeat results in a mutant gene product containing an expanded polyglutamine tract, which appears to aggregate into intranuclear neuronal inclusion bodies and may interfere with (he function of the cellular proteasome in degradation of proteins (Schmidt et al. 2002). The Machado-Joseph disease phenotype may also occur in SCA-2, with slowly progressive ataxia, eyelid retraction, and facial fasciculations (Geschwind et al. 1997). Patients often have slow saccades or ophthalmoparesis and may have reduced or absent deep tendon reflexes. SCA-2 is caused by an expanded polygluta mine-encoding CAG triple repeat sequence on chromosome 12q.
Adult Hexosaminidase-A Deficiency (OMIM 606869) Adult Hex-A deficiency is an autosomal recessively inherited late-onset G M 2 gangliosidosis (the other subtypes being infantile and juvenile). All three subtypes are caused by an abnormal accumulation of GM 2 ganglioside in neurons due to a deficiency in the activity of the lysosomal enzyme. Hcx-A is encoded by a gene on chromosome 15q23-q24 and normally degrades GM> ganglioside. Only about 1 0 % of Hex-A activity is required for normal health, but in the severe infantile form of this disorder, also known as Tay-Sacbs disease, mutations in the w-subunit of Hex-A
DISORDERS OF UPPER AND LOWER MOTOR NEURONS
result in complete deficiency of enzyme activity. Juveniles and adults with Hex-A deficiency, however, are compound heterozygotes with varying degrees of residual enzymnric activity and thus A deficiency is a later onset disorder with considerable variability in the phenotype. The adult form may present as slowly progressive weakness of predominantly proximal muscles of the upper and lower extremities. In some patients, severe cramps may present in association with muscle weakness, mimicking SMA, In others, however, a combination of dysarthria, spasticity, and LMN signs may resemble ALS. Additional sensory, cerebellar, cognitive, psychiatric, and extrapyramidal features may later develop. The EDX may reveal prominent complex repetitive discharges and abnormal SNAPs. Generally, this constellation of symptoms and signs is not easily mistaken for ALS, but in the relatively early stages, patients with Hex-A deficiency may not manifest many features other than motor system dysfunction. Genetic counseling is important before assaying a patient's serum or leukocytes for deficiency of Hex-A activity.
Triple-A Syndrome (OMIM 231550) Triple-A syndrome (Allgrove's syndrome) is a rare autosomal recessive disorder that derives its name from the combination of achalasia, dlacrima, and ddrenocorticotrophic insufficiency. The A A AS gene is located on chromosome 12ql3 and encodes a ubiquitous protein called aladin, which is heavily expressed in the neuroendocrine system and may be important in regulation of the cell cycle, cell signaling intracellular transport, and the cell cytoskeleton. The syndrome manifests a range of neurological problems, including mental retardation, optic atrophy, and seizures. A recent case report suggested that a further two A's be added to the name; they described a woman with additional features of autonomic disturbance (dry mouth, postural hypotension, and syncope) and bulbospinal amyotrophy (amyottophy of limbs and tongue with tongue fasciculations) (Goizet et al. 2002).
Disinhibhion-Dementia-Parkinsonism-Amyotrophy Complex (Wilhelmsen-Lynch disease) (OMIM 600274) Disinhibition-dementi a-par kin son ism-amyotrophy complex (DDPAC) is an autosomal dominant progressive neurodegenerative disease described in a large Irish American family (family Mo) in the United States and is characterized clinically by disinbibited behavior (including excessive eating and inappropriate sexual behavior), personality changes, dementia, patkinsonian manifestations, and in two cases, amyotrophy with fasciculations. Autopsy studies showed widespread neuronal loss in the substantia nigra, cerebral cortex, and anterior horn of the spinal cord,
2261
together with extensive spongy degeneration in the temporal and frontal lobes. Subsequent research identified the presence of tau-immunorcactive inclusion bodies in affected regions of the CNS. Splice-site donor mutations in the gene encoding microtubule-associated protein tau are associated with DDPAC (Lynch et al. 1994).
Autosomal Dominant Frontotemporal Dementia with Motor Neuron Disease Up to 5% of patients with SALS may also manifest overt signs of dementia, which is usually of the frontotemporal type. However, for more than half a century, various observers have pointed out that symptoms and signs of ALS and LTD appear to occur together in some families with increased frequency. A recent analysis of multiple pedigrees identified a locus for autosomal dominant ALS and FTD on chromosome 9q21-22. The mean age at disease onset in these families was about 54 years (range 40-62 years). Some patients developed symptoms and signs of ALS alone, but others also developed inappropriate behavior, impulsiveness, and eventually impaired memory. Both neuroimaging and pathological studies revealed frontotemporal atrophy and histology identified gliosis, vacuoles, rare Pick's bodies, and some neurofibrillary tangles and senile plaques (Hosier et al. 2000).
Adult Polyglucosan Body Disease Polyglucosan body disease is a very rare, late-onset, slowly progressive disorder characterized by a combination of U M N a n d LMN signs, cognitive decline, distal sensory loss, and disturbances of bladder and bowel function. MRI of the brain may reveal diffuse white matter signal increase on T2-wcighted images. The diagnosis is clinched by the finding of characteristic pathological changes in tissue from peripheral nerve, cerebral cortex, spinal cord, or skin. Axons and neural sheath cells contain non-membranebound cytoplasmic periodic acid-Schiff-positive polyglucosan bodies. Ultrastructural examination shows that the inclusions consist of 6-8 nm branched filaments and arc most abundant in myelinated nerve fibers. In Ashkenazi Jewish patients (and one reported non-Ashkenazi Jewish patient), the disorder is caused by a deficiency of the glycogen-branching enzyme, but in other patient populations, this enzyme activity is normal. The recent (albeit inadvertent) generation of muscle polyglucosan bodies in a transgenic mouse engineered to overexpress glycogen synthase in the presence of normal levels of glycogenbranching enzyme suggests that an imbalance in the activities of these two enzymes is the possible molecular mechanism underlying this unusual disorder (Raben et al. 2001). It is interesting to note that two types of polyglucosan body may be seen in ALS, Lafora's bodies
2262
NEUROLOGICAL DISEASES
and corpora amylacea, although neither is considered a characteristic pathological feature.
Paraneoplastic Motor Neuron Disease There is evidence rhat motor neuron disease may rarely be a paraneoplastic phenomenon. Patients may present with features that are rather typical of pure "spinal" ALS or manifest in a manner akin either to PMA or PLS. Other motor neuron manifestations may represent only one part of a larger paraneoplastic syndrome, such as anti-Hu antibody associated encephalomyelitis, with atypical features such as dysautonomia or ataxia. Unfortunately, most paraneoplastic motor disorders are unresponsive to treatment of the underlying tumor. Rare motor disorders have been described in association with other paraneoplastic antibodies, including anti-Yo antibody in a patient with ovarian carcinoma, and a novel antincuronal antibody in a patient with breast cancer. A subacute, painless, and progressive LMN disorder has been well characterized in lymphoma (both Hodgkin's and non-Hodgkin's types). Patients may eventually develop UMN signs and some may improve either with treatment of the cancer or spontaneously. Elevated CSL protein levels or the presence of a paraprotein in the blood should prompt a detailed investigation for lymphoma. Although there is insufficient evidence to conclude that there is increased risk of cancer in ALS, a combination of UMN and LMN signs has been well described in patients with breast, uterine, ovarian, and non-small cell cancer. This ALS-like disorder is quite rapidly progressive and does not appear ro respond either to treatment of the underlying cancer or to immune therapies. UMN signs and symptoms that mimic PLS may rarely occur in patients with breast tumors and may in fact precede the cancer diagnosis by a few months. In general, one should invesiigate for a paraneoplastic disorder if there arc atypical features such as ataxia, sensory loss, and dysautonomia, and it would seem to be prudent to carry out bteast screening on women with a PLS presentation.
