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CURRENT THERAPY IN NEUROLOGIC DISEASE Copyright © 2006, Mosby Inc.
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ISBN-13: 978-0-323-03432-6 ISBN-10: 0-323-03432-2
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Contributors Neha P. Amin, B.S., B.A.S.
Anish Bhardwaj, M.D., F.A.H.A., F.C.C.M.
Medical Student, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Associate Professor of Neurology, Neurological Surgery, and Anesthesiology Critical Care Medicine; Director, Neuroscience Critical Care Fellowship Program; Vice Chairman, Department of Neurology, Johns Hopkins University School of Medicine; Co-Director, Neurosciences Critical Care Division; Attending Physician, Johns Hopkins Hospital and Bayview Medical Center, Baltimore, Maryland
Optic Neuritis
Charles E. Argoff, Ph.D. Assistant Professor of Neurology, New York University School of Medicine; Director, Cohn Pain Management Center, North Shore University Hospital, Bethpage, New York
The Unconscious Patient
Chronic Pain Management: General Principles
Kevin M. Biglan, M.D., M.P.H. Allen J. Askamit, Jr., M.D. Associate Professor of Neurology, Mayo College of Medicine; Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota
Assistant Professor of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York Huntington’s Disease
Acute Bacterial Meningitis
Tom J. Blanchard, M.R.C.P., DTM&H, Ph.D.
Alon Y. Avidan, M.D., M.P.H.
Senior Lecturer in Tropical Medicine, Clinical Research Group, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
Assistant Professor of Neurology, University of Michigan Medical School; Director, Sleep Disorders Clinic, University of Michigan Health System, Ann Arbor, Michigan Parasomnias
Cerebral Malaria
John B. Bodensteiner, M.D.
Associate Professor of Neurology and Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Professor of Clinical Pediatrics and Neurology, Department of Pediatrics, University of Arizona College of Medicine; Chief, Pediatric Neurology, St. Joseph’s Hospital and Children’s Health Center, and Barrow Neurological Institute, Phoenix, Arizona
Optic Neuritis
Tuberous Sclerosis Complex
Tallie Z. Baram, M.D., Ph.D.
Devin L. Brown, M.D.
Laura J. Balcer, M.D., M.S.C.E.
Professor of Pediatrics, Anatomy/Neurobiology, and Neurology and Danette Shepard Professor of Neurological Sciences, Department of Pediatrics, University of California, Irvine, School of Medicine, Irvine, California
Assistant Professor of Neurology, University of Michigan Medical School; Staff Neurologist, Stroke Program, University of Michigan Health System, Ann Arbor, Michigan
Neonatal Seizures and Infantile Spasms
Emboli of Cardiac Origin
Allan J. Belzberg, M.D.
John C. M. Brust, M.D.
Associate Professor of Neurosurgery, Johns Hopkins University School of Medicine; Attending Neurosurgeon, Johns Hopkins Hospital, Baltimore, Maryland Peripheral Nerve Injury
Professor of Clinical Neurology, Columbia University College of Physicians and Surgeons; Director, Department of Neurology, Harlem Hospital Center, New York, New York Alcohol Intoxication and Withdrawal
Sara E. Benjamin, M.D. Chief Resident, Department of Neurology, George Washington University School of Medicine and Health Sciences, Washington, DC Wernicke Disease and Korsakoff Psychosis
Arthur L. Burnett, M.D. Professor of Urology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Hospital, Baltimore, Maryland Urinary and Sexual Dysfunction in Multiple Sclerosis and Myelitis
Anthony S. Burns, M.D. Assistant Professor of Rehabilitation Medicine, Jefferson Medical College of Thomas Jefferson University; Assistant Director, Regional Spinal Cord Injury Center of the Delaware Valley, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Acute Spinal Cord Injury
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iv
Contributors
Peter Calabresi, M.D.
Ricardo Cruciani, M.D., Ph.D.
Associate Professor of Neurology, Johns Hopkins University School of Medicine; Director, Multiple Sclerosis Center, Johns Hopkins Hospital, Baltimore, Maryland
Assistant Professor, Department of Neurology and Anesthesiology, Albert Einstein College of Medicine of Yeshiva University, Bronx; Director, Research Division, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, New York
Multiple Sclerosis
Grant L. Campbell, M.D., Ph.D. Chief, Arboviral Diseases Branch, Epidemiology Section, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado Arthropod-Borne Virus Infections
Herpes Zoster and Postherpetic Neuralgia
Marinos C. Dalakas, M.D. Chief, Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland Immune-Mediated Inflammatory Myopathies
Vinay Chaudhry, M.D., F.R.C.P. Professor of Neurology, Johns Hopkins University School of Medicine; Vice Chair, Clinical Affairs, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Josep Dalmau, M.D., Ph.D.
Intravenous Immunoglobulin and Plasmapheresis in the Treatment of Neurologic Disease
Associate Professor of Neurology, University of Pennsylvania School of Medicine; Attending Neurologist, Section of Neuro-oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
William P. Cheshire, Jr., M.D., M.A.
Remote Effects of Cancer: Treatment of Paraneoplastic Neurologic Syndromes
Associate Professor of Neurology, Mayo Clinic College of Medicine, Jacksonville, Florida
Stephanie K. Daniels, Ph.D.
Trigeminal and Glossopharyngal Neuralgia
Kenneth Cohen, M.D., M.B.A. Associate Professor of Oncology and Pediatrics, Johns Hopkins University School of Medicine; Director, Pediatric Neuro-oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland Childhood Brain Tumors
Andrew J. Cole, M.D., F.R.C.P.C.
Adjunct Assistant Professor, Department of Psychiatry and Neurology, Tulane University School of Medicine; Research Speech Pathologist, Research Service, VA Medical Center, New Orleans, Louisiana Dysphagia: Diagnosis and Treatment
Larry E. Davis, M.D., F.A.A.N., F.A.C.P. Professor of Neurology, University of New Mexico School of Medicine; Chief, Neurology Service, New Mexico VA Health Care System, Albuquerque, New Mexico
Associate Professor of Neurology, Harvard Medical School; Director, MGH Epilepsy Service, Neurology Service, Massachusetts General Hospital, Boston, Massachusetts
Fungal Infections
First Generalized Seizure
Professor of Neurology, Mayo Clinic College of Medicine, Scottsdale, Arizona
Anne Comi, M.D.
Chronic Daily Headache
Assistant Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Director, Johns Hopkins–Kennedy Krieger Sturge-Weber Syndrome Center, Baltimore, Maryland Sturge-Weber Syndrome
James J. Corbett, M.D.
David W. Dodick, M.D.
Heinrich Elinzano, M.D. Postdoctoral Fellow in Neuro-oncology, Medical Oncology Department, Johns Hopkins University School of Medicine, Baltimore; Clinical Fellow in Neuro-oncology, Neuro-oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
McCarly Professor and Chair, Department of Neurology, and Professor of Ophthalmology, University of Mississippi School of Medicine, Jackson, Mississippi; Lecturer in Ophthalmology, Harvard Medical School/Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
Epidural Spinal Cord Compression and Leptomeningeal Metastasis
Idiopathic Intracranial Hypertension
Neurogenic Orthostatic Hypotension
Andrea M. Corse, M.D.
Anne L. Foundas, M.D.
Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Attending Neurologist and Director, Neuromuscular Pathology Laboratory, Johns Hopkins Hospital, Baltimore, Maryland
Professor of Neurology, Department of Psychiatry and Neurology, Tulane University School of Medicine; Research Clinician, Neurology Service, VA Medical Center, New Orleans, Louisiana
Myasthenia Gravis
Dysphasia: Diagnosis and Treatment
Nathan E. Crone, M.D.
Jacqueline A. French, M.D.
Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Professor of Neurology, University of Pennsylvania School of Medicine; Co-Director, Penn Epilepsy Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Absence Seizures
Robert D. Fealey, M.D. Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota
Treatment of Newly Diagnosed Complex Partial Seizures
Contributors
Linda P. Fried, M.D., M.P.H.
Benjamin M. Greenberg, M.D., M.H.S.
Professor of Medicine, Epidemiology, Health Policy, and Nursing, Johns Hopkins University School of Medicine; Director, Division of Geriatric Medicine and Gerontology; Director, Center on Aging and Health, Johns Hopkins Medical Institutions, Baltimore, Maryland
Instructor, Johns Hopkins University School of Medicine; Fellow, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland
v
Intravenous Immunoglobulin and Plasmapheresis in the Treatment of Neurologic Disease
Frailty in Older Adults
Adam L. Hartman, M.D. Scott Fromherz, M.D. Fellow, Sleep Disorders Clinic, Stanford University Hospital and Clinics, Stanford, California
Fellow, Department of Pediatric Neurology, Johns Hopkins Hospital, Baltimore, Maryland Febrile Seizures
Narcolepsy
Susan T. Herman, M.D. Professor of Neurology, Section of Child Neurology, Indiana University School of Medicine; Pediatric Neurologist, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
Assistant Professor of Neurology, University of Pennsylvania School of Medicine; Director, Epilepsy Monitoring Unit, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Neurofibromatosis
Treatment of Newly Diagnosed Complex Partial Seizures
Donald L. Gilbert, M.D., M.S.
Argye E. Hillis, M.D., M.A.
Associate Professor of Pediatrics and Neurology, Division of Neurology, University of Cincinnati School of Medicine; Director, Movement Disorders Clinics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
Associate Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland Acute Ischemic Stroke
Tourette’s Syndrome
Michio Hirano, M.D.
Mark R. Gilbert, M.D.
Associate Professor of Neurology, Columbia University College of Physicians and Surgeons; Associate Attending, Department of Neurology, New York–Presbyterian Hospital, Columbia University Medical Center, New York, New York
Bhuwan P. Garg, M.B., B.S.
Associate Professor and Deputy Chairman, Department of Neuro-oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Mitochondrial Encephalomyopathies
Glioma
David Irani, M.D. Donald H. Gilden, M.D. Louise Baum Professor and Chairman, Department of Neurology, University of Colorado Health Sciences Center School of Medicine; Staff Physician, University of Colorado Hospital, Denver, Colorado
Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Attending Neurologist, Johns Hopkins Hospital, Baltimore, Maryland Transverse Myelitis
Bell’s Palsy
Sallu Jabati, M.D.
Frank G. Gilliam, M.D., M.P.H.
Attending, Spine Institute, Department of Surgery, Cleveland Clinic Foundation, Cleveland, Ohio
Professor of Neurology, Columbia University College of Physicians and Surgeons; Director, Columbia Comprehensive Epilepsy Center; Staff Neurologist, New York–Presbyterian Hospital, New York, New York Recurrent Generalized and Partial Seizures
Jonathan P. Gladstone, B.Sc., M.D.
Herpes Zoster and Postherpetic Neuralgia
Alan C. Jackson, M.D., F.R.C.P.C. Professor, Departments of Medicine (Neurology) and Microbiology and Immunology, Queen’s University Faculty of Medicine; Attending Neurologist, Kingston General Hospital, Kingston, Ontario, Canada
Division of Neurology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada
Rabies Virus Infection
Chronic Daily Headache
Jee-Hyang Jeong, M.D.
Jonathan D. Glass, M.D.
Fellow, Department of Neurology, University of California, San Francisco, School of Medicine, San Francisco, California
Professor of Neurology and Pathology, Emory University School of Medicine, Atlanta, Georgia
Frontotemporal Degeneration
Toxic Neuropathy
H. A. Jinnah, M.D., Ph.D.
David S. Goldstein, M.D., Ph.D.
Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Chief, Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland Complex Regional Pain Syndromes
Joao A. Gomes, M.D. Neurocritical Care Fellow, Departments of Neurology, Anesthesia, and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Management of Subarachnoid Hemorrhage
The Dystonias
S. Claiborne Johnston, M.D., Ph.D. Associate Professor, Departments of Neurology and Epidemiology, University of California, San Francisco, School of Medicine; Director, Stroke Service, UCSF Medical Center, San Francisco, California Management of Intracranial Aneurysms and Other Vascular Malformations
vi
Contributors
Burk Jubelt, M.D.
Robert Laureno, M.D.
Professor of Neurology, Department of Microbiology/Immunology; Director, Neuroscience Program, State University of New York Upstate Medical University College of Medicine; Attending Neurologist, University Hospital, Syracuse, New York
Professor of Neurology, George Washington University School of Medicine and Health Sciences; Chairman, Department of Neurology, Washington Hospital Center, Washington, DC Wernicke Disease and Korsakoff Psychosis
Enterovirus Infections
Rafael H. Llinás, M.D., F.A.H.A. Douglas Kerr, M.D., Ph.D. Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Hospital, Baltimore, Maryland
Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Director, Cerebrovascular Disease Section, Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland
Cervical Spondylosis
Transient Ischemic Attacks
Richard M. Kimball, M.S.
Elan D. Louis, M.D., M.S.
Research Nurse, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
Associate Professor of Neurology, Columbia University College of Physicians and Surgeons; Associate Attending Neurologist, G.H. Serievsky Center, Columbia University Medical Center, New York, New York
Amyotrophic Lateral Sclerosis
Essential Tremor
Kleopas A. Kleopa, M.D. Senior Consultant Neurologist, Division of Clinical Neurosciences, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
Yukari Manabe, M.D.
Familial Neuropathies
Tuberculous Meningitis
Carol Lee Koski, M.D.
Nicholas J. Maragakis, M.D.
Professor of Neurology, University of Maryland School of Medicine; Director, Neuromuscular Division, University of Maryland Medical Systems, Baltimore, Maryland
Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Assistant Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Amyotrophic Lateral Sclerosis
Chronic Inflammatory Demyelinating Polyneuritis
Morri E. Markowitz, M.D. Eric H. Kossoff, M.D. Assistant Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Staff, John M. Freeman Pediatric Epilepsy Center, Baltimore, Maryland
Professor of Pediatrics, Albert Einstein College of Medicine of Yeshiva University; Director, Pediatric Environmental Science Clinic, Children’s Hospital at Montefiore, Bronx, New York
Headaches in Children
Management of Lead Poisoning in Children
Allan Krumholz, M.D.
Christina M. Marra, M.D.
Professor of Neurology, University of Maryland School of Medicine; Director, Epilepsy Center, University of Maryland Medical Center, Baltimore, Maryland
Professor of Neurology, University of Washington School of Medicine; Attending, Harborview Medical Center, Seattle, Washington
Psychogenic Nonepileptic Seizures
Neurosyphilis
Roger W. Kula, M.D.
Laura Marsh, M.D.
Associate Professor of Clinical Neurology, State University of New York Downstate Medical Center College of Medicine, Brooklyn; Medical Director, The Chiari Institute, North Shore University Hospital, Manhasset; Director, Neuromuscular Clinic, Long Island Jewish Medical Center, New Hyde Park; Co-Director, Neuromuscular Clinic, Pediatric Neurology, Schneider Children’s Hospital, New Hyde Park, New York
Associate Professor of Psychiatry and Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Chiari Malformations and Syringomyelia
Depression in Neurological Disorders
James A. Mastrianni, M.D., Ph.D. Assistant Professor of Neurology, The University of Chicago Pritzker School of Medicine; Co-Director, Center for Comprehensive Care and Research on Memory Disorders, The University of Chicago Hospitals, Chicago, Illinois The Prion Diseases
Ralph W. Kuncl, M.D., Ph.D. Adjunct Professor of Neurology, University of Pennsylvania School of Medicine; Staff, Hospital of the University of Pennsylvania, Philadelphia; Professor of Biology and Provost, Bryn Mawr College, Bryn Mawr, Pennsylvania
Justin C. McArthur, M.B.B.S., M.P.H.