Viral Hypothesis and Human Immunodeficiency Virus Type 1-Associated Motor Neuron Disorder Many viruses are neurotropic, that is, they have a unique capacity to gain access to and teplicate within cells of the CNS. As such, viral infection may be important in the pathogenesis of ALS. Of the many candidate viruses, greatest attention has been paid to enteroviruses (including pohovirus) and retroviruses. However, an as yet unidentified virus may be the culprit. Although rare cases of patients who previously had poliomyelitis later present with a combination of both UMN and LMN degeneration, there is insufficient evidence to implicate poliovirus in the pathogenesis of ALS.
However, other as yet unidentified enteroviruses may be important. One study identified enteroviral sequences in 88.3% of AI.S spinal cord tissue, but only 3.4% of control tissue (Berger et al. 2000). Tt appears that retroviruses may be closely linked to motor neuron pathology. Using a highly sensitive reverse transcriptase assay, investigators showed that 59% of patients in their study group with motor neuron disease were positive but only 3% of controls. However, their findings suggested that a novel retrovirus might be present because none of the usual human retroviruses such as HTV1 or HTLV-1 was identified (Andrews et al. 2000). It is already known that HTI V-l can very rarely cause an ALSmimic syndrome that may be clinically distinguished by the presence of sphincter disturbance. Indeed, certain protein sequences of both HTLV-1 and HTLV-2 have been detected with increased frequency in the peripheral blood lymphocytes ol pa lieu is with \ \ I . S . A retrospective review of 1700 cases of HIV-1-infected patients with neurological symptoms identified 6 cases presenting as a reversible ALS-like syndrome (Moulignicr et al. 2001), representing a 27-fold increased risk of developing an ALS-like disorder in that particular HIV-1 patient population. Overall, patients were somewhat younger than the normal ALS population, all but one being younger than 40 yeats at the time of diagnosis. Onset was characteristically in a monomelic pattern followed by a very rapid spread to other regions over a period of weeks. There were clinical features of both UMN and LMN involvement, with fasciculations, cramps, and bulbar symptoms. Two patients also had rapidly progressive dementia, with other features suggesting an additional diagnosis of AIDS-dementia complex. Sensory and sphincter disturbances were not apparent. CSK protein levels were sometimes mildly increased and a lymphocytic pleocytosis was evident in three patients, but all remaining laboratory results il ll\ -1 sempositivit} apart were negative. l.D.X revealed a widespread disorder of anterior horn cells in the absence of dcmyelinating conduction block, and MRI in one patient showed diffuse white matter signal increase suggestive of AIDS-dementia complex. In each case, antiretroviral therapy was beneficial either in stabilizing or in two instances curing the disease. No similar cases have been identified in this patticular study population since the introduction of highly active antiretroviral combination chemotherapy in the management of HIV infection, Another case report found similar clinical features in a 32-year-old HIV-positive patient who also enjoyed a complete response to antiretroviral therapy. MRI of brain showed increased T2-weighted signal in the brachium pontis with some minimal contrast enhancement. The resolution of motor symptoms coincided with a lack of detectable HIV in plasma and CSF. In addition, the abnormal MRI signal almost completely resolved (MacGowan, Scelsa, and Waldron 2001). Other forms of HIV may also be related ro the pathogenesis of motor neuron
DISORDERS (IF UPPER AND LOWER MOTOR NEURONS disease; a pure L M N syndrome w a s described in a w o m a n w h o w a s seropositive for H I V - 2 ,
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Johanscn, C. 6c Olson, J. H. 1998, "Mortality from amyotrophic lateral sclerosis, other chronic disorders, and electrical shocks among utility workers," Am J Epidemiol, vol. 148, no. 4, pp. 362-368 Karz, J, S., Barohn, R. J., Kojan, S., et al. 2002, "Axonal multifocal motor neuropathy without conduction block or other features of demyelination," Neurology, vol. 58, no. 4, pp. 615-620 Kaufmann, P. & Mitsumoto, H. 2002, "Amyotrophic lateral sclerosis: objective upper motor neuron markers," Cur Neurol Neuroses Rep, vol. 2, pp. 55-60 Khabazian, I., Bains, J. S., Williams D. E., er al. 2002, "Isolation of various forms of sterol heta-o-glucosidc for the seed of Cycas circinalis: Neurotoxicity and implicarions for ALSparkinsonism dementia complex,"} Neurocbem, vol. 82, no. 3, pp. 516-528 Kleopa, K. A., Sherman, M., Neal, B., et al. 1999, "RiPAP improves survival and rate of pulmonary function decline in patients with ALS," / Neurol Sci, vol. 164, pp. 82-88 Klivcnyi, P., Ferrari tc, R. J., Matthews, R, T., et al. 1999, "Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis," Nut Med, vol. 5, pp. 347-350 Lamonte, B. H., Wallace, K. E., Holloway, B. A., er al. 2002, "Disruption or dytu-iii/dviiaciin inhibits axonal transport in motor neurons causing late-onset progressive degeneration," Neuron, vol. 34, no. 5, pp. 715-727 Le Eoresrier, N,, Maisonobe, T., & Piquard, A. 2001, "Does primary lareral sclerosis exist? A study of 20 patients and ;i review of the literature," Brain, vol. 124, no. 10, pp. 19891999 I.omen-Hoerth, C, Anderson, T., & Miller, B. 2002, "The overlap of amyotrophic lateral sclerosis and fron to temporal dementia," Neurology, vol. 59, pp. 1077-1079 Lynch, T., Sano, M., Marder, K. S., et. al. 1994, "Clinical characteristics of a family with chromosome 17-iinked d ism hi hit ion-dementia-parkinsonism-amyotrophy complex," Neurology, vol. 44, pp. 1878-1884 MacCowan, D. J. 1.., Scelsa, S. N„ & Waldron, M, 2001, "An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy," Neurology, vol. 57, pp. 1094-1097 Miller, R, G., Rosenberg, J. A., Gelinas, D. F., et al. 1999, "Practice parameter: The care of the patient with amyotrophic lateral sclerosis (an evidence-based review): Report of the quality standards subcommittee of the American Academy oi Neurology: ALS Practice Parameters Task Eorce," Neurology, vol. 52, pp. 1311-1323 Miller, R. G., Mitchell, J. D., Lyon, M., & Moore, D. H. 2002, Riiuzole for Amyotrophic Lateral Sclerosis (ALS)IMotor Neuron Disease (MND) |Cochrane Review], Update Software, Oxford, The Cochrane Library, issue 3 Mitsumoto, IL, Chad, D., & Pioro, E. P. 1997, Amyotrophic Lateral Sclerosis. Contemporary Neurology Series, F. A, Davis, Philadelphia Mitsumoto, H. et al, 1997, "Motor neuron diseases," in Continuum, ed E. L. Mancall, Williams £c Wilkins, Baltimore Mitsumoto, H. & Tsu/aka, K. 1999, "Neurotropic factors and neuromuscular disease. II. GDNF, other neurotrophic factors, and future directions," Muscle Nerve, vol. 22, pp. 1000-1021 Moulard, B., Salachas, F., Chassandc, B., et al. 1998, "Association between centromeric deletions of the SMN gene and sporadic