Use and Misuse of Corticosteroids
Giant Cell Arteritis and CNS Vasculitis
John Laterra, M.D., Ph.D.
Una D. McCann, M.D.
Professor, Departments of Neurology, Oncology, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland Epidural Spinal Cord Compression and Leptomeningeal Metastasis
Professor of Neurology, Pathology, and Epidemiology and Acting Chair, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Associate Professor of Psychiatry, Johns Hopkins University School of Medicine; Attending, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Overdose and Withdrawal in Drug Abuse
Contributors
vii
Micheline McCarthy, M.D., Ph.D.
Avindra Nath, M.D.
Associate Professor of Neurology, University of Miami Leonard M. Miller School of Medicine; Associate Chief, Neurology Service, Miami Veterans Affairs Medical Center, Miami, Florida
Professor of Neurology, Johns Hopkins University School of Medicine; Director, Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Baltimore, Maryland
Herpesvirus Infections
Human Immunodeficiency Virus Infections
Emmanuel Mignot, M.D., Ph.D.
Elizabeth O’Hearn, M.D.
Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford; Director, Stanford Center for Narcolepsy; Investigator, Howard Hughes Medical Institute, Palo Alto, California
Assistant Professor, Department of Neurology and Neurosciences, Johns Hopkins University School of Medicine; Staff Neurologist, Johns Hopkins Hospital, Baltimore, Maryland
Narcolepsy
Inherited Cerebellar Ataxia
Bruce Miller, M.D.
Richard K. Olney, M.D.
A.W. Margaret Clausen Distinguished Professor, Department of Neurology, University of California, San Francisco, School of Medicine, San Francisco, California
Professor of Neurology, University of California, San Francisco, School of Medicine, San Francisco, California
Frontotemporal Degeneration
Guillain-Barré Syndrome
Steven P. Miller, M.D., C.M., F.R.C.P.C.
Andrew R. Pachner, M.D.
Assistant Adjunct Professor, Departments of Neurology and Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, California; Assistant Professor, Department of Pediatrics, University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
Professor of Neurology, UMDNJ–New Jersey Medical School, Newark, New Jersey
Neonatal Encephalopathy
Assistant Professor of Neurology and Pathology, Johns Hopkins University School of Medicine; Staff Neurologist, Johns Hopkins Hospital, Baltimore, Maryland
Lewis B. Morgenstern, M.D. Associate Professor of Neurology, Emergency Medicine, Neurosurgery, and Epidemiology, University of Michigan Medical School and School of Public Health; Director, Stroke Program, University of Michigan Health System, Ann Arbor, Michigan Emboli of Cardiac Origin
Lyme Disease
Carlos A. Pardo-Villamizar, M.D.
Neurosarcoidosis
Roy A. Patchell, M.D. Chief, Neuro-oncology Division, Department of Neurosurgery, University of Kentucky Chandler Medical Center, Lexington, Kentucky Brain Metastases
Richard T. Moxley III, M.D. Professor of Neurology and Pediatrics, Department of Neurology, University of Rochester School of Medicine and Dentistry; Attending Physician, Strong Memorial Hospital; Director, Neuromuscular Disease Center, Department of Neurology, University of Rochester Medical Center, Rochester, New York
Michael Polydefkis, M.D.
Muscular Dystrophies
Beth S. Porter, M.D., Ph.D.
Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Johns Hopkins Hospital, Baltimore, Maryland Diabetic Neuropathies
Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Assistant Professor, Department of Medicine, Division of Infectious Diseases, University of New Mexico School of Medicine; Staff Physician, Spinal Cord Injury Center and Department of Infectious Diseases, New Mexico VA Health Care System, Albuquerque, New Mexico
Painful Neuropathy
Fungal Infections
Neal J. Naff, M.D.
Michael Pourfar, M.D.
Beth Murinson, M.S., M.D., Ph.D.
Assistant Professor of Neurosurgery, Johns Hopkins University School of Medicine; Chief of Neurosurgery, Sinai Hospital of Baltimore, Baltimore, Maryland
Staff Physician, Center for Parkinson’s Disease and Other Movement Disorders, Columbia University Medical Center, New York, New York
Failed Back Syndrome
Essential Tremor
Vinodh Narayanan, M.D.
Tyler Reimschisel, M.D.
Associate Professor of Clinical Pediatrics and Neurology, Department of Pediatrics, University of Arizona College of Medicine; Pediatric Neurologist, St. Joseph’s Hospital and Children’s Health Center and Barrow Neurological Institute, Phoenix; Adjunct Professor, School of Life Sciences, Arizona State University, Tempe, Arizona Tuberous Sclerosis Complex
Assistant Professor of Neurology, Washington University, St. Louis, Missouri The Dystonias
George A. Ricaurte, M.D., Ph.D. Associate Professor of Neurology, Johns Hopkins University School of Medicine; Attending, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Overdose and Withdrawal in Drug Abuse
viii
Contributors
Daniele Rigamonti, M.D.
Jehuda Sepkuty, M.D.
Professor of Neurosurgery, Johns Hopkins University School of Medicine; Director, Division of Stereotatic Radiosurgery; Co-Director, Adult Hydrocephalus Program, Johns Hopkins Hospital, Baltimore, Maryland
Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Director, Intraoperative Neuromonitoring; Attending Neurologist, Epilepsy Monitoring Unit, Johns Hopkins Hospital, Baltimore, Maryland
Normal Pressure Hydrocephalus
Status Epilepticus
Stacie L. Ropka, Ph.D., M.B.A. Research Assistant Professor, Department of Neurology, State University of New York Upstate Medical University College of Medicine, Syracuse, New York Enterovirus Infections
Barbara E. Shapiro, M.D., Ph.D. Associate Professor of Neurology, Case School of Medicine; Director, Neuromuscular Research, University Hospitals of Cleveland, Cleveland, Ohio The Periodic Paralyses—Current Therapy
Paul Rosenberg, M.D. Assistant Professor of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore; Director of Neuropsychiatry, The Copper Ridge Institute, Sykesville, Maryland
Rachelle Smith Doody, M.D., Ph.D.
Depression in Neurological Disorders
Alzheimer’s Disease
Robert L. Ruff, M.D., Ph.D.
Yuen T. So, M.D., Ph.D.
Professor of Neurology, Case School of Medicine; Director, Spinal Cord Injury Unit, Cleveland VA Medical Center, Cleveland, Ohio
Professor of Neurology, Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Director, Neurology Clinic, Stanford Hospital and Clinics, Stanford, California
The Periodic Paralyses
Effie Marie Cain Chair in Alzheimer’s Disease Research, Department of Neurology, Baylor College of Medicine; Active Staff, Department of Neurology, The Methodist Hospital, Houston, Texas
Entrapment Neuropathies
David B. Rye, M.D., Ph.D. Associate Professor of Neurology, Emory University School of Medicine; Director, Emory Healthcare Program in Sleep Medicine, Atlanta, Georgia Restless Legs Syndrome
Steven S. Scherer, M.D., Ph.D. William N. Kelley Professor, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Tom Solomon, M.D., Ph.D. Senior Lecturer in Neurology, Department of Neurological Science; Senior Lecturer in Medical Microbiology and Genitourinary Medicine, University of Liverpool; Honorary Consultant Neurologist, Walton Centre for Neurology and Neurosurgery and Royal Liverpool University Hospital, Liverpool, United Kingdom Cerebral Malaria
Familial Neuropathies
Elijah W. Stommel, M.D., Ph.D.
Jacob P. Schwarz, M.D. Instructor in Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
Associate Professor of Medicine, Section of Neurology, Dartmouth Medical School, Hanover; Attending Neurologist, Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
Failed Back Syndrome
Marine Toxins and Assorted Biological Toxins
Erick Scott, M.D.
Gene Sung, M.D., M.P.H.
Fellow, Department of Psychiatry and Behavioral Sciences, Stanford Center for Narcolepsy, Stanford, California Cervical Spondylosis
Director, Neurocritical Care and Stroke Section, Department of Neurology, Keck School of Medicine of USC, Los Angeles, California Intracerebral Hemorrhage
James J. Sejvar, M.D. Neuroepidemiologist, Division of Vector-Borne Infectious Diseases and Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Arthropod-Borne Virus Infections
Tricia Ting, M.D. Assistant Professor of Neurology, University of Maryland School of Medicine; Director, Ambulatory Services, Maryland Epilepsy Center, University of Maryland Medical Center, Baltimore, Maryland Psychogenic Nonepileptic Seizures
Michael E. Selzer, M.D., Ph.D. Professor of Neurology, Departments of Neurology and Physical Medicine and Rehabilitation, University of Pennsylvania School of Medicine; Attending Physician, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
B. Todd Troost, M.D.
Acute Spinal Cord Injury
Migraine and Cluster Headache
Professor of Neurology Emeritus, Wake Forest University School of Medicine; Chief Emeritus, Department of Neurology, North Carolina Baptist Hospital, Winston-Salem, North Carolina
Contributors
ix
Eileen P. G. Vining, M.D.
Michael A. Williams, M.D.
Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Associate Director, Pediatrics Epilepsy Clinic, Johns Hopkins Hospital, Baltimore, Maryland
Associate Professor of Neurology, Johns Hopkins University School of Medicine; Director, Adult Hydrocephalus Program, Johns Hopkins Hospital, Baltimore, Maryland Normal Pressure Hydrocephalus
Febrile Seizures
Max Wiznitzer, M.D. Jerrold L. Vitek, M.D., Ph.D. Co-Chairman, Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, Ohio Parkinson’s Disease
Associate Professor of Pediatrics, Neurology, and International Health, Case School of Medicine; Pediatric Neurologist, Rainbow Babies and Childrens Hospital, Cleveland, Ohio Attention Deficit Hyperactivity Disorders and Learning Disabilities
Kathryn R. Wagner, M.D., Ph.D. Assistant Professor of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Wendy L. Wright, M.D.
Muscular Dystrophies
Professor of Neurology, Emory University School of Medicine; Active Staff, Neuroscience Critical Care Division, Emory University Hospital, Atlanta, Georgia
Mark F. Walker, M.D.
Brain Abscess and Parameningeal Infection
Assistant Professor of Neurology, Johns Hopkins University School of Medicine; Active Staff, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Kaleb Yohay, M.D.
Vertigo and Disequilibrium
Instructor, Department of Neurology, Division of Child Neurology, Johns Hopkins University, Baltimore, Maryland Childhood Brain Tumors
Laurence Walsh, M.D. Assistant Professor of Clinical Neurology and Medical and Molecular Genetics; Director, Child Neurology Section, Department of Neurology, Indiana University School of Medicine; Director, Pediatric Neurology, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
Phyllis C. Zee, M.D., Ph.D.
Neurofibromatosis
Parasomnias
Benjamin L. Walter, M.D.
Wendy C. Ziai, M.D.
Associate Staff, Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, Ohio
Assistant Professor, Departments of Neurology and Anesthesia/Critical Care Medicine, Johns Hopkins University School of Medicine; Attending Physician, Neurocritical Care, Johns Hopkins Hospital and Bayview Medical Center, Baltimore, Maryland
Parkinson’s Disease
Michael R. Watters, M.D., F.A.A.N. Professor of Medicine, Division of Neurology, University of Hawaii JAB School of Medicine; Core Neurologist, Office of Neurology and Aging Research, Specialized Neuroscience Research Program in NeuroAIDS; Associate Director of Medical Education, Queen’s Neuroscience Institute, Honolulu, Hawaii Marine Toxins and Assorted Biological Toxins
Professor of Neurology, Northwestern University Feinberg School of Medicine; Director, Sleep Disorders Center, Department of Neurology, Northwestern Memorial Hospital, Chicago, Illinois
Management of Subarachnoid Hemorrhage
Andrew W. Zimmerman, M.D. Associate Professor of Neurology, Psychiatry, and Pediatrics, Johns Hopkins University School of Medicine; Pediatric Neurologist, Kennedy Krieger Institute and Johns Hopkins Hospital, Baltimore, Maryland Autism
Preface Current Therapy in Neurologic Disease 7 marks the 20th anniversary of this series. Technically, this is not the seventh “edition,” since each of the seven volumes has been a fresh collection of statements on management and therapy by a new group of specialists. This series was launched to fill a perceived shortcoming in the neurology literature. Many fine textbooks and monographs cover the etiology, pathogenesis, clinical symptoms and signs, imaging, and pathology of neurology diseases. Instruction on management, specific therapy, and patient education, however, tends to be presented in generalizations replete with conflicting views. The practical issues of when and how to initiate drugs and at what doses, the management of complications of the disease and the drugs, and advice on when to call for aid of colleagues in other fields are left to the informal education of corridor or curbstone consultation. Since its introduction, this series has presented a specific stepby-step approach to patient management given by a seasoned clinician. It has provided an informal practical consultation for the neurologist, neurosurgeon, internist, pediatrician, or family practitioner. Because authors, and therefore options, are changed with each volume, you, like the editors, may wish to save volumes 5 and 6 for a “second opinion” that you may favor over an opinion in this volume. The advice of the contributors is not necessarily the approach of the editors or a consensus of the neurologic community; they are
the management techniques of an experienced clinician. Today, neurologic practice should be driven by “evidencebased” neurology, and obviously class I evidence from randomized clinical trials plays a major role in the choice of therapy. Usually, however, this evidence is not adequate to provide advice regarding specifics of management of the patient. This book provides not only “evidence-based” approaches but “experience-based” approaches from expert authors. As before, some new topics have been added and others dropped—at least for this edition. New additions include daily headache, autism, Sturge-Weber syndrome, Bell’s palsy, Creutzfeldt-Jakob disease, and new general topics of the fragile elderly, plasmapheresis and intravenous immunoglobulin G, and the use and abuse of corticosteroids in neurologic practice. Each author has been given the same charge: to describe his or her approach to treatment and management of patients. Drug dosages have been checked, but the reader should always scrutinize product information sheets or online sources for dosage, interactions, and contraindications. The editors thank Sofia Rodriguez for editorial assistance. Richard T. Johnson, M.D., F.R.C.P. John W. Griffin, M.D. Justin C. McArthur, M.B.B.S., M.P.H.
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SECTION 1 ●
Disorders of Consciousness The Unconscious Patient Anish Bhardwaj, M.D.
States of Altered Consciousness Consciousness is a state of awareness of self and environment and is dependent on two essential elements that have an anatomic basis: arousal, which is related to the integrity of the ascending reticular activating system, and awareness, which is related to the integrity of the cerebral cortex. Derangement in the level of consciousness comprises a spectrum of disorders ranging from acute confusional states to coma (Table 1). Disturbances in its content range from global cognitive impairment to more focal brain dysfunction, including deficits in language, memory, sensation and perception, motivation, and executive function.
Initial Diagnostic Work-up and Emergent Management of an Unconscious Patient The classification and major causes of altered consciousness are presented in Table 2. The diagnosis and management of an unconscious patient are presented here in algorithmic fashion as follows: ESTABLISH AND MAINTAIN THE AIRWAY, BREATHING, AND CIRCULATION (ABCs)
Place oropharyngeal airway and provide bag-mask ventilation, intubation (fiberoptic if spinal cord injury is suspected) Monitor oxygenation with pulse oximetry and maintain SaO2 higher than 90% with supplemental O2 ↓ MONITOR VITAL SIGNS
Hypotension can result from hypovolemia, myocardial infarction, pulmonary embolism, sepsis, acidosis— provide fluid resuscitation with isotonic fluids and Johnson: Current Therapy in Neurologic Disease (7/E)
vasopressors to keep mean arterial blood pressure above 70 mm Hg Hypertension can result from brain injury (intracranial hypertension, drug intoxication with cocaine or amphetamines)—administer labetalol 10 to 20 mg intravenously (IV) every 10 minutes (up to a maximum of 300 mg) Hypothermia can result from neuroendocrine disorders (hypopituitarism, hypothyroidism), drug ingestion (barbiturates, alcohol, general anesthetics), Wernicke’s encephalopathy, diencephalic injury Hyperthermia can result from thyrotoxicosis, sepsis, hypothalamic injury, malignant hyperthermia, heat stroke Tachycardia can result from hypo`volemia, infection/ sepsis, pain and discomfort, pulmonary embolism Bradycardia can result from intracranial hypertension, drug overdose (e.g., tricyclic antidepressants) Malignant cardiac arrhythmias can result from ventricular fibrillation, ventricular tachycardia (e.g., amphetamine overdose) ↓ INITIATE FLUID MANAGEMENT
Establish IV access and commence IV infusion of isotonic fluids (1 to 1.5 mL/kg/hr of 0.9% saline) ↓ ASSESS NEUROLOGIC FUNCTION
Assess level of consciousness Cranial nerves—Observe eye movements, pupillary and corneal responses, oculocephalic/vestibulo-ocular reflex, cough and gag reflexes Motor examination—Observe resting posture, spontaneous motor activity, response to stimulation ↓ ORDER LABORATORY SCREENING
Obtain blood samples for Glucose—hypoglycemia, hyperglycemia (nonketotic) Arterial blood gases—hypoxemia, hypercarbia, acidosis (drug ingestion, ketoacidosis, lactic acidosis) Electrolytes—hyponatremia/hypernatremia, hypocalcemia/hypercalcemia, hypomagnesemia/hypermagnesemia, azotemia 1
2
The Unconscious Patient
TABLE 1 States of Altered Consciousness Type of State
Manifestations
Acute confusional state
Impaired attention, memory, and thinking Incoherent conversation with easy distraction Acute confusional state accompanied by autonomic dysfunction (fever, hypertension, sweating, and tachycardia) Little or no awareness of surroundings Absence of spontaneous motor activity Minimal motor response to noxious stimuli Intact sleep-wake cycles Consciousness preserved Selective deafferentation of all extremities and lower cranial nerves resulting in quadriplegia and inability to vocalize Sparing of vertical eye movements, blinking, hearing, and respiratory function Usually results from an acute pontine lesion Complete unawareness of self and surroundings Spontaneous eye opening may occur with some response to verbal stimuli that is not meaningful Inability to follow commands or localize to noxious stimulus Intact sleep-wake cycles and circulatory, respiratory, and brainstem reflexes Identified as such if state persists for >1 mo for nontraumatic etiology and >1 yr following traumatic brain injury Mental dullness or blunting with increased sleeping time Can be aroused to follow commands but with slowed responses and little interest in surroundings Reduced mental and physical activity Can be aroused with repeated and vigorous stimuli Restlessness; stereotypic motor responses “Sleeplike” state of unresponsiveness with absence of awareness of self and environment; does not respond to stimuli Motor impairment variable No spontaneous eye opening or reaction to stimulus Absent sleep-wake cycles
Delirium Akinetic mutism
Locked-in syndrome
Persistent vegetative state
Obtundation Stupor Coma
Thyroid function tests—hypothyroidism, myxedema Liver function tests—hyperammonemia White blood cell count—leukocytosis (infection/ sepsis) Obtain urine specimen for urinalysis and urine toxicology screen—urosepsis, drug intoxication Check serum glucose level at bedside ↓ INITIATE SPECIFIC TREATMENT
Administer thiamine, 100 mg IV, followed by 25 gm of glucose (50 mL of 50% solution) Naloxone (0.4 to 2 mg IV every 3 minutes or continuous IV infusion 0.8 mg/kg/hr) if narcotic overdose is suspected—may precipitate rapid and florid withdrawal syndrome Flumazenil, 0.2 mg/min, maximum dose 1 mg IV, only if benzodiazepine overdose is suspected—may precipitate cardiac arrhythmias and lower seizure threshold Lavage with activated charcoal (60 to 100 gm) and normal saline for suspected drug ingestion ↓ OBTAIN DETAILED HISTORY AND PERFORM SYSTEMATIC EXAMINATION
↓
PERFORM ADDITIONAL DIAGNOSTIC TESTS
Obtain the following diagnostic tests as needed: Nonenhanced computed tomographic (CT) scan of the brain, particularly in patients with focal neurologic findings Lumbar puncture for suspected infection (meningitis, encephalitis), subarachnoid hemorrhage Cerebral angiography for suspected vertebrobasilar insufficiency Electroencephalography for suspected nonconvulsive seizures Magnetic resonance imaging with venography for suspected basilar artery thrombosis and sinus venous thrombosis
Neurologic Evaluation of Altered Consciousness Neurologic examination of an unconscious patient is focused on four major components: level of consciousness, cranial nerve and motor examinations, and respiratory pattern. Johnson: Current Therapy in Neurologic Disease (7/E)
The Unconscious Patient
Structural Brain Injury Hemisphere Unilateral (with midline shifts/displacement) Intracerebral and subarachnoid hemorrhage Large hemispheric ischemic stroke with accompanying edema Hemorrhagic contusion Cerebral abscess Brain tumor Bilateral Penetrating traumatic brain injury, traumatic brain contusions, diffuse axonal injury Multiple cerebral cortical infarcts (vasculitis, coagulopathy, cardiac embolism) Bilateral thalamic infarcts Malignancy (lymphoma, gliomatosis, multiple brain metastasis) Encephalitis (viral, paraneoplastic) Acute disseminated encephalomyelitis Anoxic-ischemic encephalopathy Cerebral edema Acute hydrocephalus Leukoencephalopathy (chemotherapy or radiation) Brainstem Pontine hemorrhage Basilar artery occlusion Central pontine myelinolysis Brainstem hemorrhagic contusion Brainstem tumor Cerebellum (with displacement causing brainstem compression) Cerebellar infarct Cerebellar hematoma Cerebellar abscess Cerebellar glioma or metastatic tumor Acute Metabolic-Endocrine Derangement Disturbances in serum glucose (hypoglycemia, hyperglycemia) Disturbances in serum sodium (hyponatremia, hypernatremia) Addison’s disease Hypercalcemia Acute panhypopituitarism Hypothyroidism (myxedema coma) Acute azotemia/uremia Hypoxia, hypercapnia Diffuse Physiologic Brain Dysfunction Drug overdose and poisoning Generalized tonic-clonic seizures or nonepileptic seizures Hypothermia Gas inhalation (carbon monoxide) Basilar migraine Psychogenic Unresponsiveness Acute (lethal) catatonia, malignant neuroleptic syndrome Hysterical coma Malingering Adapted from Wijdicks EFM: Neurologic complications of critical illness, ed 2, New York, 2002, Oxford University Press; and Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press.
Johnson: Current Therapy in Neurologic Disease (7/E)
LEVEL OF CONSCIOUSNESS Level of unresponsiveness should be established. Special attention should be paid to body position, spontaneous motor activity, and eye movements. The Glasgow Coma Scale (GCS), originally designed for patients with traumatic brain injury, is used widely in patients with neurologic impairments as an objective scoring system because of its easy interexaminer reliability and reproducibility. GCS comprises eye opening and motor and verbal responses; however, it does not incorporate focal sensory-motor deficits and is limited in patients with craniofacial trauma resulting in orbital swelling.
Disorders of Consciousness
TABLE 2 Classification and Major Causes of Alterations in Consciousness
3
CRANIAL NERVE EXAMINATION Pupillary Responses Pupillary dilation indicates ipsilateral uncal herniation secondary to a lesion (e.g., tumor, abscess, intraparenchymal hematoma, cerebral edema) impinging on the pupillary dilator fibers encasing the oculomotor nerve. Unilateral miosis is suggestive of Horner’s syndrome due to sympathetic denervation. Bilateral fixed, dilated pupils are indicative of massive drug overdose (e.g., tricyclic antidepressants, amphetamines, carbamazepine), extensive brainstem injury, or central herniation leading to brain death. Bilateral miotic pupils are indicative of narcotic overdose, pontine injury, organophosphate ingestion, or local instillation of miotic eye drops. Other Changes Spontaneous eye opening does not necessarily reflect awareness, in that patients in coma (e.g., persistent vegetative state) may have spontaneous eye opening. Nystagmus at primary gaze is indicative of seizure activity or of diffuse brain injury. A variety of other gaze abnormalities and spontaneous eye movements (skew deviation, ocular bobbing, ping-pong gaze, tonic upward or downward gaze deviation, roving eye movements, convergence nystagmus) that are of localizing value have been well described. Impaired oculocephalic and vestibulo-oculocephalic reflexes are indicative of brainstem dysfunction. The corneal response tests the integrity of the trigeminal (afferent) and facial (efferent) nerves. Facial asymmetry may be indicative of central or peripheral facial nerve palsy. The glossopharyngeal and vagus nerves are tested with the cough and gag reflexes by stimulation of the posterior pharynx. MOTOR EXAMINATION Special attention should be paid to resting posture and spontaneous movements or those in response to stimulation. Motor responses that are commonly observed include (1) involuntary movements that may suggest focal or generalized seizures, myoclonic activity, or enhanced tremor frequently associated with toxicmetabolic etiologies; and (2) those to stimuli that may be absent, reflexic, or purposeful and may be of localizing value.
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Vertigo and Disequilibrium
Flexor (“decorticate”) posturing characterized by flexion and abduction of the arms and wrists and extension of the lower extremities is indicative of loss of inhibitory influences from the higher centers and suggests damage to the cerebral hemispheres and the thalamus with structures below the diencephalons remaining intact. Extensor (“decerebrate”) posturing characterized by adduction, extension, and pronation of the arms and wrists and extension of the lower extremities is indicative of injury to deep bilateral cerebral hemispheres, midbrain and pons, above the vestibular nuclei, and may accompany severe toxicmetabolic brain injury. Triple flexion in the lower extremities is a spinal reflex of no localizing value. Flaccidity accompanied by no response to painful stimuli is indicative of injury to the lower medulla or severe injury to the central and peripheral nervous systems. RESPIRATORY PATTERN Altered states of consciousness are frequently accompanied by changes in respiratory patterns that may reflect injury to brainstem respiratory centers. Hypotonia of the upper airway due to bulbar dysfunction (oropharynx, tongue) manifests itself as hypoxia and hypercapnia, whereas lower airway dysfunction, secondary to weakness of intercostal muscles or diaphragmatic paralysis, leads to reduced vital capacity and hypercarbia. Localizing value of respiratory patterns is frequently obscured by a combination of toxic-metabolic and neurogenic etiologies. Cheyne-Stokes breathing (tachypnea alternating with apnea) is usually indicative of severe bilateral hemispheric dysfunction. Biot’s breathing (irregular Cheyne-Stokes) suggests a localization in the lower brainstem. Central neurogenic hyperventilation typically accompanies damage to the rostral brainstem tegmentum and the paramedian pontine reticular formation. Apneustic breathing (brief end-inspiratory pauses alternating with end-expiratory pauses) is indicative of injury to the respiratory centers in midcaudal pons. Ataxic breathing is commonly seen with injury to the reticular formation of the dorsomedial medulla extending to the obex and occurs with acute medullary compression.
hyperventilation to maintain a PaCO2 level of 25 to 30 mm Hg, osmotherapy (mannitol 1 gm/kg IV) and diuretics (furosemide 10 to 20 mg IV), and neurosurgical consultation for external drainage of cerebrospinal fluid or emergent surgical procedures for decompression. Admission and emergent transfer of such a patient to a critical care unit setting are necessary for appropriate further management.
SUMMARY Although the causes of coma are numerous, the principles of management of an unconscious patient center on early recognition and timely evaluation of possible reversible or treatable causes. These principles include (1) providing cardiopulmonary support to maintain oxygenation and cerebral perfusion to limit propagation of secondary brain injury; (2) close and frequent neurologic follow-up examinations to detect early deterioration; and (3) emergent measures for brain resuscitation in patients with severe brain injury. Following emergent critical care, the clinician has the luxury of time to embark on a more thorough evaluation of history of illness and further diagnostic tests to arrive at an etiologic diagnosis. Adherence to these principles can frequently lead to good outcomes in patients with treatable causes of coma from brain injury. SUGGESTED READING Bhardwaj A: Cerebral edema and intracranial hypertension. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press. Plum F, Posner JB: The pathologic physiology of signs and symptoms of coma. In The diagnosis of stupor and coma, ed 3, New York, 1982, Oxford University Press, 1-86. Wijdicks EFM: Coma and other states of altered awareness. In Neurologic complications of critical illness, ed 2, New York, 2000, Oxford University Press, 3-27. Ziai WC: Coma and altered consciousness. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press.
Brain Resuscitation Alterations in the level of consciousness from catastrophic brain injuries including trauma and subdural, subarachnoid, and intraparenchymal hemorrhage are encountered commonly in clinical practice. Early recognition of herniation syndromes or clinical evidence of intracranial hypertension warrants an emergent response to confirm clinical diagnosis with a noncontrast CT scan of brain and institution of therapies for brain resuscitation. General measures include avoidance of agitation and fever, maintenance of a euvolemic state and systemic blood pressure, facilitating venous outflow by elevating the head to 30 degrees, and maintaining the neck in a midline position. Specific therapies include emergent endotracheal intubation for controlled
Vertigo and Disequilibrium Mark F. Walker, M.D.
Dizziness is a common complaint because it encompasses a wide variety of symptoms, and terms such as dizziness, light-headedness, and even disequilibrium may have many different meanings. Thus, an important first step in the treatment of patients with dizziness is to make the correct diagnosis. Too often, patients are simply labeled as having “vertigo” and given a vestibular suppressant medication without an adequate attempt to characterize the actual symptom or its underlying cause. Johnson: Current Therapy in Neurologic Disease (7/E)
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Vertigo and Disequilibrium
Flexor (“decorticate”) posturing characterized by flexion and abduction of the arms and wrists and extension of the lower extremities is indicative of loss of inhibitory influences from the higher centers and suggests damage to the cerebral hemispheres and the thalamus with structures below the diencephalons remaining intact. Extensor (“decerebrate”) posturing characterized by adduction, extension, and pronation of the arms and wrists and extension of the lower extremities is indicative of injury to deep bilateral cerebral hemispheres, midbrain and pons, above the vestibular nuclei, and may accompany severe toxicmetabolic brain injury. Triple flexion in the lower extremities is a spinal reflex of no localizing value. Flaccidity accompanied by no response to painful stimuli is indicative of injury to the lower medulla or severe injury to the central and peripheral nervous systems. RESPIRATORY PATTERN Altered states of consciousness are frequently accompanied by changes in respiratory patterns that may reflect injury to brainstem respiratory centers. Hypotonia of the upper airway due to bulbar dysfunction (oropharynx, tongue) manifests itself as hypoxia and hypercapnia, whereas lower airway dysfunction, secondary to weakness of intercostal muscles or diaphragmatic paralysis, leads to reduced vital capacity and hypercarbia. Localizing value of respiratory patterns is frequently obscured by a combination of toxic-metabolic and neurogenic etiologies. Cheyne-Stokes breathing (tachypnea alternating with apnea) is usually indicative of severe bilateral hemispheric dysfunction. Biot’s breathing (irregular Cheyne-Stokes) suggests a localization in the lower brainstem. Central neurogenic hyperventilation typically accompanies damage to the rostral brainstem tegmentum and the paramedian pontine reticular formation. Apneustic breathing (brief end-inspiratory pauses alternating with end-expiratory pauses) is indicative of injury to the respiratory centers in midcaudal pons. Ataxic breathing is commonly seen with injury to the reticular formation of the dorsomedial medulla extending to the obex and occurs with acute medullary compression.
hyperventilation to maintain a PaCO2 level of 25 to 30 mm Hg, osmotherapy (mannitol 1 gm/kg IV) and diuretics (furosemide 10 to 20 mg IV), and neurosurgical consultation for external drainage of cerebrospinal fluid or emergent surgical procedures for decompression. Admission and emergent transfer of such a patient to a critical care unit setting are necessary for appropriate further management.