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DISORDERS OF UPPER AND LOWER MOTOR NEURONS Silva, K. A., Orsuki, K., I.citc, A. C, et al. 2002, "HT1.V-H infection associated with a chronic neurodegenerative disease: Clinical and molecular analysis," / Med Virol, vol. 66, no. 2, pp. 253-2.57 Smith, C. D. 2002, "Serial MR1 findings in a case of primary lateral sclerosis," Neurology, vol. 57, pp. 647-649 Stambler, N., Charatan, M., Cedarbaum, J. M., et al. 1998, "Prognostic indicators of survival in Al.S, n ' Neurology, vol. 50, pp. 66-72 Suhy, J., Miller, R. G., Rule, R., et al. 2002, "Early detection and longitudinal changes in amyotrophic lateral sclerosis by ' l l MRSI," Neurology, vol. 58, pp. 773-779 Taylor, It. V., Wright, R. A„ I [arper, C. M„ & Dyck, P. J. 2000, "Natural history of 46 patients with multifocal motor neuropathy with conduction block," Muscle Nertv, vol. 23, pp. 900-908 Umapathi, T., Hughes, R. A., Nobile-Orazio, E., & Leger, J. M. 2002, Immunosuppressive Treatment for Multifocal Motor Neuropathy (Cochrane Review), Cochrane Database Syst Rev, vol. 2, no. CD0032I7
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Chapter 81 Disorders of Nerve Roots and Plexuses David A. Chad Disorders of Nerve Roots Aii.mimiL.il Features Traumatic Radiculopathies Diabetic Polyradiculoneuropathy Neoplastic Polyradiculoneuropathy (Neoplastic Meningitis) Infectious Radiculopathy Acquired PL-myciinatiiii: f'nh lMdiciiloii^uroniirhy Acquired Disorders of the Dorsal Root Ganglia Radiculopathies Simulating Motor Neuron Disease Disorders of the Brachial Plexus Anatomical Features Clinical Features and Diagnosis Neurological F.xamination
2267 2267 2269 227.5 2276 2277 2280 .': >H1 2282 2282 2282 2284 2284
DISORDERS OF NERVE ROOTS The anterior and posterior nerve roots run from the spinal cord to the dorsal root ganglia, where they unite to form the spinal nerve. They are susceptible to diseases specific to their location and to many of the disorders that affect the peripheral nerves in general. Although surrounded by a rigid bony canal, they are delicate structures subject to compression and stretching. Bathed by cerebrospinal fluid (CSF), they may be injured by infectious, inflammatory, and neoplastic processes that involve the leptomeningcs. Separated from the blood by an incomplete blood-nerve barrier, the dorsal root ganglion (DRG) neurons may be injured by circulating neurotoxins. In the clinical sphete, it is usually not difficult to recognize that a group of symptoms and signs is caused by a lesion of a nerve root. Radicular pain and paresthesias are accompanied by sensory loss in the dermatome (the area of skin innervated by one nerve root), weakness in the myotome (defined as muscles innervated by the same spinal cord segment and nerve root), and diminished deep tendon reflex activity at a segmental level subserved by the nerve root in question. When many roots are involved by a disease process (polyradiculopathy), however, the clinical picture may resemble a disorder of the peripheral nerves, as in a polyneuropathy, or of the anterior horn cells, as in the progressive muscular atrophy form of amyotrophic lateral sclerosis (ALS). Diagnosis therefore may become more difficult. Clinicians then turn to laboratory studies for help in arriving at a diagnosis.
F.Iectrodiagnostic Studies Radiological Studies Traumatic Plexopathy Neurogenic Thoracic Outlet Syndrome Metastatic and Radiation-Induced Brachial Plexopathy in Patients with Cancer Idiopathic Brachial Plexopathy Disorders of the Lumbosacral Plexus Anatomical Features Clinical Features Differential Diagnosis Structural Lumbosacral Plexopathy Nonstructural Lumbosacral Plexopathy Idiopathic Lumbosacral Plexopathy
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A disorder of the nerve roots is favored by abnormalities of the CSF (raised protein concentration and pleocytosis), of the paraspinal muscle needle electromyographic (EMG) examination (presence of positive shatp waves and fibrillation potentials), and of spinal cord magnetic resonance imaging (MRI) (compromise or contrast enhancement of the nerve roots per se). The sections that follow cover some anatomical features relevant to an understanding of the pathological conditions that affect the nerve roots, as well as specific nerve root disorders.
Anatomical Features Each nerve root is attached to the spinal cord by four to eight rootlets, which arc splayed out in a longitudinal direction (Stewart 1993). The dorsal roots are attached to the spinal cord at a well-defined posterolateral sulcus. The ventral rootlets are more widely separated and emerge over a greater area. At each spinal cord segment, a pair of dorsal and ventral roots unite just beyond the DRG to form a short mixed spinal nerve, which divides into a thin dorsal ramus and a thicker ventral ramus (Figure 8 1.1). The dorsal ramus innervates the deep posterior muscles of the neck and trunk (the paraspinal muscles) and the skin overlying these areas. The ventral ramus (the large anterior branch) contributes to the cervical, brachial, or lumbosacral plexus and thereby supplies the limb muscles. The nerve roots lie freely in the subarachnoid space covered by a thin root sheath, which is a layer of flattened 2267
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NEUROLOGICAL D1SF.ASF.S
FIGURE 81.1 Relations of dura to bone and roots of nerve shown in an oblique transverse section. On the right, the telations between the emergent nerve and the synovial joint are seen, hut the joint between the vertebral bodies is not in the plane of the section. The dorsal and ventral roots meet at the dorsal root ganglion in the intervertebral foramen to form the mixed spinal nerve. The small dorsal ramus is the most proximal branch of the mixed spinal nerve and serves the cervical paraspinal muscles (not shown). The dura becomes continuous with the epineurium of the mixed spinal nerve at the intervertebral foramen. The posterior longitudinal {Lung.) ligament {Lig.) helps contain the intervertebral disc {not shown), preventing protrusion into the spinal canal. (C.S.F. = cerebrospinal fluid; Lig. dent. = ligament dentate.) (Reprinted with permission from Wilkinson, M. 1971, Cervical Spondylosis: Its Early Diagnosis and Treatment, W'B Saunders, Philadelphia.)