SUMMARY Although the causes of coma are numerous, the principles of management of an unconscious patient center on early recognition and timely evaluation of possible reversible or treatable causes. These principles include (1) providing cardiopulmonary support to maintain oxygenation and cerebral perfusion to limit propagation of secondary brain injury; (2) close and frequent neurologic follow-up examinations to detect early deterioration; and (3) emergent measures for brain resuscitation in patients with severe brain injury. Following emergent critical care, the clinician has the luxury of time to embark on a more thorough evaluation of history of illness and further diagnostic tests to arrive at an etiologic diagnosis. Adherence to these principles can frequently lead to good outcomes in patients with treatable causes of coma from brain injury. SUGGESTED READING Bhardwaj A: Cerebral edema and intracranial hypertension. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press. Plum F, Posner JB: The pathologic physiology of signs and symptoms of coma. In The diagnosis of stupor and coma, ed 3, New York, 1982, Oxford University Press, 1-86. Wijdicks EFM: Coma and other states of altered awareness. In Neurologic complications of critical illness, ed 2, New York, 2000, Oxford University Press, 3-27. Ziai WC: Coma and altered consciousness. In Bhardwaj A, Mirski MA, Ulatowski JA, editors: Handbook of neurocritical care, Totowa, NJ, 2004, Humana Press.
Brain Resuscitation Alterations in the level of consciousness from catastrophic brain injuries including trauma and subdural, subarachnoid, and intraparenchymal hemorrhage are encountered commonly in clinical practice. Early recognition of herniation syndromes or clinical evidence of intracranial hypertension warrants an emergent response to confirm clinical diagnosis with a noncontrast CT scan of brain and institution of therapies for brain resuscitation. General measures include avoidance of agitation and fever, maintenance of a euvolemic state and systemic blood pressure, facilitating venous outflow by elevating the head to 30 degrees, and maintaining the neck in a midline position. Specific therapies include emergent endotracheal intubation for controlled
Vertigo and Disequilibrium Mark F. Walker, M.D.
Dizziness is a common complaint because it encompasses a wide variety of symptoms, and terms such as dizziness, light-headedness, and even disequilibrium may have many different meanings. Thus, an important first step in the treatment of patients with dizziness is to make the correct diagnosis. Too often, patients are simply labeled as having “vertigo” and given a vestibular suppressant medication without an adequate attempt to characterize the actual symptom or its underlying cause. Johnson: Current Therapy in Neurologic Disease (7/E)
Vertigo and Disequilibrium
nerves should also be tested, keeping in mind the need to rule out a cerebellar or brainstem lesion. Finally, patients with recurrent vertigo should be subjected to positional testing (i.e., the Dix-Hallpike maneuver) to look for evidence of positional vertigo and nystagmus. Laboratory testing of vestibular function includes caloric testing, which is best for identifying a unilateral vestibular deficit, and rotatory chair testing, which is best for identifying bilateral vestibular hypofunction.
Treatment of Vertigo The treatment of vertigo depends on the underlying cause. We consider the most common entities here. ACUTE PROLONGED VERTIGO Acute prolonged vertigo refers to a single episode (nonrecurrent) of spontaneous vertigo, usually accompanied by nausea, vomiting, and imbalance, that lasts for hours to days. It is important to make sure that the vertigo is continuous rather than occurring in multiple frequent but brief episodes (e.g., positional vertigo). Causes of acute prolonged vertigo include vestibular neuritis (labyrinthitis) and labyrinthine ischemia. In patients who are older or otherwise at risk for vascular disease, an ischemic cause should be ruled out by magnetic resonance (MR) imaging and MR angiography of the posterior circulation, including visualization of the neck vessels from the vertebral origins. Patients in whom there is any suspicion of a central lesion should be imaged emergently to look for a brainstem or cerebellar infarct or hemorrhage. Vestibular neuritis generally improves over several days, with subsidence of vertigo and nystagmus, although there is often a lingering imbalance and
TABLE 1 Causes of Vertigo and Disequilibrium Cause Acute Prolonged Vertigo, Single Episode Vestibular neuritis/labyrinthitis Labyrinthine infarction Cerebellar or brainstem infarction or hemorrhage Recurrent Vertigo Benign paroxysmal positional vertigo Transient ischemic attacks Meniere’s disease (endolymphatic hydrops) Migraine Autoimmune (systemic or labyrinthine only) Anxiety
Johnson: Current Therapy in Neurologic Disease (7/E)
Disorders of Consciousness
Vertigo is an illusory sense of motion, such as spinning, rocking, or tilting, that is caused by an imbalance in the labyrinthine inputs or their central connections. It is important to ask patients with vertigo whether it has happened just once or if there have been multiple attacks, the duration of the episodes (e.g., minutes, hours, days), whether there are any provoking factors (e.g., head movement), and what, if any, are the associated symptoms (e.g., hearing loss, ear pain/pressure, posterior circulation symptoms). A basic differential diagnosis of common causes is given in Table 1. Disequilibrium is a less precisely defined symptom. I use this term to describe feelings of imbalance or unsteadiness, most prominent when standing and generally minimal when at rest. Other symptoms that may be labeled “dizziness” but should be distinguished from true vertigo include motion sickness, whether evoked by true motion or by motion of the visual scene (e.g., when watching television), presyncopal sensations, and anxiety. Obviously, this is important, because faintness due to intermittent hypotension requires a cardiovascular evaluation, and an anxiety disorder may need psychiatric treatment. In addition to the history, a careful examination is essential. Patients with dizziness should be evaluated for any evidence of reduced vestibular function in one or both ears. The most useful bedside test of peripheral vestibular function is the head impulse or head thrust test. This is a rapid small-amplitude manual rotation performed while the subject fixates the examiner’s nose. If vestibular function is reduced on the side to which the head is rotated, the eyes will move with the head, and after the head stops, a catch-up saccade will be seen as the eyes return to the original target. Hearing should also be tested, including audiometry, particularly to look for a unilateral hearing loss that would support a peripheral problem. The other cranial
5
Comments
Vertigo, nausea, and vomiting lasting hours to days; slow recovery over weeks to months Similar to vestibular neuritis but caused by ischemia
Attacks provoked by changes in head position relative to gravity, lasting for seconds; positive Dix-Hallpike maneuver Episodes generally last minutes, often accompanied by other posterior circulation symptoms Severe vertigo, nausea, and vomiting, lasting hours; accompanied by transient low-frequency hearing loss, low-pitched tinnitus, ear pain and/or fullness in the affected ear Wide range of symptoms from brief attacks of vertigo to prolonged disequilibrium; may be similar to Meniere’s disease, but without hearing loss; vestibular symptoms often occur without headache Fluctuating vertigo and hearing loss; may progress to bilateral deafness if not treated Panic attacks and chronic anxiety may include vertiginous sensations and disequilibrium
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Vertigo and Disequilibrium
motion sensitivity that may last for months. It has been proposed to treat acute vestibular neuritis with steroids and/or antiviral agents, based on the hypothesis that an inflammatory process, perhaps related to a herpesvirus, is responsible. A recent randomized study found that patients begun on a methylprednisolone taper within 3 days of symptom onset had less caloric asymmetry 12 months later (implying greater recovery in the affected ear). Valacyclovir had no effect. Thus, it is reasonable to treat patients with steroids in the acute stage if there are no contraindications, keeping in mind that it is not yet known whether there is a difference in functional outcome. If acute hearing loss is present, high-dose steroids (e.g., a prednisone taper beginning at 60 to 100 mg/day) should be given, and the patient should be referred to a neuro-otologist; autoimmune inner ear disease can cause severe bilateral hearing loss, if not treated promptly. Patients with vestibular neuritis usually benefit from a vestibular suppressant and/or an antiemetic (see later), which should only be given for several days, while symptoms are most severe. Long-term vestibular suppression should be avoided because it may interfere with central compensatory mechanisms that promote functional recovery. To facilitate compensation, it is important that normal activity be resumed as quickly is possible. Patients should be referred for vestibular therapy, if it is available. MENIERE’S DISEASE Meniere’s disease, also called endolymphatic hydrops, is thought to be due to an excess of endolymph fluid in the inner ear. Clinically, it produces recurrent episodes characterized by pain, pressure, and fullness in the affected ear; a low-pitched, “roaring” tinnitus; low-frequency hearing loss; and acute vertigo with nausea and vomiting. Episodes typically last for hours. Although hearing generally recovers between attacks, over time, after repeated episodes, there may be a permanent loss. The hearing loss associated with Meniere’s disease is most severe at low frequencies; this helps to distinguish it from other causes of sensorineural hearing loss, which typically affect the high frequencies. Diagnosis of Meniere’s disease is made on clinical grounds. Audiometry is important, and transtympanic electrocochleography may help, by demonstrating abnormal evoked electrical potentials that occur with hydrops. Patients who have recurrent vertigo without hearing loss or other aural symptoms are more likely to have another cause, such as vestibular migraine. Patients in whom Meniere’s disease is suspected should be tested for inflammatory and infectious causes with an erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, rheumatoid factor, thyroidstimulating hormone, and rapid plasma reagin/fluorescent treponemal antibody (autoimmune disease and otosyphilis can mimic Meniere’s disease). Initial treatment of Meniere’s disease includes sodium restriction (1 gm of Na+ per day) and diuretic therapy. Options include acetazolamide hydrochlorothiazide and hydrochlorothiazide/triamterene. If attacks persist, the patient should be referred to a
neuro-otologist for consideration of ablative therapy. Intratympanic gentamicin is the current treatment of choice. If this is done properly, enough hair cell damage can be effected to alleviate attacks without causing severe vestibular hypofunction or significant hearing loss. Since the advent of gentamicin therapy, surgical ablation (labyrinthectomy or vestibular nerve section) is seldom needed. When attacks are prolonged and cannot be fully controlled, a vestibular suppressant (see later) may be prescribed to be taken at the onset of an attack. VESTIBULAR MIGRAINE Migraine is one of the most common causes of episodic vestibular symptoms. Migraine-related dizziness may have many forms, including attacks of vertigo that last from minutes to hours, as well as disequilibrium and motion sensitivity that may last for days to weeks or longer. Sensitivity to visual motion (e.g., watching movies or television) is common. Occasionally, vertigo occurs as an aura followed by headache, but most often dizzy spells and headaches occur independently. There is also a vestibular form of migraine in children (benign paroxysmal vertigo of childhood). Vestibular migraine is treated similarly to other forms of migraine (see Chapter 18). In general, vestibular symptoms are reduced or prevented by the usual migraine prophylactic agents. The choice of a particular drug often is based on comorbidities (e.g., anxiety, depression, hypertension). It is important to be aware that depression and anxiety are common in these patients, particularly those with more severe chronic symptoms. In those cases, assessment by a psychiatrist may be helpful. If a prophylactic medication is given, the dose must be titrated up to a therapeutic level, and sufficient time (weeks to several months) must be given to determine its full effect. I most commonly begin treatment with an antidepressant (e.g., nortriptyline or venlafaxine). I begin with nortriptyline 10 to 25 mg at bedtime and titrate the daily dose by 10 to 25 mg once a week, up to a total dose of 75 to 100 mg if needed and tolerated. Venlafaxine XR is started at 37.5 mg per day, usually best taken in the morning, and titrated by 37.5 mg per day once a week. Most patients need doses of 150 to 300 mg per day for adequate prophylaxis. Other options include beta blockers (if the blood pressure will tolerate them), calcium channel blockers (e.g., verapamil), and anticonvulsants (e.g., gabapentin, topiramate, valproate). BENIGN PAROXYSMAL POSITIONAL VERTIGO Benign paroxysmal positional vertigo (BPPV) is caused by otoconial debris that dislodges from the otolith membrane and becomes free-floating in the endolymph. If it falls into one of the semicircular canals (usually the posterior), it can cause excitation of the canal when the head moves relative to gravity. The typical scenario is brief (90%) in patients with definite cataplexy. This association lends support to the hypothesis that narcolepsy is an autoimmune disorder. Hypocretin has tight functional interactions with cholinergic and monoaminergic systems regulating sleep. Without hypocretin, narcoleptic patients have sleepiness, inappropriate rapid eye movement (REM) paralysis during wakefulness (cataplexy, sleep paralysis), REM dreaming before falling asleep (hypnagogic hallucinations), and disorganized night-time sleep. Rapid transitions into REM sleep (REM latency below 20 minutes) called sleep-onset REM periods (SOREMPs) can be observed during nocturnal sleep and while napping.
Clinical Characteristics Cataplexy is a sudden, short-lived (seconds, rarely more than minutes), bilateral loss of muscle tone elicited by emotions. The existence of a typical trigger is crucial to the recognition of genuine cataplexy. It is usually produced by humor or laughter, especially when the patient himself or herself is telling a joke or relating a funny story. Less commonly, anger, surprise, elation, playful excitement may be involved. There is no sensory component or loss of consciousness. Attacks can be mild, such as an inability to retain facial muscle tone, or severe, leading to complete collapse. Reflexes are abolished, but the episodes are rarely long enough to evaluate by physical examination. Respiration can be hampered by position or made slightly more difficult, but it is always maintained. Johnson: Current Therapy in Neurologic Disease (7/E)
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Narcolepsy
The International Classification of Sleep Disorders. 2005, Westchester, IL: American Academy of Sleep Medicine. Hobson JA, Silvestri L: Parasomnias, Harvard Mental Health Lett 15:3-5, 1999. Kales A, Soldatos CR, Kales JD: Sleep disorders: insomnia, sleepwalking, night terrors, nightmares, and enuresis, Ann Intern Med 106:582-592, 1987. Kavey NB, Whyte J, Resor SR Jr, Gidro-Frank S: Somnambulism in adults, Neurology 40:749-752, 1990. Klackenberg G: Incidence of parasomnias in children in a general population, New York, 1987, Raven Press, 99-113. Kowey PR, Mainchak RA, Rials SJ, et al: Things that go bang in the night, N Engl J Med 327:1884, 1992. Llorente MD, Currier MB, Norman SE, Mellman TA: Night terrors in adults: phenomenology and relationship to psychopathology, J Clin Psychiatry 53:392-394, 1992. Mahowald MW: Overview of parasomnias. In National sleep medicine course, Westchester, IL, 1999, American Academy of Sleep Medicine. Mahowald MW, Ettinger MG: Things that go bump in the night: the parasomnias revisited, J Clin Neurophysiol 7:119-143, 1990. Mahowald MW, Rosen GM: Parasomnias in children, Pediatrician 17:21-31, 1990. Mahowald MW, Schenck CH: Diagnosis and management of parasomnias, Clin Cornerstone 2:48-57, 2002. Mahowald MW, Schenck CH: NREM sleep parasomnias, Neurol Clin 14:675-696, 1996. Mahowald MW, Schenck CH: REM sleep behavior disorder, Philadelphia, 1994, WB Saunders, 574-588. Masand P, Popli AP, Weilburg JB: Sleepwalking, Am Family Physician 51:649-654, 1995. Milliet N, Ummenhofer W: Somnambulism and trauma: case report and short review of the literature, J Trauma Injury Infect Crit Care 47:420-422, 1999. Ohayon MM, Guilleminault C, Priest RG: Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders, J Clin Psychiatry 60:268-276, 1999. Parkes JD: The parasomnias, Lancet 2:1021-1025, 1986. Plazzi G, Corsinin R, Provini F: REM sleep behavior disorders in multiple system atrophy, Neurology 48:1094-1097, 1997. Reid WH, Ahmed I, Levie CA: Treatment of sleepwalking: a controlled study, Am J Psychother 35:27-37, 1981. Rosen GM, Mahowald MW, Ferber R: Sleepwalking, confusional arousals, and sleep terrors in the child. In Ferber A, Kryger M, editors: Principles and practice of sleep medicine in the child, Philadelphia, 1995, WB Saunders, 99-106. Schenck CH, Bundlie SR, Mahowald MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder, Neurology 46:388-393, 1996. Schenck CH, Bundlie SR, Patterson AL, Mahowald MW: Rapid eye movement sleep behavior disorder: a treatable parasomnia affecting older adults, JAMA 257:1786-1789, 1987. Schenck CH, Mahowald MW: REM sleep parasomnias, Neurol Clin 14:697-720, 1996. Schenck CH, Mahowald MW: Two cases of premenstrual sleep terrors and injurious sleepwalking, J Psychosom Obstet Gynaecol 16:79-84, 1995. Shneerson J: Handbook of sleep medicine, Malden, 2000, Blackwell Science, 136-162. Takeuchi N, Uchimura N, Hashizume Y, et al: Melatonin therapy for REM sleep behavior disorder, Psychiatry Clin Neurosci 55:267-269, 2001. Tassi P, Muzet A: Sleep inertia, Sleep Med Rev 4:341-353, 2000. Thorpy MJ, Glovinsky PB: Parasomnias, Psychiatr Clin North Am 10:623-639, 1987. Wise MS: Parasomnias in children, Pediatr Ann 26:427-433, 1997.