cells continuous with the pial and arachnoidal coverings of the spinal cord. They lack the epineurial and perineuria] coverings found in peripheral nerves. Compared with spinal nerves, the roots have many fewer connective tissue cells in the endonenrium and considerably less collagen. A capillary network derived from the radicular arteries provides the blood supply to the spinal nerve roots (Levin 2002 . Where the nerve roots form the mixed spinal nerve, the pial covering of the root becomes continuous with spinal nerve perineurium, and nerve takes the dutal nerve root sheath through the intervertebral foramen to become continuous with the epineurium of the mixed netve. At the intervertebral foramen, the root-DRG-spinal nerve complex is securely attached by a fibrous sheath to the transverse process of the vertebral body. In general, the DRG is located in a protected position within the mien. encbijl hii.uimu. hut ;it !:unhnr and S.KT;I1 levels, the DRG resides proximal to the neural foramina, in an
intraspinal location (Levin 2002). There, they may be vulnerable to disc herniation and the complications of osteoarthritis (vide infra). Nerve fibers, together with their meningeal coverings, occupy 3 5 - 5 0 % of the cross-sectional area of an intervertebral foramen. The remaining space is occupied by loose areolar connective tissue, fat, and blood vessels. On computed tomographic (CT) and MRI scans, the fat acts as an excellent natural contrast agent that defines the thecal sac and nerve roots, allowing detection of nerve root compression. The dorsal roots contain sensory fibers that are central processes of the unipolar neurons of the DRG, On reaching the spinal cord, these fibers either synapse with other neurons of the posterior horn or pass directly into the posterior columns. In the ventral root, most fibers ate essentially direct extensions of anterior horn motor neurons (alpha, beta, and gamma) or of neurons in the in ter mediolateral horn (preganglionic sympathetic neurons found in
DISORDERS OF NERVE ROOTS AND PLEXUSES
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lower cervical and thoracic segments). In addition, ventral roots contain a population of unmyelinated and thinly myelinated axons, which come from sensory and sympathetic ganglia (Hildebrand, Karlsson, and Risling 1997]. There are 31 pairs of spinal nerves that run through the intervertebral foramina of the vertebral column: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal (Figure 81.2). A feature of clinical relevance is the pattern formed by the lumbar and sacral roots as they leave the spinal cotd and make their way to their respective DRG to form spinal nerves (see Figure 81.2). In the adult, the spinal cord is much shorter than the spinal column, ending usually between LI and 1.2. Therefore the lumbar and sacral roots descend caudally from the spinal cord to reach the individual intervertebral foramina, forming the cauda equina; the concentration of so many nerve roots in a confined area makes this structure vulnerable to a range of pathological processes (vide infra).
Traumatic Radiculopathies Nerve
Root Avulsion
The spinal roots have approximately one tenth the tensile strength of the peripheral nerves because of lesser amounts of collagen and the absence of epineurial and penneurial sheaths in the roots. Therefore the nerve roots are the weak link in the nerve root-spinal nerve-plexus complex, and nerve root avulsion from the spinal cord typically results from a severe traction injury. Ventral roots are more vulnerable to avulsion than dorsal roots, a consequence of the dorsal roots having the interposed DRG and a thicker dural sheath. In most cases, root avulsion occurs in the cervical region. Lumbosacral nerve root avulsions are rare with only 35 cases reported between 1955 and 1996 and when they occur are generally associated with fractures of the sacroiliac joint with diastasis of the symphysis pubis or fractures of the pubic rami (Chin and Chew 1997). In most cases, avulsion at the level of the cervical roots results in two distinct clinical syndromes. One is ErbDuchenne palsy, in which the arm hangs at the side internally rotated and extended at the elbow because of paralysis of C5- and C6-innervated muscles (the supraspinatus and infraspinatus, deltoid, biceps). The second is Dejcrine-Klumpke palsy, in which there is weakness and wasting of the intrinsic hand muscles with a characteristic claw-hand deformity because of paralysis of C8- and Tl-innervated muscles. Injuries responsible for ErbDuchenne palsy are those that cause a sudden and severe increase in the angle between the neck and shoulder, generating stresses that are readily transmitted in the direct line along the upper portion of the brachial plexus to the C5 and C6 roots. Today, motorcycle accidents are the most common causes of this injury, but the incidence of C5 and C6 root avulsions in the newborn during obstetrical
FIGURE 81.2 The relationship of spinal segments and nerve roots to the vertebral bodies and spinous processes in the adult. The cervical roots CI in i',7 (i.e., all except C8) exit through foramina above the vertebral body of the same number. The C8 root passes through the C7-T1 neural foramen and all thoracic, lumbar, and sacral roots leave the spinal canal below the body of the vertebrae of the same number. The spinal cord is shorter than the spinal column, ending between vertebral bodies 1.1 and L2, The lumbar and sacral roots form the cauda equina and descend caudally, beside and below the spinal curd, ro exit at the intervertebral foramina. (Reprinted with permission from Haymaker, W. Si Woodhall, B. 1953, Peripheral Nerve Injuries, 2nd ed, WB Saunders, Philadelphia.)
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NEUROLOGICAL DISEASES
procedures is increasing with the decline in the use of cesarean section. Brachial plexus injuries in the newborn are discussed in Chapter 86. The Dejerine-Klumpke palsy occurs when the limb is elevated beyond 90 degrees and tension falls directly on the lower trunk of the plexus, C8, and Tl roots. Such an injury may occur in a fall from a height in which the outstretched arm grasps an object to arrest the fall, leading to severe stretching of the C7, C8, and Tl roots. Clinical Features and Diagnosis. At the onset of root avulsion, flaccid paralysis and complete anesthesia develop in the myotomes and dermatomes served by ventral and dorsal roots, respectively. Clinical features supplemented by electrophysiological and radiological studies help determine whether the cause of severe weakness and sensory loss is root avulsion or an extraspinal plexus lesion. For example, C5 root avulsion results in virtually complete paralysis of the rhomboids and spinatus muscles (innervated primarily by C5) and a varying degree of weakness of the deltoid, biceps, brachioradialis, and serratus anterior {which receive additional innervation from C6). A clinical sign of Tl root avulsion is an ipsilateral Horner's syndromi- caused by damage to preganglionic sympathetic fibers as they traverse the ventral root to their destination in the superior cervical ganglion. The electrophysiological tests include the measurement of a sensory nerve action potential (SNAP) and needle EMG examination of the cervical paraspinal muscles. In the setting of an isolated C5 root avulsion, the SNAP should be preserved, despite complete anesthesia in the dermatome because the peripheral axons and the DRG cell bodies remain intact. Needle EMG of the cervical paraspinal muscles permits separation of damage of the plexus and of ventral root fibers because the posterior primary ramus, which an-:--. |HM lic\nid LV l)R(, ami proximal re tinplexus as the first branch of the spinal nerve, innervates these muscles (see Figure 81.1). Thus cervical paraspinal fibrillation potentials support the diagnosis of root avulsion. Paraspinal muscles have also been evaluated radiologically in the setting of root avulsion. Contrastenhanced MRI studies of the cervical paraspinal muscles showing severe atrophy were accurate in indicating root avulsion injuries, and abnormal enhancement in the multifidus muscle was the most accutatc among paraspinal muscle findings (Hayashi et al. 2002), Intraspinal neuroimaging using postmyelographic CT or MRl usually demonstrates an outpouching of the dura filled with contrast or CSF at the level of the avulsed root. This post-traumatic meningocele results from tears in the dura and arachnoid sustained during root avulsion. Postmyelographic CT with 1- to 3-mm axial slices provides accurate diagnosis on the status of nerve roots in 8 5 % of patients, compared to 5 2 % for MRI (Carvalho et al. 1997). Gadolinium-enhanced MRI appears to offer a promising noninvasive means to evaluate traumatized nerve roots by
visualizing the spinal cord surface at the root entry /one ("root-stump" enhancement) and by noting enhancement of intradural nerve roots (Hayashi et al. 1998}. In most cases, these tests are helpful in ascertaining whether root avulsion has occurred. Sometimes, however, clinical assessment is difficult and results of testing are ambiguous. The physical examination may be limited because of severe pain. An absent SNAP indicates sensory axon loss distal to the ORG but docs not exclude coexisting root avulsion. Even when rhis test of sensory function points to avulsion of the dorsal component of the root, the status of the ventral root may remain uncertain if paraspinal fibrillation potentials are not found. There arc two reasons for their absence: First, they do not appear for 7-10 days after the onset of axonotmesis, and second, even if the timing of the needle EMG is right, they may not be seen because of innervation of the paraspinal muscles from multiple segmental levels. Finally, imaging studies are nor always diagnostically accurate, at times disclosing classic post-traumatic meningoceles in patients without root avulsion (but only dura] tear) or revealing normal findings in true root avulsion (dc Verdier, Collctti, and Terk 1993). The difficulty in establishing a definitive diagnosis of root avulsion based on FMG and ncuroiinaging in some cases has led to a potentially important role for intraoperative evoked potentials to establish whether the root in question is in continuity (Oberle et al. 1998). Treatment. Root avulsion produces a severe neurological deficit that has long been considered an unbeatable injury. Carlstedt et al. (1995), however, repotted on a patient who had an avulsion injury involving C6-T1 in whom they were able to implant successfully two ventral roots (C6, directly; and C7, via sural nerve grafts) into the spinal cord through slits in the pia mater. The surgical treatment of patients with avulsion injuries is an area of active ongoing investigation with the promise that if continuity between spinal cord and nerve roots can be restored, subsequent recovery of function may be possible (Fournier et al. 2001). Until repair of spinal nerve roots has become a more effective and reliable procedure, other approaches to management will be needed. When paralysis of the limb is complete, amputation may be indicated. With a less profound degree of injury, muscle and tendon transplants are sometimes used. In the case of a more restricted injury affecting only the low cervical roots and T l , eatly belowelbow amputation plus a below-elbow prosthesis has been recommended. The sometimes intractable pain of cervical root avulsion injuries may be successfully treated with dorsal root entry zone coagulation procedures (Samii et al. 2001). Disc
Herniation
beginning in I he third or fourth decade of life, cervical and lumbar intervertebral discs are liable to herniate into the
DISORDERS OF NERVE ROOTS AND PLEXUSES
2271
FIGURE SI.3 Dorsal view of the lower lumbar spine and sacrum, showing the different types of herniations and how different routs and the cauda equina an be compressed. (Reprinted with permission from Stewart, J. D. 1993, focal Peripheral Neuropathies, 2nd cd, Raven Press, New York.)
spinal canal or intervertebral foramina and impinge on the spinal cord (in the case of cervical disc herniations), nerve roots (in both cervical and lumbosacral regions), or both (at the cervical level, where on occasion large central and paracentral disc herniations may produce a myeloradiculopathy) (see Chapter 79). Two factors contribute to this alteration in the intervertebral discs: degenerative change and trauma. The fibers of the annulus fibrosus that surround the nucleus pulposus lengthen, weaken, and fray with age and use, thereby allowing the disc to bulge posteriorly. In the setting of such changes, relatively minor ttauma leads to further tearing of annular fibers and ultimately to herniation of disc material. This "soft-disc" herniation occurs mainly during the third and fourth decades of life when the nucleus is still gelatinous. In fact, although disc herniations may be preceded by unaccustomed strain or direct injury, in many instances, there is no history of clinically significant trauma preceding the onset of radiculopathy. Reinforcing the annulus fibrosus posteriorly is the posterior longitudinal ligament, which in the lumbar region is dense and sttong ccnttally and less well developed in its lateral portion. Because of this anatomical feature, the direction of lumbar disc herniations tends to be posterolateral, compressing the nerve roots in the lateral recess of the spinal canal, I.ess commonly, more lateral (foraminal) herniations compress the nerve root against the
vertebral pedicle in the intervertebral foramen (Figure 81.3). On occasion, the degenerative process may be particularly severe. This leads to large rents in the annulus and posterior longitudinal ligament, thereby permitting disc material to herniate into the spinal canal as a free fragment with the potentially damaging capacity to migrate superiorly or inferiorly and compress two or more nerve roots of the cauda equina. Most cervical disc herniations are posterolateral or foraminal. In the cervical and lumbar regions, alteration in the integrity of the disc space is a component of a degenerative condition, tetmed spondylosis, characterized by osteoarthritic changes in the joints of the spine, the disc per se (desiccation and shrinkage of the normally semisolid, gelatinous nucleus pulposus) and the facet joints. [mmunohistochemica! examination of herniated cervical discs points to an inflammatory process associated with neovascularization and increased expression of matrix mctalloproteinase and inducible nitric oxide (NO) synthetase (Furusawa ct al. 2001), The release of NO by disc cells may contribute to the process of disc degeneration by inducing apoptosis of disc cells (Kohyama et al. 2000). Because it spawns osteophyte formation, spondylosis leads to compromise of the spinal cord in the spinal canal and the nerve roots in the i met vertebral foramina. The restriction in the dimensions of these bony canals may be exacerbated by thickening and hypertrophy of the ligamentum flavum,
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NEUROLOGICAL DISEASES
which is especially detrimental in patients with congenital cervical or lumbar canal stenosis. In the cervical region, nerve root compression in patients older than 50 years is often caused by disc herniation superimposed on chronic spondylotic changes. Isolated "soft" cervical disc herniation tends to occur in younger people in the setting of neck trauma. In the lumbosacral region, isolated acute disc herniation is a common cause of radiculopathy in the younger patient (M>;is. quadriceps, and hip adductors), reduced or absent patellar reflex, and mild impairment of sensation over the anterior thigh. As rime passes, there may be territorial spread, a term used by Bastron and Thomas in 19S1 to describe proximal, distal, or contralateral involvement as the polyradiculoneuropathy evolves. Worsening may occur in a steady or a stepwise fashion, and it may take several weeks to progress from onset to peak of the disease, At its peak, weakness varies in seventy and extent from a mildly affected patient, with slight, unilateral thigh weakness, to a profound degree of bilateral leg weakness in the territory of the L2-S2 nerve roots. Upper extremity involvement appears to occur in approximately 1 5 % of patients with diabetic lumbosacral radicular plexopathy as
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NEUROLOGICAL DISEASES