Narcolepsy Scott Fromherz, M.D., and Emmanuel Mignot, M.D., Ph.D.
Together with obstructive sleep apnea (OSA), insufficient sleep, and idiopathic central nervous system hypersomnia, narcolepsy is a common cause of excessive daytime sleepiness. Even when narrowly defined by the presence of cataplexy, narcolepsy is not rare and affects 1 in 2000 individuals in North America and Western European countries.
Definition and Pathophysiology The classic narcolepsy “tetrad” includes daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Cataplexy, a sudden loss of muscle tone, triggered by strong emotions, is almost pathognomonic but is not required for diagnosis. Other symptoms include disrupted night-time sleep and automatic behaviors. Narcolepsy is associated with human leukocyte antigen (HLA) DQB1*0602. Postmortem studies have shown a selective loss of 50,000 to 100,000 posterior hypothalamic neurons, producing the neuropeptide hypocretin (orexin). The HLA association and associated hypocretin deficiency is particularly strong (>90%) in patients with definite cataplexy. This association lends support to the hypothesis that narcolepsy is an autoimmune disorder. Hypocretin has tight functional interactions with cholinergic and monoaminergic systems regulating sleep. Without hypocretin, narcoleptic patients have sleepiness, inappropriate rapid eye movement (REM) paralysis during wakefulness (cataplexy, sleep paralysis), REM dreaming before falling asleep (hypnagogic hallucinations), and disorganized night-time sleep. Rapid transitions into REM sleep (REM latency below 20 minutes) called sleep-onset REM periods (SOREMPs) can be observed during nocturnal sleep and while napping.
Clinical Characteristics Cataplexy is a sudden, short-lived (seconds, rarely more than minutes), bilateral loss of muscle tone elicited by emotions. The existence of a typical trigger is crucial to the recognition of genuine cataplexy. It is usually produced by humor or laughter, especially when the patient himself or herself is telling a joke or relating a funny story. Less commonly, anger, surprise, elation, playful excitement may be involved. There is no sensory component or loss of consciousness. Attacks can be mild, such as an inability to retain facial muscle tone, or severe, leading to complete collapse. Reflexes are abolished, but the episodes are rarely long enough to evaluate by physical examination. Respiration can be hampered by position or made slightly more difficult, but it is always maintained. Johnson: Current Therapy in Neurologic Disease (7/E)
Narcolepsy
Diagnosis The diagnosis of narcolepsy is primarily clinical, but confirmatory tests are usually necessary to verify the diagnosis (Figure 1). The presence of definite cataplexy is Johnson: Current Therapy in Neurologic Disease (7/E)
most important (see later). Questions about sleep patterns, medications that cause somnolence, signs of sleep apnea such as snoring, symptoms of restless leg syndrome, and evidence of sleep insufficiency or a circadian rhythm disturbance must be asked. If there is suspicion of OSA, an overnight polysomnogram (PSG) is mandatory. Finally, evaluation must include questions about sleep paralysis, hypnagogic and hypnopompic hallucinations, automatic behaviors, and disrupted night-time sleep. Because of its importance to the diagnosis, questions regarding cataplexy should be asked carefully to avoid leading the patient. Cataplexy is rarely observed during interviews, although small facial attacks are sometimes observed when severely affected patients recount emotional events. A question like “Does anything unusual happen when you are laughing?” is more appropriate than “Do you feel weak when you are laughing?” Similarly, the clinician should not be satisfied with a simple affirmative response. Rather, the patient should be asked to recall the specific circumstances. In this regard, it is useful to ask for a description of the first or last episode experienced. Patients describing unclear events or events that have occurred only once should be considered without cataplexy for the purpose of further evaluation and treatment strategies (Figure 2; see also Figure 1). If a patient has both hypersomnia and definite cataplexy, a clinical diagnosis can be made. However, it is still recommended that a PSG followed by a multiple sleep latency (MSL) test be done to document sleepiness and evaluate comorbid sleep disorders. Proper documentation also permits more aggressive treatment in the future. Approximately 15% of patients with cataplexy do not display typical MSL test abnormalities, so the diagnosis must remain clinically based. If there is no cataplexy, an MSL test (preceded by PSG) is mandatory (see Figure 1). The MSL test objectively quantifies daytime sleepiness. It consists of five 20-minute daytime naps at 2-hour intervals. The amount of time it takes to fall asleep (sleep latency) and the occurrence of REM sleep is recorded. An MSL of less than 8 minutes and two or more SOREMPs is diagnostic for narcolepsy. The MSL test must always be preceded by a PSG to rule out other causes of short MSL or SOREMPs such as OSA, insufficient sleep, or delayed sleep phase syndrome. At least 6 hours of sleep must have occurred prior to the MSL test. Sleep logs or actigraphy for the preceding 2 weeks can be helpful to exclude chronic sleep deprivation. It must also be conducted after withdrawal of psychotropic medications (generally > 2 weeks). Antidepressants, most notably, suppress REM sleep and/or may create REM rebound if stopped too recently prior to testing. The PSG may also show a short sleep latency (< 10 minutes) and a SOREMP (< 20 minutes on the PSG). Periodic limb movements, fragmented sleep and low sleep efficiency are often observed. The MSL test may be difficult to interpret in the presence of disturbed nocturnal sleep or in patients with combined sleep pathologies (e.g., OSA or severe periodic limb movements and narcolepsy). When conducted
Disorders of Consciousness
This definition allows one to rule out possible mimics. Syncope, sleep attacks, and generalized seizures all involve a loss of consciousness. The bilateral distribution of weakness and temporal course are inconsistent with most strokes. The short duration and lack of correlation with intense exercise are inconsistent with episodic or fluctuating neuromuscular disorders. The lack of positive phenomena rules out most seizures. Because startle alone is not a typical trigger, hyperekplexia can be excluded. It is also important to differentiate genuine cataplexy from normal physiologic reactions. For example, a person may laugh so hard that his face hurts or feels weak. When laughing hard, non-narcoleptic patients might also feel “rubber knees” or roll onto the floor. In true cataplexy, muscle weakness is obvious and must occur more than a few times in a lifetime. Sleepiness in narcolepsy is usually more severe than in other sleep disorders; however, contrary to popular belief, it is not easy to differentiate from sleepiness due to insufficient sleep or OSA. Napping is common, and short naps are typically refreshing. A misperception in narcolepsy is the nature of “sleep attacks.” Some have a mistaken impression that the term sleep attack refers to sudden sleep that is so severe it may cause extraordinary events such as falling asleep into a soup bowl. Others are confusing cataplexy and sleep attacks. The correct definition of sleep attack is an irresistible desire to fall asleep that can lead to unintentional sleep. It can present rapidly, but its onset is not as acute as cataplexy. For example, people with narcolepsy may feel awake and nonsleepy until they are in a sedentary or nonstimulating situation, at which point they may rapidly fall asleep. It is not an “attack” so much as an unexpected nap. Other symptoms are more straightforward to identify but lack diagnostic specificity. Sleep paralysis is an inability to move that occurs at sleep onset or on awakening. Hypnagogic and hypnopompic hallucinations are dreamlike visual or auditory perceptions that occur at sleep onset and on awakening, respectively. Hallucinations and sleep paralysis may occur in combination and are typically frightening. Automatic behaviors are actions that occur without full awareness or memory, for example continuing to talk on the phone without making sense, because of sleepiness or microsleep. It is merely an indication of the severity of daytime sleepiness independent of any etiology. Disturbed nocturnal sleep is present in approximately 50% of patients and can be quite disabling. In narcolepsy, it is usually not characterized by a difficulty falling asleep but rather by recurrent night-time awakenings and a feeling of restlessness during the night. All symptoms except cataplexy can also be found in normal individuals, idiopathic hypersomnia, and OSA in some circumstances.
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Narcolepsy
Hypersomnia
Clinical evaluation: Ask about cataplexy, evaluate severity of sleepiness and presence of sleep paralysis, hypnagogic hallucinations, or automatic behaviors. Rule out more common causes of hypersomnia such as obstructive sleep apnea, insufficient sleep syndrome, or a circadian rhythm disorder. Also, confirm that it is primarily a problem of sleepiness rather than fatigue.
Definite cataplexy
No cataplexy or atypical cataplexy
Diagnosis of narcolepsy • Proceed with PSG/MSLT to objectively document a firm diagnosis and allow for more aggressive treatment later. Treat comorbid sleep disorders if needed (e.g. OSA, but rarely PLMs) • If MSLT is negative (MSL > 8 or < 2 SOREMPs) the results should be interpreted within the context of the clinical history as the presence of cataplexy is sufficient to diagnose narcolepsy. If necessary, the MSLT can be repeated • Consider LP for CSF hypocretin-1 levels if patient:
MSLT • Must be preceded by PSG to rule out comorbid sleep disorders and document adequate nocturnal sleep. • If significant sleep disorder detected on PSG, then disorder must be treated before proceeding with MSLT.
1. is already being treated with psychotropic medications 2. has clinically significant associated sleep disorders 3. has disabling neurological or psychiatric disorders, confounding the clinical picture or disrupting the ability to conduct an MSLT 4. is very young and cannot follow MSLT instructions properly
MSL > 8 minutes or < 2 SOREMPs
MSL < 8 minutes or ≥ 2 SOREMPs
Not narcolepsy (If clinical suspicion high, consider repeat MSLT or LP for CSF hypocretin-1 levels)
Diagnosis of narcolepsy
FIGURE 1. Evaluation of narcolepsy. MSLT, Multiple sleep latency test; MSL, mean sleep latency; PSG, polysomnogram; SOREMP, sleep-onset rapid eye movement period; OSA, obstructive sleep apnea; PLM, periodic limb movement; LP, lumbar puncture; CSF, cerebrospinal fluid.
in the absence of sleep deprivation or delayed sleep phase, it is considered to be a highly predictive test. Large sample population–based MSL test evaluations in controls are lacking, but it is estimated that only a small percentage of the general population has SOREMPs during MSL testing. Cerebrospinal fluid (CSF) hypocretin-1 measurements can also be used to diagnose narcolepsy. In patients with cataplexy, CSF hypocretin-1 levels are absent or very low in more than 90% of the cases. In patients with various other neurologic disorders, only 2% have low CSF hypocretin-1, mostly in the context of severe neurologic conditions. Levels are normal in controls independent of psychotropic treatment and/or presence of other sleep disorders. Unfortunately, the test is less predictive in patients without cataplexy, with only 16% having low levels, often in younger subjects who may later develop cataplexy.
Positive MSL test findings may be absent in some narcoleptics, especially young children. Approximately 15% of patients with definite narcolepsy and hypocretin deficiency have a negative first-time MSL test. If the MSL test is negative, but clinical suspicion for narcolepsy is high, repeat the MSL testing or measure CSF hypocretin-1. Serum HLA typing for DQB1*0602 is positive in many patients with narcolepsy, but it is also positive in approximately 20% to 25% of normal subjects. DQB1*0602 positivity does not confirm narcolepsy.
Pharmacologic Treatments Modafinil is now first-line standard-of-care treatment for sleepiness associated with narcolepsy. Headache can be a problematic side effect, but that usually resolves with time and can often be avoided by slowly increasing Johnson: Current Therapy in Neurologic Disease (7/E)
Narcolepsy
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Behavioral methods: • Scheduled naps • Fixed wake-up time • Regular sleep schedule
Definite cataplexy
No disrupted nighttime sleep
Disrupted nighttime sleep
Sodium oxybate: • Starting dose 4.5 grams split in two nightly doses (at bedtime and 2 hours later). Dose can be increased by 1.5 grams every two weeks, up to a maximum of 9 grams per night. • Consider adding modafinil and anticataplectics on a short-term basis until sodium oxybate has full effect (up to 6 months later). • If successful treatment, consider decreasing or stopping dose of anticataplectics and stimulants.
No cataplexy or atypical cataplexy
Disorders of Consciousness
Diagnosis of narcolepsy
• Treat cataplexy with anticataplectic monoamine reuptake inhibitors: Venlafaxine 75–300 mg/day Atomoxetine 18–100 mg qd or split bid Fluoxetine 20–60 mg/day Clomipramine 25–200 mg qhs Protriptyline 2.5–20 mg/bid • If no (or minimal) response, consider reevaluating presence of true cataplexy. An LP for CSF hypocretin-1 levels may be necessary to confirm diagnosis. • If patient responds to anticataplectics, but sideeffects are limiting, effect is insufficient, or disrupted nighttime sleep appears, consider sodium oxybate.
Treat daytime sleepiness with modafinil 200–600 mg/day (if insufficient, can add two pulse doses of 5 mg methylphenidate at peak times of sleepiness)
Use caution before proceeding to stronger CNSstimulating agents, given the potential for abuse and tolerance. Confirm MSLT results and consider LP for CSF hypocretin-1. If patient is hypocretin-1 deficient, consider sodium oxybate.
• Methylphenidate SR 20 mg in am with two pulse doses of 5 mg methylphenidate (non-SR) at peak times of sleepiness • Dextroamphetamine SR 10–15 mg in am with 5 mg pulse dosing as with methylphenidate
• If onset is recent, adjust treatment with appearance of new symptoms • Evaluate stable patients every six months • Watch for weight gain and development of OSA or additional sleepiness FIGURE 2. Treatment of narcolepsy. CNS, Central nervous system; MSLT, multiple sleep latency test; CSF, cerebrospinal fluid; LP, lumbar puncture; OSA, obstructive sleep apnea.
the dose. The safest starting dose for modafinil is 100 mg in the morning, which can be gradually increased to a maximum of 400 to 600 mg. This may be split into a morning and a noon dose. Amphetamine-like stimulants, such as methylphenidate, dextroamphetamine, amphetamine racemic mixture, and methylamphetamine, can also be used but have a number of disadvantages. They are potentially addictive and should be reserved for patients with a well-established diagnosis. Additionally, side effects such as palpitations, hypertension, and nervousness may occur because of their action on the autonomic nervous system. The mode of action of amphetamine-like stimulants and modafinil on Johnson: Current Therapy in Neurologic Disease (7/E)
wakefulness is thought to involve increase dopaminergic transmission. The most important concept in using stimulants for treating daytime sleepiness is timing. A typical scenario is to use modafinil or an extended-release amphetamine formulation in the morning, with pulse dosing of shortacting medication at appropriate times throughout the day. For example, a student who still has problems with sleepiness after lunch might take 5 to 15 mg of shortacting methylphenidate at that time in addition to the morning modafinil. Although stimulants are used primarily for daytime sleepiness, amphetamines (not modafinil) also have some effect on cataplexy at high doses.