a unilateral or asymmetrical sensorimotor neuropathy that primarily affects hands and forearms. Like the lumbosacral syndrome, EMG findings suggest a multifocal axon-loss process localized to roots, plexus, or peripheral nerve (Karz et al. 2001). Rarely, the process of territorial spread is so extensive that ir involves a multiplicity of nerve roots along the entire spinal cord and leads to profound generalized weakness, a condition designated diabetic cachexia. Diabetic polyradiculoneuropathy tends to affect patients in the sixth or seventh decade of life, who are known to have non-insulin-dependent diabetes of several years' duration. The syndrome of painful polyradiculoneuropathy, whether referable to thoracic or lumbosacral roots, may, however, be the presenting manifestation of diabetes. In 3 0 - 5 0 % of patients, the disorder is preceded by substantial weight loss of 30-40 pounds. 1 abnnitory studies disclose devated fasting blood glucose in the vast majority of patients; when values arc normal, they ate found in treated diabetics. The erythrocyte sedimentation rate is usually normal, but in a subgroup of patients with diabetic lumbosacral polyradiculoneuropathy, it is elevated, a clue perhaps to an immune-mediated pathogenesis (vide infra). The typical electrodiagnostic findings comprise features of a sensorimotor axon-loss polyneuropathy with additional needle electrode examination findings of lumbosacral root and plexus involvement (active and chronic denervation changes in paraspinal, pelvic-girdle, and thigh muscles). Although clinical findings may point to unilateral involvement, the electrodiagnostic examination generally discloses bilateral signs. Imaging studies of the thoracic and lumbosacral spinal canal with CT, myelography, and MRI are typically normal and almost always necessary to exclude a structural abnormality of the nerve roots that may simulate diabetic polyradiculopathy. The CSF protein level is usually increased to an average of 120 mg/dL, but in some patients, values exceed 350 mg/dL; pleocytosis is not a feature of this condition. Biopsy of proximal nerve sensory branches reveals axon loss and dcmyclination; in more severely affected patients, inflammatory cell infiltration and vasculitis is found {Said et al. 1994). Further studies of nerve biopsy specimens indicate that a microscopic vasculitis {involvement of small arterioles, venules, and capillaries) leads to ischemic injury, which in turn causes axonal degeneration and secondary segmental demyelination (Dyck, Norell, and Dyck 1999). The presence of a smallvessel vasculitis with distinctive pathological features including transmural polymorphonuclear leukocyte infiltration of postcapillary venules and endothelial deposits of immunoglobulin M (IgM) and activated complement supports an immune-mediated inflammatory pathogenesis for this disorder (Kelkar, Masood, and Parry 2000). Electrophysiological studies have suggested that a demyelinating polyneuropathy indistinguishable from chronic inflammatory demyelinating polyneuropathy occurs frequently in diabetes and may be the cause of a severe
motor sensory polyneuropathy, sometimes with features of a plexopathy (Sharma et al. 2002a, 2002b). The natural history of diabetic polyradiculoneuropathy is for improvement to occur in most patients, although the recovety phase is lengthy, ranging between 1 and 18 months with a mean of 6 months. Pain and dysesthesias improve or disappear entirely in 8 5 % of patients; numbness improves or recovers in 5 0 % ; and strength is partially or completely restored in 7 0 % . In some patients, episodes recur. Therapy is usually directed toward ameliorating the severe pain of this condition. The tricyclics, especially nortriptyline (with a better side-effect profile than amitriptyline), selective serotonin reuptake inhibitors (such as sertraline and nefazodone hydrochloride), anticonvulsants (gabapentin and carbamazepine), clonazepam, baclofen, clonidine, mexiletine, intravenous lidocaine, and topical capsaicin may have a role separately or in combination. Histopathological findings {vide supra) indicative of an immune-media ted pathogenesis have led to treatment of selected patients with intravenous immunoglobulin or immunosuppressive treatment or both (Krendcl, Costigan, and Hopkins 1995; Younger, Rosoklija, and Hays 1998). Although immunotherapy may be beneficial, spontaneous improvement in some patients with painful proximal diabetic neutopathy with different patterns of inflammatory nerve lesions has been described (Said et al. 1997). Prospective studies have suggested a role for immunotherapy in the treatment plan of diabetic polyradiculoneuropathy where electrophysiological findings arc those of chronic infla minatory d c : m d u u t m g poK in'iinipailn (Sharma et al. 2002a, 2002b). The major differential diagnostic considerations are polyradiculoneuropathies related to degenerative disc disease and infectious, inflammatory, and neoplastic processes. These can usually be excluded by history, examination, and routine laboratory investigations, including CSF analysis. In our experience, however, the clinical presentation provoking the most anxiety is the frail elderly patient not known to be diabetic who has weight loss and the abrupt onset of lower extremity pain and weakness that progresses over months. In such a patient, the specter of neoplasia looms large, and thorough imaging studies of the nerve roots and plexuses are mandatory.
Neoplastic Polyradiculoneuropathy (Neoplastic Meningitis) A wide variety of neoplasms are known to spread to the leptomeninges. These include solid tumors (carcinoma of the breast and lung and melanoma), non-Hodgkin n s lymphomas, leukemias, and intravascular lymphomatosis (Viali et al. 2000), Although neoplastic polyradiculoneuropathy usually occurs in patients known to have an underlying neoplasm, meningeal symptoms may be the first
DISORDERS OF NERVE ROOTS AND PLEXUSES
2277
FIGURE 81.6 Cauda equina in leptomeningeal carcinomatosis. Seeding of multiple nerve roots by adenocarcinoma produces a nodular appearance. (Courtesy Dr. T. W. Smith, Department of Pathology [Neuropathology!, University of Massachusetts Medical Center, Worcester.) manifestation of malignancy. The clinical features of neoplastic polyradiculoneuropathy include radicular pain, dermatoma) sensory loss, areflexia, and weakness of the lower motor neuron type (Balm and Hammack 1996). Often, the distribution of the sensory and motor deficits is widespread and simulates a severe sensorimotor polyneuropathy. Often, associated clinical manifestations result from infiltration of the meninges, such as nuchal rigidity, confusion, and cranial polyneuropathies. At postmortem examination, the cauda equina shows discrete nodules or focal granularity (Figure 81.6). Microscopy discloses spinal roots encased by tumor cells, which appear to infiltrate the root. It is presumed that disturbed nerve root function results from several mechanisms, including nerve fiber compression and ischemia. The most revealing diagnostic procedure is the lumbar puncture, which is almost always abnormal, disclosing one or more or the following: mononuclear pleocytosis, reduced CSF glucose, elevated protein, and neoplastic cells. Spinal fluid cytology is, however, persistently negative in about 10% of patients with leptomeningeal carcinomatosis (Grossman and Krabak 1999}. A sensitive electrophysiological indicator of nerve root involvement is a change in the F wave. In the symptomatic patient with cancer, prolonged F-wave latencies or absent F responses should raise suspicion of leptomeningeal metastases. Postmyelqgraphy CTadds srrong evidence in support of the diagnosis if it demonstrates multiple nodular defects on the nerve roots. Spinal MRI, especially with gadolinium enhancement, however, is the test of choice in the patient with cancer in whom leptomeningeal involvement of the spine is suspected {Watanabe, Tanaka, and Takeda 1993). Approximately
5 0 % of patients with neoplastic meningitis and spinal symptoms have abnormalities on these studies. Gadoliniumenhanced MRI of the brain discloses abnormalities, including contrast enhancement of the basilar cisterns or cortical convexities and hydrocephalus. Standard therapy for neoplastic meningitis that increases median survival to 3-6 months includes radiotherapy to sires of symptomatic disease, intrathecal chemotherapy [methotrexate, thiotcpa, and Ara-C), and optimal treatment of the underlying malignancy. A complication of aggressive treatment is a necrotizing leukoenecphalopathy that becomes symptomatic months after treatment with radiation and intrathecal methotrexate (Grossman and Krabak 1999).