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Narcolepsy
Antidepressants are commonly used to treat cataplexy. They are also effective for sleep paralysis and hypnagogic hallucinations, a sometime disabling symptom. Tricyclic antidepressants are highly effective but have anticholinergic side effects. Selective serotonin reuptake inhibitors are efficacious, but relatively high doses are generally needed. Newer medications targeting norepinephrine reuptake, such as venlafaxine and atomoxetine, are most effective. The dual serotoninergic/noradrenergic reuptake inhibitor venlafaxine, 75 to 300 mg/day, is now a typical first-line treatment. If this is not helpful, atomoxetine, 18 to 100 mg daily or split to twice daily; fluoxetine, 20 to 60 mg/day; or even tricyclic antidepressants (e.g., protriptyline, 2.5 to 20 mg/day, or clomipramine, 25 to 200 mg/day) can be used. Atomoxetine is unique in being the only U.S. Food and Drug Administration– approved medication that selectively blocks norepinephrine reuptake. Patients should be warned that rebound cataplexy usually occurs when medications are discontinued, changed, or skipped. Sodium oxybate (gamma-hydroxybutyrate [GHB]) is unique because it is efficacious on all symptoms. This naturally occurring compound is a potent but shortacting hypnotic that consolidates slow-wave and REM sleep, most likely via gamma-aminobutyric acid type B agonistic effect. It has been available since the 1970s but was only recently approved for the treatment of cataplexy. It is thought that the consolidation of nocturnal sleep and REM sleep leads to decreased daytime symptoms. The starting dose is 4.5 gm per night, divided in two nightly doses (before bedtime and 2 to 3 hours later, once the first dose has metabolized). The patient should prepare both doses, lie down after taking the drug, and possibly set up an alarm for the second dose. The dose can be increased every 2 weeks by 1.5-gm increments to a maximum of 9 gm per night. The most common side effects are dizziness, nausea, and, at a higher dose, enuresis. Sodium oxybate should not be taken with alcohol or other central nervous system depressants. Narcolepsy is frequently associated with other sleep disorders. OSA is common and must be treated, especially if GHB is to be used. Periodic limb movements are also common but rarely need treatment unless associated with restless leg syndrome.
Behavioral Treatments Good sleep hygiene, education, and treatment compliance are important to the management of narcolepsy. Referral to support groups such as the Narcolepsy Network is helpful. Fixed wake-up times, sleep diaries, and regular sleep schedule are recommended. Obesity may develop, especially in young children when disease onset is abrupt. It is useful to restrict the diet, encourage exercise, and treat sleepiness aggressively at this stage.
The risk of driving while sleepy, especially prior to adequate therapy, must be discussed and if appropriate, regulatory agencies notified. Patients with narcolepsy must avoid jobs that put others in danger and should consider activities that are less sedentary. Jobs that involve repetitive tasks or sitting down and looking at a computer all day can be difficult. Employers or teachers should be asked to accommodate 15- to 30-minute scheduled naps. SUGGESTED READING Dauvilliers Y, Billiard M, Montplaisir J: Clinical aspects and pathophysiology of narcolepsy, Clin Neurophysiol 114:2000-2017, 2003. Lammers GJ, Overeem S: Pharmacological management of narcolepsy, Expert Opin Pharmacother 4:1739-1746, 2003. Mignot E, Lammers GJ, Ripley B, et al: The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias, Arch Neurol 59:1553-1562, 2002. Mignot E, Lin L, Rogers W, et al: Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups, Am J Hum Genet 68:686-699, 2001. Taheri S, Zeitzer JM, Mignot E: The role of hypocretins (orexins) in sleep regulation and narcolepsy, Annu Rev Neurosci 25:283-313, 2002.
PATIENT RESOURCES American Academy of Sleep Medicine One Westbrook Corporate Center, Suite 920 Westchester, IL 60154 Phone: 708-492-0930 http://www.aasmnet.org/ Narcolepsy Network, Inc. 10921 Reed Hartman Highway, Suite 119 Cincinnati OH 45242 Phone: 513-891-3522 E-mail:
[email protected] http://www.narcolepsynetwork.org/ National Organization for Rare Disorders 55 Kenosia Avenue P.O. Box 1968 Danbury, CT 06813-1968 Phone: 800-999-6673 Email:
[email protected] http://www.rarediseases.org/ National Sleep Foundation 1522 K Street NW, Suite 500 Washington, DC 20005 Phone: 202-347-3471 E-mail:
[email protected] http://www.sleepfoundation.org/ Stanford Center for Narcolepsy Department of Psychiatry and Behavioral Sciences Psychiatry and Behavioral Sciences Building 401 Quarry Road—Room 3354 Stanford, CA 94305-5730 Phone: 650-725-6512 http://www.med.stanford.edu/school/psychiatry/narcolepsy/ Talk About Sleep, Inc. P.O. Box 146 Chaska, MN 55318 Phone: 952-448-5511 http://www.talkaboutsleep.com/
Johnson: Current Therapy in Neurologic Disease (7/E)
SECTION 2 ●
Seizures Neonatal Seizures and Infantile Spasms
is uncommon. If you add benzodiazepines, be prepared to intubate. If the seizures or the cause are focal, phenytoin may be considered. Here, if a dose of phenytoin, 20 mg/kg, with serum levels greater than 20 μg/mL is ineffective, then further doses are unlikely to be helpful.
Tallie Z. Baram, M.D., Ph.D.
Infantile Spasms
Neonatal Seizures Most seizures in a newborn are symptomatic—they are caused by acute or remote insults to the developing brain. Some of these may be eliminated or reversed; others may require concurrent treatment. Therefore, a diagnostic evaluation should precede or coincide with therapeutic intervention (see later). A second unique feature of many neonatal seizures is their unusual or subtle nature compared with seizures later in life. In addition to tonic, clonic, focal, or apparent generalized motor seizures, neonatal seizures may consist of fragmented, nonrhythmic movements, eye blinking, singleextremity posture, or electroencephalographic seizures without overt motor manifestations. Thus, the clinician should have a high level of suspicion for seizures in an ill neonate. Tachycardia or bradycardia, unexplained oxygen desaturation, or abnormal mental status may signify ongoing seizures. Finally, the outcome of neonatal seizures is best predicted by their cause. For example, hypocalcemia-induced seizures in an otherwise normal fullterm infant typically remit, with good outcome. In contrast, seizures following severe hypoxia/ ischemia, severe neonatal infection, or congenital brain malformation may respond to treatment, but the infant’s prognosis would be guarded. TREATMENT (Figure 1) There is no “absolute best” drug. Phenobarbital is recommended here because it is both rapid and long acting and has no “ceiling”; repeated boluses can be used in severe cases as monotherapy with high likelihood of success. Ignore serum levels; in any event, they are not steady-state. Use remission as your guideline. With phenobarbital monotherapy, respiratory depression Johnson: Current Therapy in Neurologic Disease (7/E)
Infantile spasms (West’s syndrome) are a severe, relatively common (~1:2400 births), and often missed diagnosis. It is important to recognize infantile spasms because they respond poorly to conventional anticonvulsants, but remit in most infants when treated with high-dose adrenocorticotropic hormone (ACTH) (see later) (Figure 2). A broad consensus suggests that cognitive outcome is better in infants with infantile spasms who are treated successfully. Infantile spasms are considered a form of myoclonic seizures that occur in clusters. They are prevalent in 3- to 12-month-old infants and are associated with a highly abnormal (interictal), chaotic electro-encephalogram (EEG) (hypsarrhythmia). This pathognomonic EEG pattern is most commonly observed during sleep. The seizures may be flexor, extensor, or mixed, subtle, or massive, and “flattening” of the EEG during a spasm is typical. Most infantile spasms are symptomatic, resulting from a large variety of insults or genetic causes. A variant associated with tuberous sclerosis may be particularly responsive to vigabatrin (100 to 150 mg/kg/day). This medication is available outside the United States, and the side effects of visual-restrictive retinal changes should be considered. In some cases the causes of infantile spasms may be treatable, with seizure remittance. Mostly, treatment of the spasms with a goal of eliminating them and normalizing the EEG is required. Early, successful therapy seems to improve cognitive outcome. The latter is grim in symptomatic cases but excellent in remitting idiopathic cases. The most efficacious treatment is high-dose ACTH, with greater than 85% success. A 2-week treatment with this potent hormone results in unpleasant but rarely dangerous side effects such as acne, hypertension, voracious appetite, and irritability. Long-lasting treatment may lead to immunosuppression or gastric bleeding. Because efficacy is a function of the dose, and 23
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Neonatal Seizures and Infantile Spasms
ALGORITHM FOR MANAGEMENT OF NEONATAL SEIZURES 1. Assure adequate airway protection and oxygenation 2. Initiate diagnostic evaluation: • History/physical for obvious causes (placenta previa, multiorgan failure with hypoxic ischemic encephalopathy (HIE), severe prematurity, etc). • Metabolic: Glucose (in an infant of diabetic mother, give oral or iv glucose), calcium, electrolytes • Infection: CBC, cultures, chest x-ray. Spinal tap mandatory (consider metabolic causes of low CSF glucose). • Evaluate for congenital infection, particularly if petechiae, liver enlargement, cataracts or other clues present. • CT/MRI: periventricular hemorrhage in severe prematurity, malformation, tuberous sclerosis, infarcts, abnormal basal ganglia signal indicating HIE, etc. • Obtain EEG, if infant ill or seizures subtle consider continuous EEG to monitor results of therapy. 3. Treat A. Address treatable causes (calcium, glucose, infection) B. Give phenobarbital 20 mg/kg. This is a loading dose that should lead to barely therapeutic serum levels.
Seizures remit
Cause transient or resolved: stop treatment Cause persistent or unknown, baby abnormal: continue treatment
Seizures remit
More PB or benzodiazepine. Reassess diagnostic workup. Consider intubation.
Seizures persist
Repeat PB at 10–20 mg/kg* Obtain EEG. If seizures focal consider phenytoin (20 mg/kg) • Barbiturates have no ‘ceiling’ effect. May be used at very high doses, to seizure remission • Mixing barbiturates and benzodiazepines should be done with caution in unintubated infants, because of potential respiratory depression.
Seizures persist
FIGURE 1. Algorithm for management of neonatal seizures. CBC, Complete blood count; CSF, cerebrospinal fluid; EEG, electroencephalogram; PB, phenobarbital.
ALGORITHM FOR MANAGEMENT OF INFANTILE SPASMS 1. Establish the diagnosis • History/physical: to rule out (sleep) myoclonus, myoclonic seizures, GE reflux The age, clusters of spasms, hypsarrhythmic EEG are diagnostic • Consider treatable causes (mass lesion, metabolic derangement). Try to establish diagnosis, particularly tuberous sclerosis, infection, other genetic/acquired insult (CT/MRI, basic metabolic workup). Normal baby = idiopathic IS: prognosis better Abnormal baby with diagnosis (symptomatic IS), or no diagnosis (cryptogenic) prognosis for cognitive outcome guarded 2. Treat A. Address treatable causes (hydrocephalus, infection) B. Give ACTH depot (ACTHARGEL): 150 units/square meter per day (~ 80 U per 10 kg baby) in two daily divided doses for 2 weeks.
Spasms remit (>80%)
Spasms persist
Obtain EEG or video-EEG to verify. Often hypsarrhythmia will disappear revealing other abnormalities.
Verify that medication given as directed. Try another ‘batch’ of ACTH.
Spasms persist No spasms, no hypsarrhythmia
Taper ACTH over 2 weeks
Consider vigabatrin 100 mg/kg/day. Consider topiramate, valproate, B-6, ketogenic diet.
FIGURE 2. Algorithm for management of infantile spasms. EEG, Electroencephalogram; GE, gastroesophageal; IS, infantile spasm; ACTH, adrenocorticotropic hormone. Johnson: Current Therapy in Neurologic Disease (7/E)
Febrile Seizures
Febrile Seizures Adam L. Hartman, M.D., and Eileen P. G. Vining, M.D.
Febrile seizures occur in approximately 3% of children, making them the most common type of seizure in this age group. They are seizures in infancy or childhood (typically between 3 months and 5 years of age) associated with fever and without evidence of central nervous system infection or other defined cause, such as metabolic abnormalities due to dehydration. Ordinarily, they are generalized (tonic-clonic or tonic) in nature and brief. The fact that they are common to pediatric practices (and often to neurologic consultation) makes it important to understand many of the concerns associated with their occurrence and to understand the information that has reshaped our approach to this problem. In fact, this has resulted in reconsideration of our overall approach to seizures. Given the generally benign prognosis in febrile seizures, counseling the family is the primary form of “therapy.” One way to consider the issues involved in febrile seizures is to organize the information in a format that answers parents’ questions and provides a framework for providing ongoing care. This can even include anticipatory guidance, which is so vital to the practice of pediatrics. Johnson: Current Therapy in Neurologic Disease (7/E)
Seizures
side effects are a function of the duration of treatment, it is best to initiate ACTH treatment at the high dosage and limit duration to 2 weeks, with a 2-week taper. Complete dramatic remission of the spasms typically occurs during the first week. Note that twice-daily dosing at the high (ActharGel, 150 U/m2 of body surface area) is required. Occasional “bad” batches of the hormone have been described. In infants with a strong focal element of the spasms, particularly with focal lesion (e.g., tuber) and focal EEG, surgical therapy should be considered. A trial of ACTH may still be indicated and may convert apparent infantile spasms to focal seizures. Other therapies may be successful at a much lower rate. Consider pyridoxine (to exclude pyridoxinedependent seizures, or as therapy), 100-150 mg/day; valproate; topiramate; and the ketogenic diet. If seizures remit and recur, verify that these are indeed infantile spasms rather than a new seizure type with focal EEG. A second course of ACTH may be effective for infantile spasm recurrence. New seizure types, instigated by the original disorder, may respond to appropriate anticonvulsant therapy.
25
TABLE 1 Risk of Experiencing a Febrile Seizure Factor General population Child in daycare Slow development Prolonged nursery stay (>28 days) Febrile seizure in first-degree relative (mother, father, sibling) Febrile seizure in two first-degree relatives Any two risk factors
Risk of Febrile Seizure (%) 2 7 10 12 10 33 28
Adapted from Bethune P, Gordon K, Dooley J, et al: Which child will have a febrile seizure? Am J Dis Child 147:35-39, 1993.
What Is the Chance That My Child Will Have Febrile Seizures? Families with a history of febrile seizures may ask this question, particularly when there are siblings with febrile seizures. Febrile seizures are more common in some families, and 10% to 20% of siblings of children with febrile seizures will also experience them. Certain other children may have an increased risk, as high as 25% if the child had a prolonged nursery stay, slow development, or daycare attendance. These factors suggest susceptibility to febrile seizures in a child who may have experienced some subtle neurologic changes and who is exposed on a more consistent basis to a wide range of infections in the daycare setting. When two or more of these factors exist, it may be appropriate at one of the early well-child visits to discuss management of fever and what to do if a febrile seizure occurs (Table 1).
What Should We Do If Our Child Has a Febrile Seizure? Most febrile seizures are brief and do not need medical intervention. If, however, the seizure has persisted longer than 5 minutes, Emergency Medical Services (i.e., “911”) should be called. Less than 5% of febrile seizures occur as status epilepticus, and it is likely that the seizure will end before medications can be given. The usual intervention is either lorazepam, 0.1 mg/kg intravenously (IV), up to 4 mg, or diazepam, 0.3 mg/kg IV given slowly at less than 1 mg/kg/min. Health care providers in emergency settings should recall that diazepam could be given rectally.* In essence, care during a febrile seizure should be the same as for any other generalized convulsion. When the seizure is over and the child has returned to baseline (often sleepiness if the seizure has occurred at night), a decision must be made concerning the *Diastat, 0.5 mg/kg rectally for children 2 to 5 years, 0.3 mg/kg rectally for children 6 to 11 years, 0.2 mg/kg rectally for children older than 11 years, all rounded to the nearest syringe size; one dose may be repeated after 30 minutes, if necessary.
2
Febrile Seizures
Febrile Seizures Adam L. Hartman, M.D., and Eileen P. G. Vining, M.D.
Febrile seizures occur in approximately 3% of children, making them the most common type of seizure in this age group. They are seizures in infancy or childhood (typically between 3 months and 5 years of age) associated with fever and without evidence of central nervous system infection or other defined cause, such as metabolic abnormalities due to dehydration. Ordinarily, they are generalized (tonic-clonic or tonic) in nature and brief. The fact that they are common to pediatric practices (and often to neurologic consultation) makes it important to understand many of the concerns associated with their occurrence and to understand the information that has reshaped our approach to this problem. In fact, this has resulted in reconsideration of our overall approach to seizures. Given the generally benign prognosis in febrile seizures, counseling the family is the primary form of “therapy.” One way to consider the issues involved in febrile seizures is to organize the information in a format that answers parents’ questions and provides a framework for providing ongoing care. This can even include anticipatory guidance, which is so vital to the practice of pediatrics. Johnson: Current Therapy in Neurologic Disease (7/E)
Seizures
side effects are a function of the duration of treatment, it is best to initiate ACTH treatment at the high dosage and limit duration to 2 weeks, with a 2-week taper. Complete dramatic remission of the spasms typically occurs during the first week. Note that twice-daily dosing at the high (ActharGel, 150 U/m2 of body surface area) is required. Occasional “bad” batches of the hormone have been described. In infants with a strong focal element of the spasms, particularly with focal lesion (e.g., tuber) and focal EEG, surgical therapy should be considered. A trial of ACTH may still be indicated and may convert apparent infantile spasms to focal seizures. Other therapies may be successful at a much lower rate. Consider pyridoxine (to exclude pyridoxinedependent seizures, or as therapy), 100-150 mg/day; valproate; topiramate; and the ketogenic diet. If seizures remit and recur, verify that these are indeed infantile spasms rather than a new seizure type with focal EEG. A second course of ACTH may be effective for infantile spasm recurrence. New seizure types, instigated by the original disorder, may respond to appropriate anticonvulsant therapy.
25
TABLE 1 Risk of Experiencing a Febrile Seizure Factor General population Child in daycare Slow development Prolonged nursery stay (>28 days) Febrile seizure in first-degree relative (mother, father, sibling) Febrile seizure in two first-degree relatives Any two risk factors
Risk of Febrile Seizure (%) 2 7 10 12 10 33 28
Adapted from Bethune P, Gordon K, Dooley J, et al: Which child will have a febrile seizure? Am J Dis Child 147:35-39, 1993.
What Is the Chance That My Child Will Have Febrile Seizures? Families with a history of febrile seizures may ask this question, particularly when there are siblings with febrile seizures. Febrile seizures are more common in some families, and 10% to 20% of siblings of children with febrile seizures will also experience them. Certain other children may have an increased risk, as high as 25% if the child had a prolonged nursery stay, slow development, or daycare attendance. These factors suggest susceptibility to febrile seizures in a child who may have experienced some subtle neurologic changes and who is exposed on a more consistent basis to a wide range of infections in the daycare setting. When two or more of these factors exist, it may be appropriate at one of the early well-child visits to discuss management of fever and what to do if a febrile seizure occurs (Table 1).
What Should We Do If Our Child Has a Febrile Seizure? Most febrile seizures are brief and do not need medical intervention. If, however, the seizure has persisted longer than 5 minutes, Emergency Medical Services (i.e., “911”) should be called. Less than 5% of febrile seizures occur as status epilepticus, and it is likely that the seizure will end before medications can be given. The usual intervention is either lorazepam, 0.1 mg/kg intravenously (IV), up to 4 mg, or diazepam, 0.3 mg/kg IV given slowly at less than 1 mg/kg/min. Health care providers in emergency settings should recall that diazepam could be given rectally.* In essence, care during a febrile seizure should be the same as for any other generalized convulsion. When the seizure is over and the child has returned to baseline (often sleepiness if the seizure has occurred at night), a decision must be made concerning the *Diastat, 0.5 mg/kg rectally for children 2 to 5 years, 0.3 mg/kg rectally for children 6 to 11 years, 0.2 mg/kg rectally for children older than 11 years, all rounded to the nearest syringe size; one dose may be repeated after 30 minutes, if necessary.
2
26
Febrile Seizures
evaluation of the precipitating fever. The American Academy of Pediatrics has published guidelines outlining the approach to these patients, summarized here and in Figure 1. If this is the patient’s first febrile seizure (particularly if in a young infant or toddler), the child should be examined immediately to detect and/or treat the cause of the fever. A seizure in the setting of a fever must be excluded from a seizure resulting from meningitis. Generally this is not difficult since an alternative source can be found or the child is acting normally without evidence of significant illness. A lumbar puncture (LP) should be done whenever there is concern about the possibility of meningitis. It is usually performed in children younger than 1 year of age who have had a first febrile seizure and in settings where there is concern about the reliability of remaining in contact with the medical care providers. There are certain indications that increase the likelihood that an LP will be positive: (1) a physician visit within the 48 hours preceding the seizure, (2) seizure occurring or persisting in the emergency department setting, (3) focal seizure, or (4) suspicious findings on either physical or neurologic examination. Additional laboratory work should be done depending on the nature of the illness and the questions being asked. A computed tomographic scan or magnetic resonance imaging is not necessary in simple febrile seizures. An EEG is also not necessary; if done within a Simple FS, no meningeal signs
Routine imaging, EEG, blood studies not indicated if first simple FS
Age < 12 months?
Age > 18 months? Age 12–18 months?
Strongly consider LP
Consider LP
LP unnecessary
1. Manage concurrent illness (e.g., UTI or otitis media). 2. Manage fever, pain, and discomfort. 3. Counsel family at the appropriate time (preferably at office visit) about risk factors, recurrence risk, management of another seizure, risk of epilepsy.
First FS or duration < 15 min.?
No treatment necessary
Recurrent FS or duration > 15 min.?
Discuss option of rectal diazepam with caregivers
week of the seizure, it is often minimally abnormal, displaying evidence of the postictal features of the brain. There is no evidence that these findings are predictive of an outcome, either of recurrent seizures or of epilepsy. Usually, the child can be discharged from the emergency department without ongoing medications (other than those appropriate for infection). It is critical that followup be arranged to discuss the meaning of the febrile seizure and how the situation should be managed in the future. If the seizure is recurrent and brief, the physician should be called and plans should be made to assess the source of fever.
What Else Could It Have Been Besides a Febrile Seizure? What Causes Febrile Seizures? The differential diagnosis of febrile seizures includes the first presentation of epilepsy unmasked by a lowered seizure threshold caused by the fever and illness. The distinction between a febrile seizure and new-onset epilepsy need not be made on the first presentation. There are a number of reasons for this. First, the pathophysiologic relationship between febrile seizures and epilepsy later in life is debated (see later). Second, tests that help make the diagnosis of certain epilepsy syndromes (e.g., EEG) are not predictive after a first simple febrile seizure. Epilepsy will declare itself over time. Even experienced epileptologists can be challenged when making the distinction between a first febrile seizure and a first seizure with fever. Recent work has shown that some patients with a combination of febrile and afebrile seizures, known as generalized epilepsy and febrile seizures plus (GEFS+) have mutations in voltage-gated sodium channel subunits. If there is a family history of febrile and afebrile seizures (particularly severe myoclonic epilepsy of infancy), referral can be made to research groups interested in the genetics of these conditions. Meningitis can manifest as seizures and fevers, as previously discussed. Toxic ingestions of certain medications and substances with anticholinergic properties can also cause seizures and hyperthermia, though there are other historical and clinical signs that should suggest their presence. The same is true for neuroleptic malignant syndrome. In the appropriate setting, intentional exposures (e.g., chemical exposures or bioterrorism) should be considered. Associations have been made between certain pathogens (e.g., human herpesvirus 6) and febrile seizures. Investigation for these viruses is not ordinarily indicated in otherwise healthy children. Certain pathogens can cause encephalopathies that include seizures and fevers. Encephalopathic patients need extensive investigations and are not the subject of this chapter.
Did the Seizure Hurt My Child? FIGURE 1. Neurology-centered management of febrile seizures (FS). EEG, Electroencephalogram; LP, lumbar puncture; UTI, urinary tract infection.
Parents witnessing a febrile seizure fear that their child will die. We must acknowledge this emotional turmoil, Johnson: Current Therapy in Neurologic Disease (7/E)
Febrile Seizures
Will My Child Have Another Febrile Seizure? If So, When? Unfortunately, febrile seizures recur in many children. One third of the children will have a second one, and there is a 50% chance that there will be a recurrence if the child is younger than 1 year of age. Parents should be told that there is no reason to expect that a subsequent febrile seizure will be worse than the first. In fact, the first febrile seizure is usually the worst one. There is an increased risk for recurrence under a variety of circumstances (Table 2). The risk of recurrence is increased to almost 50% if the febrile seizure happened in the first hour of fever and is only 15% if the febrile seizure happened more than 24 hours into the fever. The risk of recurrence is also higher (40%) if the febrile seizure
TABLE 2 Risk of Recurrence of Febrile Seizure Factor
Risk of Recurrence (%)
Overall First febrile seizure 60 yr Obesity Renal dysfunction Hepatic dysfunction Psychosis, behavior problems, depression Noncompliance Rapid titration possible Patient example (totaled)
CBZ
GBP
LTG
LVT
OXC
PB
PHT
PRM
TPM
TGB
VPA
ZNS
Example
1
1
1
2
1
1
1
1
1
2
1
2
X
1
1
1
2
1
3
1
3
2
2
1†
2
3
1
1‡
1
2
3
3
3
2
1
1
1
3 3 3 3
2 2 1 1
2 2 2 1
2 2 1 1
2 2 2 1
3 3 3 3
3 3 3 3
3 3 3 3
2 2 2 1
2 2 2 1
3 3 3 1
2 2 2 1
X
2
1
1
1
2
3
2
3
3
2
2
2
X
2 3 1 3
1 3 2 1
1 2 1 1
1 2 2 1
2 2 1 2
3 2 2 3
3 2 2 3
3 2 2 3
2 1 2 2
2 2 1 2
2 3 1 3
2 1 2 2
1
2
1
3
2
3
2
3
2
3
1
2
Seizures
TABLE 2 Selection of AEDs for Complex Partial Seizures*
X
2 2§
3
2
2
2
1
1
2
2
3
1§
1
3 9
1 7
3 5
1 7
1 7
2 9
1 8
3 9
3 7
2 8
1 9
1 7
See text for instructions for use and example. 1 = good profile; 2 = neutral or unknown; 3 = adverse profile. CBZ, Carbamazepine; GBP, gabapentin; LTG, lamotrigine; LVT, levetiracetam; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; PRM, primidone; TPM, topiramate; TGB, tiagabine; VPA, valproate; ZNS, zonisamide. *P-450 enzyme-inducing or -inhibiting AEDs. †Relative contraindication in adolescent girls due to teratogenicity. ‡Alter lamotrigine metabolism; OK if dose is stable. §Long-acting formulation (Tegretol XR, Carbatrol, Depakote ER). OCP, Oral contraceptive pills
AEDs may be categorized into three broad groups for the initial treatment of CPSs. Group 1 drugs (phenytoin, carbamazepine, valproate, gabapentin, lamotrigine, oxcarbazepine, and topiramate) have demonstrated efficacy as monotherapy in randomized controlled trials in patients with partial-onset or partial and generalized seizures. Carbamazepine and phenytoin have long been considered drugs of first choice, and valproate is also widely used. Chronic adverse effects and complex pharmacokinetics of carbamazepine, phenytoin, and valproate, however, make these less attractive choices. The superior tolerability and adverse effect profiles of gabapentin, lamotrigine, oxcarbazepine and topiramate support the use of these AEDs as initial monotherapy in many patients. Group 2 drugs (tiagabine, levetiracetam, and zonisamide) are effective as adjunctive therapy but have not yet been demonstrated to be efficacious in monotherapy. Such medications can be used as secondline agents or as initial agents in specific patients. Group 3 drugs (phenobarbital, primidone, and felbamate), although equally efficacious, have significant adverse effects that limit their usefulness. These drugs Johnson: Current Therapy in Neurologic Disease (7/E)
are not appropriate for use as initial monotherapy of CPSs. Table 1 summarizes initial dosing, titration schedules, and serious adverse effects of currently available AEDs. Therapy should be initiated with a single drug. Using a low dose and slow titration schedule minimizes adverse effects, but frequent seizures necessitate more rapid dose escalations. Polytherapy increases the risk for adverse effects and is not appropriate for new-onset seizures. A reasonable approach is to select two or three appropriate AEDs for presentation to the patient, discuss their potential side effects, and then choose an AED based on patient preference. Avoidance of side effects and use of twice-daily formulations improves compliance with chronic therapy and thereby seizure control. Table 2 presents a tool to select potential best therapies among the wide range of AED options. To determine AED options for an individual patient, choose all relevant patient factors on the left; then add the numbers in the selected rows for each drug. AEDs with the lowest total score may offer a good adverse effect profile for that patient, although the physician must still weigh the
38
Treatment of Newly Diagnosed Complex Partial Seizures
relative importance of each factor individually. The last row and column show an example of a 26-year-old woman executive, weighing 200 lb, who is planning her first pregnancy. Lamotrigine (safety in pregnancy, weight neutrality) would be a reasonable first choice for this patient, but several of the other newer AEDs would also be options. The dose of the initial AED should be gradually increased until seizures are completely controlled or until side effects occur. If the first AED fails, a second AED should be substituted and the first AED withdrawn. Combinations of AEDs, the vagus nerve stimulator, and epilepsy surgery are possible options if seizures remain difficult to control (see Chapter 11). Serum AED levels may be useful in assessing compliance, maintaining stable levels during pregnancy or after initiation of a second AED, assessing the presence of drug interactions, or determining the etiology of side effects. Routine monitoring of serum AED levels is not necessary in patients with well-controlled seizures. Many of the newer AEDs do not have well-established therapeutic ranges. CBC, chemistry panel, and LFTs should be checked 1 to 2 months after initiating a new AED. Repeated monitoring of laboratory tests is indicated for some AEDs but not others. For example, more frequent monitoring is indicated early in treatment with valproate due to potential for thrombocytopenia and hepatic failure. CBC and LFTs should be monitored during the first 6 months of carbamazepine and phenytoin use, due to remote risk of aplastic anemia and hepatic failure. Several sodium levels should be drawn for patients receiving carbamazepine/oxcarbazepine to check for hyponatremia. After the first 6 months, serial monitoring rarely detects new clinically significant abnormalities, but annual blood work may still be reasonable. The choice of an AED for women with new-onset CPSs should take into consideration potential effects on contraception, reproductive health, and pregnancy. AEDs that induce the hepatic P-450 enzyme system (phenytoin, carbamazepine, primidone, and, to a lesser extent, topiramate and oxcarbazepine) reduce the efficacy of hormonal contraception, resulting in increased risk of unplanned pregnancy. Oral contraceptive pills, estrogen patches, and depot progesterone all may be affected. Women taking enzyme-inducing AEDs should take an oral contraceptive pill containing at least 50 μg of estrogen or use a barrier contraceptive method. Of note, hormonal contraceptives induce the metabolism of lamotrigine. Women should be counseled to report any change in contraception. Both enzyme-inducing and enzyme-inhibiting (e.g., valproate) AEDs may be associated with reproductive dysfunction, such as anovulatory menstrual cycles, infertility, and polycystic ovaries. These effects appear to be most problematic with valproate. Symptoms and signs of reproductive endocrine dysfunction include hirsutism, weight gain, irregular menstrual cycles, and infertility and should trigger a gynecologic evaluation. Many of the AEDs are teratogens. The risk of congenital malformations in children of women with epilepsy taking AEDs is 4% to 8%, compared with 2% to 3% in the general population. The risk is increased with high AED doses and with polytherapy. Malformations can include cardiac, midline facial, neural