Infectious Radiculopathy Tabes Dor sal is Tabes dorsalis, the most common form of neurosyphilis, begins as a spirochetal {Treponema pallidum) meningitis (see Chapter 59). After 10-20 years of persistent infection, damage to the dorsal roors is severe and extensive, producing a set of characteristic symptoms and signs. Symptoms are lightning pains, ataxia, and bladder disturbance; signs are Argyll Robertson pupils, areflexia, loss of proprioceptive sense, Charcot joints, and trophic ulcers. Lancinating or lightning pains are brief, sharp, and stabbing; they are more apt to occur in the legs than elsewhere. Sensory disturbances, such as coldness, numbness, and tingling, also occur and are associated with
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NEUROLOGICAL DISEASES
impairment of light-touch, pain, and thermal sensation. Sudden visceral crises, characterized by the abrupt onset of epigastric pain that spreads around the body or up over the chest, occur in some 2 0 % of patients. Most of the features of tabes dorsaiis can be explained In lesions D] rlu' posterior roots. Ataxia is caused by fludestruction of proprioceptive fibers; insensitivity to pain is the result of partial loss of small myelinated and unmyelinated fibers; and bladder hypotonia with overflow incontinence, constipation, and impotence is the result of sacral root damage. Pathological study discloses thinning and grayness of the posterior roots, especially in the lumbosacral region, and the spinal cord shows degeneration of the posterior columns. A mild reduction of neurons in the ORG occurs, and there is little change in the peripheral nerves. Inflammation may occur all along the posterior root. The CSF is abnormal in active cases. The opening pressure is elevated in 10% of patients. Fifty percent of patients have a mononuclear pleocytosis (5-165 cells/mL). More than 50% have mild protein elevation (45-100 mg/dL, with rare instances of values between 100-250 mg/dL), and 72% have positive CSF serology. In all cases of neurosyphilis, antibodies specific for T. pallidum are found, and the preferred treatment is aqueous penicillin C, 2-4 million units intravenously every 4 hours for 10-14 days, with careful CSF follow-up. CSF examination 6 months after treatment should demonstrate a normal cell count and decreasing protein content. If not, a second course of therapy is indicated. The CSF examination should be repeated every 6 months for 2 years or until the fluid is normal. Polyradiculoneuropathy in Virus-Infected Patients
Human
Immunodeficiency
Cytomegalovirus (CMV) polyradiculoneuropathy is a rapidly progressive, opportunistic infection that usually occurs late in the course of human immunodeficiency virus (HIV) infection, when the CD4 count is very low (:Hinini \ a n d the nerve 11 b i t s
have received a neuropraxic injury with minimal axonotmesis, then return of normal strength and sensation is expected. In the face of axonotmesis, the main factor limiting return of function is the distance the regenerating axon sprouts must traverse before making contact with end organs. Unless the muscles and sensory receptors are rcinnervated within approximately 1 year, a good functional result is unlikely. Thus recovery of proximal muscle strength from upper portions of the plexus is more likely than recovery of hand function when lower elements have been damaged.
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NEUROLOGICAL DISEASES
Often, surgery must be performed to provide an exact intraoperative definition of the lesion's extent (see Chapter 56D) (Berger and Becker 1994). Intraoperative motor evoked potentials are helpful in assessing the functional state of anterior motor roots and motor fibers. Depending on the findings, neurolysis, nerve grafting, or re-neurotization is performed. Primary nerve reconstruction combined with joint fusion and tendon transfers provides a worthwhile return of function to many patients. The joint and tendon surgeries are best performed as secondary operations after a period of physiotherapy. Intensive physiotherapy and use of orthoses are often necessary to help restore maximum function. In general, the outcome after nerve grafting is relatively good for recovery of elbow flexors and extensors and for those of the shoulder girdle, but it is very pooi for forearm and hand ir.lniisic muscles. Ou.iliu "I life surveys after brachial plexus surgery indicate that 78% of patients report at least moderate satisfaction (Choietal. 1997).
electrophysiological findings point to a lesion of the lower trunk of the brachial plexus. Levin, Wilbourn, and Maggiano {1998) have refined our understanding of the precise lesion localization of the neurogenic thoracic syndrome. They compared electrophysiological results between a group of patients with true neurogenic thoracic outlet syndrome and a group with "brachial plexopathy" stemming from median sternotomy. In the former group, the findings pointed to severe axon loss in the medial antebrachial cutaneous nerve and the abductor pollicis brevis, both sharing Tl root innervation. In the latter, an iatrogenic disorder resulting from rib retraction, the findings indicated axon loss in the ulnar sensory and motor nerves, conforming most to involvement predominantly of C8. These findings suggest that thoracic outlet syndrome and median sternotomy brachial plexopathy are more accurately described as "extraspinal radiculopathies" with damage i the root fillers .n die level of die anterior primary rami (Levin 2002)—distal to the C8 or Tl nerve roots per se, but proximal to the lower trunk of the brachial plexus.
Neurogenic Thoracic Outlet Syndrome
In most patients, a fibrous band extending from the rip of a rudimentary cervical rib to the scalene tubercle of the first rib causes angulation of either the C8 and Tl roots or the lower trunk of the brachial plexus (Figure 81.10). Surgical division of the fibrous band can be expected to relieve pain and paresthesias and arrest muscle wasting and weakness in the majority of patients; return of muscle bulk and strength, however, is unlikely.
Although it is frequently diagnosed, neurogenic thoracic outlet syndrome is a rare entity, seen only once or twice a year in busy EMG laboratories. Most patients are women. The mean age at onset is 32 years, but patients as young as 13 and as old as 73 years have been reported. Pain is usually the first symptom, with either aching noted on the inner side of the arm or soreness felt diffusely throughout the limb. Tingling sensations accompany pain and are felt along the inner side of the forearm and in the hand. Most patients note slowly progressive wasting and weakness of the hand muscles. The physical examination discloses hand muscle weakness and atrophy, most marked in the lateral part of the thenar eminence. In a smaller number of patients, there is mild atrophy and weakness in the forearm muscles. Sensory loss is present along the inner side of the forearm. Except for the occasional Ravnaud's-type episode, vascular symptoms and signs are uncommon. In many cases, cervical spine roentgenograms disclose small bilateral cervical ribs or enlarged down-curving C7 transverse processes. When not visualized in anteroposterior radiographs of the cervical spine, they can he seen on oblique views. MRI of the brachial plexus is a useful diagnostic method, revealing deviation or distortion of nerves or blood vessels and suggesting the presence of radiographically invisible bands (Panegyres et al. 1993). Electrodiagnostic studies on the affected side disclose a reduced median motor response with normal median sensory amplitudes along with a mildly reduced ulnar motor response and reduced ulnar sensory amplitude. The needle electrode examination typically discloses features of chronic axon loss with mild fibrillation potential activity in C8- and Tl-innervated muscles. The cluneal and
Metastatic and Radiation-Induced Brachial Plexopathy in Patients with Cancer Metastatic
Plexopathy
Damage to the brachial plexus in patients with cancer is usually secondary to either metastatic plexopathy or radiation-induced injury. Lung and breast carcinoma are the tumors that most commonly metastasize to the brachial plexus; lymphoma, sarcoma, melanoma, and a variety of other types are less common. Tumor metastases spread via lymphatics, and the area most commonly involved is adjacent to the lateral group of axillary lymph nodes. The hallmark of metastatic plexopathy is pain, which is often severe. It is generally located in the shoulder girdle and radiates to the elbow, medial portion of the forearm, and fourth and fifth digits of rhe hand. In many patients, the neurological examination discloses signs referable to the lower plexus and its divisions; more than one half the patients have Horner's syndrome, whereas few have lymphedema of the affected limb. The predilection for involvement of the C8 and Tl spinal nerves and the lower trunk can be explained by the fact that the lateral group of axillary lymph nodes that drain the commonly located sites (breast and lung J are in close contact with the divisions of
DISORDERS OF NF.RVF. ROOTS AND PI.F.XUSKS
119,7
FIGURE 81.10 (A) The normal relationships of the subclavian artery and the brachial plexus as they course over the first rib between the scalenus medius and anterior muscles. {15} From the end of a short cervical rib arises a fibrous band {arrow), which attaches to the upper surface of the normal first rib. This stretches and angulates chiefly the lower trunk of the brachial plexus, causing neurogenic thoracic outlet syndrome. (Reprinted with permission from Stewart, J. 1), 1993, Focal Peripheral Neuropathies, 2nd ol, R.uvn I'IVSS. New York.)
the lower trunk; the upper trunk and its divisions arc remarkably free of lymph nodes. Some patients have signs indicating involvement of the entire plexus. In most of these patients, however, cervical CT myelography or MRI discloses epidural deposits that explain the upper plexus (C5 and C6 root) signs. An important syndrome first described by Pancoast in 1932 is a superior pulmonary sulcus rumor, the vast majority of which are non-small cell bronchogenic carcinomas (Arcasoy and Jett 1997). The tumor arises near the pleural surface of the apex of the lung and grows into the paravertebral space and posterior chest wall, invading the C8 and Tl extraspinal roots, the sympathetic chain and stellate ganglion, the necks of the first three ribs, and the transverse processes and borders of the vertebral bodies of C7 through T 3 . The tumor may eventually invade the spinal canal and compress the spinal cord. Clinical features include a number of symptoms and signs: severe shoulder pain tadiating to the head and neck, axilla, chest, and arm; pain and paresthesias of the medial aspect of the arm and the fourth and fifth digits; and weakness with atrophy of intrinsic hand muscles. On occasion, metastatic brachial plexopathy may be difficult to distinguish from radiation plexopathy (see Radiation-Induced Plexopathy, later in this section). Imaging studies are usually informative. In patients with metastases, MRI can identify a mass adjacent to the brachial plexus and reveal whether the tumor has
encroached on the epidural space. CT remains a valued alternative investigation technique for this region because it provides good definition of the vertebral bodies. Nevertheless, sometimes exploration and biopsy by direct visualization may he the only definitive way to distinguish metastatic from radiation-induced plexopathy. Results of the treatment of metastatic plexopathy are disappointing. Radiotherapy to the involved field and chemothetapy of the underlying tumor are the mainstays of treatment. Radiotherapy may relieve pain in 5 0 % of patients but has little effect on return of muscle strength. A variety of procedures have been implemented to ameliorate the severe pain of this condition, including transcutaneous stimulation, paravertebtal sympathetic blockade, and dorsal rhizotomies. In the patient with Pancoast's tumor, preoperative radiotherapy followed by extended surgical resection is the most common treatment, with an overall 5-year survival rate of 2 0 - 3 5 % (Arcasoy and Jett 1997). Radiation-Induced
Plexopathy
Radiation-induced plexopathy is unlikely to occur if the dose is less than 6000 eGy. If more than 6000 cGy is given, the interval betw-een the end of radiation therapy and the onset of symptoms and signs of radiation plexopathy ranges from 3 months to 26 years, with a mean interval of approximately 6 years. The brachial plexus is more vulnerable to large fraction size, and thus fractions of
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NEUROLOGICAL DISEASES
200 cGy or less are recommended. Cytotoxic therapy adds to the damaging effect of radiotherapy (Olsen et al. 1993). Limb paresthesias and swelling arc common complaints. Although the pain of radiation plexopathy is usually less intense than that of metastatic plexopathy, it may nonetheless be problematic (severe and persistent) requiring opioids; and in refractory cases responding to chemical sympathectomy (Fathers et al. 2002). Weakness is usually most prominent in muscles innervated by branches of the upper trunk, but involvement of the entire limb, from damage to the upper and lower portions of the plexus, has also been described. Indeed, in a group of women with radiation plexopathy following treatment for carcinoma of the breast, progressive weakness resulted in loss of hand function in 9 0 % of patients (Fathers et al. 2002). The relative resistance of the lower trunk of the brachial plexus to radiation injury is perhaps explained by the protective effect of the clavicle and the relatively shorter course of the lower trunk and its divisions through the radiation port. The pathogenesis of radiation damage is thought to involve two factors: radiation-induced endoneurial and perineuria! fibrosis with obliteration of blood vessels (triggered by small-vessel endothelial injury), and direct radiation-induced damage to myelin sheaths and axons. Arteritis (radiation-induced) of large vessels was found in a patient with delayed onset of brachial plexopathy following radiation therapy for breast carcinoma (21 years), who underwent arteriography for acrocyanosis in the affected limb (Rubin et al. 2001). The natural history of radiation-induced plexopathy is that of steadily increasing deterioration, although at times a plateau may be reached after 4-9 years of progression. A diagnostic dilemma arises when symptoms and signs of brachial plexopathy develop in a patient who is known to have had cancer and radiation in the region of the brachial plexus, A painful lower trunk lesion with Horner's syndrome strongly suggests metastatic plexopathy, whereas a relatively painless upper trunk lesion with lymphedema favors radiation-induced plexopathy. MRI is inn always discriminating between metastatic and radiation because it may reveal an appearance of high signal intensity on T2-weighted images and contrast enhancement in cases of both radiation fibrosis and tumor infiltration (Wouter van Es et al. 1997). In the early and middle stages of radiation plexopathy, nerve conduction studies disclose features of de myelin a ting conduction block, but as time passes, studies reveal evidence of conversion to axon loss (Ferrante and Wilbourn 2002). Needle EMG is helpful in separating radiation-induced plexopathy from neoplastic plexopathy by the presence of myokymic discharges in the former. These are spontaneously occurring grouped action potentials {triplets or muitiplets) followed by a period of silence, with subsequent repetition of a grouped discharge of identical potentials in a
semi rhythmic manne