tube, genitourinary, and gastrointestinal anomalies. Minor anomalies of the face and digits may be seen in another 10% to 15% of children. Effect of these AEDs on cognitive development is in the early stages of investigation, but there is increasing evidence that some AEDs, valproate in particular, may lead to increased risk of learning disabilities. Because folate administration may protect against some malformations, at least 1 mg of folate daily should be prescribed to all women taking AEDs. Phenytoin, carbamazepine, valproate, phenobarbital, and primidone are pregnancy class D medications, associated with a known teratogenic risk in humans. The newer AEDs are pregnancy class C medications, showing no teratogenicity in animals but unknown safety in humans. Preliminary results from a lamotrigine pregnancy registry suggest low teratogenicity, but final results are pending. Prospective pregnancy registries in the United States and Europe will help to define the risks of the newer AEDs. At this point, we favor the use of the newer AEDs, particularly lamotrigine, in women of reproductive age because of fewer effects on the hormonal milieu and probable lower teratogenicity. Drug interactions are common with AEDs as a class. When initiating AEDs, physicians should consider current concomitant medications as well as potential future needs. One of the most problematic interactions is that of hepatic enzyme induction, which occurs with use of phenytoin, carbamazepine, primidone, and phenobarbital. Hepatic induction increases the clearance of many commonly prescribed medications. Increased clearance of oral contraceptives has already been discussed. Many cholesterol-lowering agents, anticoagulants, antihypertensives, and antiarrhythmics are also subject to induction, as are chemotherapeutic agents. For patients who may require these medications, selection of a noninducing AED may be preferable. Many patients who experience their first seizure are evaluated in the emergency department and may be started on phenytoin. Often, the patient will be referred to a neurologist within the next few weeks. At this visit, it is appropriate to reassess the individual needs of that particular patient and make changes as necessary, including discontinuation if treatment is not indicated or selection of an alterative agent. AED withdrawal may be considered when a patient has been seizure free for at least 2 years. Unfortunately, seizure recurrence rates are relatively high—40% to 50%—after drug withdrawal. Patients with normal neurologic examinations, neuroimaging, and EEG have a lower recurrence risk. Focal structural lesions or epileptiform abnormalities on EEG, however, indicate a recurrence risk of greater than 70%. Many patients elect to continue AEDs rather than run the risk of a seizure recurrence. If patients decide to discontinue AEDs, the drug should be tapered slowly to avoid withdrawal seizures. Patients should not drive for 3 to 6 months after AED discontinuation. SUGGESTED READING French JA, Kanner AM, Bautista J, et al: Efficacy and tolerability of the new antiepileptic drugs: I. treatment of new-onset epilepsy. Johnson: Current Therapy in Neurologic Disease (7/E)
First Generalized Seizure
PATIENT RESOURCES Epilepsy Foundation of America http://www.epilepsyfoundation.org/ American Epilepsy Society http://www.aesnet.org/ The Epilepsy Project www.epilepsy.com
First Generalized Seizure Andrew J. Cole, M.D., F.R.C.P.(C)
Individuals who develop new seizures, especially generalized tonic-clonic attacks, are frequently initially evaluated in an emergency department (ED) setting. When family members are not available, ED physicians obtain historical information from paramedics and from the patient who may still be confused in the postictal state. A general examination and a basic neurologic examination, in combination with computed tomographic (CT) scanning, are typically performed to rule out acute structural processes, whereas standard laboratory testing including electrolytes, blood count, and toxin screens are used to asses potential metabolic etiologies. At the completion of testing, the ED physician faces a two-part treatment decision: Should the patient be treated, and if so, with which antiepileptic drug (AED)? In making these decisions, ED physicians are particularly concerned with the short-term goal of preventing early seizure recurrence and keeping the patient safe until definitive evaluation can be accomplished. Additional factors influencing treatment choices include the time necessary to obtain a therapeutic blood level; ease of drug delivery, including available routes of administration; and their own familiarity and comfort with specific agents. In this context, phenytoin is the most commonly used AED in the ED setting. In the face of the acute issues, less attention is paid to the cognitive and long-term toxicities of potential treatments, which may properly be considered the province of neurologists. On discharge from the ED, referral to the patient’s internist or to a neurologist is typically suggested. Johnson: Current Therapy in Neurologic Disease (7/E)
The neurologist’s initial assessment of a patient with an apparent new seizure should systematically address the following questions:
Seizures
Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004. Hirtz D, Berg A, Bettis D, et al: Practice parameter: treatment of the child with a first unprovoked seizure. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 60:166-175, 2003. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Tatum WO, Liporace J, Benbadis SR, Kaplan PW: Updates on the treatment of epilepsy in women, Arch Intern Med 164:137-145, 2004. Zahn CA, Morrell MJ, Collins SD, et al: Management issues for women with epilepsy: a review of the literature, Neurology 51:949-956, 1998.
39
• Was the event in question truly an epileptic seizure? • If the event was a seizure, did it start focally and become secondarily generalized, or was it a manifestation of a primary generalized epilepsy, or secondary generalized epilepsy (typically a question in young children)? • Is the risk of recurrence sufficient to justify committing the patient to chronic treatment, and if so, with which agent? Evaluation should include a detailed history, including a personal or telephone interview with any available witness of the event, general and neurologic examination, and typically magnetic resonance (MR) imaging and EEG recording. The goals of this process are to determine the seizure type and the cause of the seizure and to evaluate the risk of recurrence, which will determine the need for ongoing treatment. Additional important goals are to detect systemic conditions that may provoke seizures and to assess the individual with special attention to characteristics that might influence the choice of long-term treatments. Ultimately, the neurologist faces the decision of whether to initiate treatment, or if treatment was already started in the acute setting, whether to continue, change, or discontinue it. Whereas the ED physician was most concerned with acute efficacy and patient safety, the neurologist must be concerned with efficacy, effectiveness (a term encompassing efficacy, tolerability, and compliance), and long-term health consequences of what is likely to be a chronic therapy.
Evaluation and Diagnosis The value of a detailed history cannot be overemphasized. Although the initial history might describe a generalized tonic attack, careful questioning might reveal the presence of a warning or evidence of focal onset of motor activity pointing to a focal seizure with secondary generalization. By contrast, a history of absence lasting less than 20 seconds, myoclonic jerks on awakening, and an early morning convulsion without warning suggest the diagnosis of a primary generalized seizure disorder, especially in teenagers and young adults. As a rule, the older the patient, the less likely that the seizure is truly of generalized origin, and for practical purposes new-onset seizures in patients older than 30 years of age should be considered to be focal unless proven otherwise. A careful history may reveal that the event in question was not in fact the first seizure, since the patient had been having minor spells for some time, or that there was a clear provocative factor such as significant sleep deprivation, use of a proconvulsant medication such as tramadol, or withdrawal from an anxiolytic such as alprazolam. In the former case, need for treatment seems clear, whereas in the latter case, many neurologists would attempt to manage the patient with lifestyle modification or avoidance of the offending agents.
2
First Generalized Seizure
PATIENT RESOURCES Epilepsy Foundation of America http://www.epilepsyfoundation.org/ American Epilepsy Society http://www.aesnet.org/ The Epilepsy Project www.epilepsy.com
First Generalized Seizure Andrew J. Cole, M.D., F.R.C.P.(C)
Individuals who develop new seizures, especially generalized tonic-clonic attacks, are frequently initially evaluated in an emergency department (ED) setting. When family members are not available, ED physicians obtain historical information from paramedics and from the patient who may still be confused in the postictal state. A general examination and a basic neurologic examination, in combination with computed tomographic (CT) scanning, are typically performed to rule out acute structural processes, whereas standard laboratory testing including electrolytes, blood count, and toxin screens are used to asses potential metabolic etiologies. At the completion of testing, the ED physician faces a two-part treatment decision: Should the patient be treated, and if so, with which antiepileptic drug (AED)? In making these decisions, ED physicians are particularly concerned with the short-term goal of preventing early seizure recurrence and keeping the patient safe until definitive evaluation can be accomplished. Additional factors influencing treatment choices include the time necessary to obtain a therapeutic blood level; ease of drug delivery, including available routes of administration; and their own familiarity and comfort with specific agents. In this context, phenytoin is the most commonly used AED in the ED setting. In the face of the acute issues, less attention is paid to the cognitive and long-term toxicities of potential treatments, which may properly be considered the province of neurologists. On discharge from the ED, referral to the patient’s internist or to a neurologist is typically suggested. Johnson: Current Therapy in Neurologic Disease (7/E)
The neurologist’s initial assessment of a patient with an apparent new seizure should systematically address the following questions:
Seizures
Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004. Hirtz D, Berg A, Bettis D, et al: Practice parameter: treatment of the child with a first unprovoked seizure. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 60:166-175, 2003. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Tatum WO, Liporace J, Benbadis SR, Kaplan PW: Updates on the treatment of epilepsy in women, Arch Intern Med 164:137-145, 2004. Zahn CA, Morrell MJ, Collins SD, et al: Management issues for women with epilepsy: a review of the literature, Neurology 51:949-956, 1998.
39
• Was the event in question truly an epileptic seizure? • If the event was a seizure, did it start focally and become secondarily generalized, or was it a manifestation of a primary generalized epilepsy, or secondary generalized epilepsy (typically a question in young children)? • Is the risk of recurrence sufficient to justify committing the patient to chronic treatment, and if so, with which agent? Evaluation should include a detailed history, including a personal or telephone interview with any available witness of the event, general and neurologic examination, and typically magnetic resonance (MR) imaging and EEG recording. The goals of this process are to determine the seizure type and the cause of the seizure and to evaluate the risk of recurrence, which will determine the need for ongoing treatment. Additional important goals are to detect systemic conditions that may provoke seizures and to assess the individual with special attention to characteristics that might influence the choice of long-term treatments. Ultimately, the neurologist faces the decision of whether to initiate treatment, or if treatment was already started in the acute setting, whether to continue, change, or discontinue it. Whereas the ED physician was most concerned with acute efficacy and patient safety, the neurologist must be concerned with efficacy, effectiveness (a term encompassing efficacy, tolerability, and compliance), and long-term health consequences of what is likely to be a chronic therapy.
Evaluation and Diagnosis The value of a detailed history cannot be overemphasized. Although the initial history might describe a generalized tonic attack, careful questioning might reveal the presence of a warning or evidence of focal onset of motor activity pointing to a focal seizure with secondary generalization. By contrast, a history of absence lasting less than 20 seconds, myoclonic jerks on awakening, and an early morning convulsion without warning suggest the diagnosis of a primary generalized seizure disorder, especially in teenagers and young adults. As a rule, the older the patient, the less likely that the seizure is truly of generalized origin, and for practical purposes new-onset seizures in patients older than 30 years of age should be considered to be focal unless proven otherwise. A careful history may reveal that the event in question was not in fact the first seizure, since the patient had been having minor spells for some time, or that there was a clear provocative factor such as significant sleep deprivation, use of a proconvulsant medication such as tramadol, or withdrawal from an anxiolytic such as alprazolam. In the former case, need for treatment seems clear, whereas in the latter case, many neurologists would attempt to manage the patient with lifestyle modification or avoidance of the offending agents.
2
40
First Generalized Seizure
General and neurologic examinations are focused on searching for coexisting conditions that may cause or predispose the patient to seizures and detecting evidence of focal or diffuse central nervous system dysfunction. Particular attention should be focused on examination of the skin; a search for endocrine or metabolic disturbances; evidence of malignancy; and especially in older patients, evidence of cerebrovascular disease. At the same time, general characteristics of the individual such as body weight, complexion, cognitive function, and even reproductive capacity should be duly noted. We routinely obtain electroencephalographic recordings without sleep deprivation as part of our initial evaluation. The goals are to search for generalized spike-and-wave discharge that is typically frontally predominant at 2.5 4 Hz, supporting a diagnosis of primary generalized epilepsy, or to find focal abnormalities including slowing or epileptiform abnormalities that support the diagnosis of focal epilepsy. This distinction is critical in therapeutic decision making (see later). A negative electroencephalogram (EEG) does not rule out the diagnosis of epilepsy, and positive findings must always be interpreted in the context of available clinical information. All adults with new-onset seizures should have highquality MR imaging, even if a negative CT scan is available. Our protocol includes axial and coronal T2-weighted fast-spin echo (FSE) sequences, axial and coronal fluid-attenuated inversion recovery (FLAIR) sequences, and a T1-weighted coronal volumetric data set with 1.2- to 1.5-mm thick cuts without skip. We do not routinely use gadolinium contrast in the assessment of new seizures, especially in patients younger than 50 years of age, although we do use contrast material to characterize foreign tissue lesions that are discovered on noncontrast scans. In patients with a history of trauma, we frequently obtain gradient echo (susceptibility) sequences as well to search for old blood products. Images should be directly reviewed by the neurologist in the context of all available information, including historical information, findings on examination, and EEG findings. It is not unusual for a neurologist to detect a lesion that had been overlooked by the radiologist, perhaps because the neurologist is in a position to formulate a hypothesis about where to look for the likely causative lesion based on clinical information not readily available to the radiologist.
Treatment Initiation Treatment decisions should be undertaken largely independent of previous decisions made by non-neurologists. Our algorithm for whether or not to initiate or continue treatment and specific agents to be used is shown in the accompanying diagram (Figure 1). Treatment agents are numbered according to whether they constitute first-line, second-line, or third-line choices. Within groups, agents are listed alphabetically, and choices should be made according to the characteristics of the individual patient. While many of the newer agents do not have a U.S. Food and Drug Administration–approved indication for use as initial monotherapy, we use them
frequently in this situation, and our practice is supported by considerable published data. General statements about the risk of recurrence can be based on population studies, but their relevance to the specific patient at hand is uncertain. In this context it is difficult to be doctrinaire about the need for treatment, and patient preference should play a substantial role in decision making. Although there are little data to guide patients and physicians with respect to the optimal duration of treatment, experienced neurologists are typically reluctant to discontinue treatment that is well tolerated, even after many years, for fear of seizure recurrence. To the extent that treatment is thus likely to be of long duration, particular attention to the long-term consequences of chronic treatment should be considered at the time of treatment initiation and not, as commonly happens, after some predictable adverse consequence of treatment becomes apparent after months or years (e.g. weight gain, osteoporosis, adverse medication interactions). Treatment of a first generalized seizure is particularly problematic because seizure frequency cannot be used as an endpoint to determine optimal treatment intensity. Dose selection must therefore be determined by an educated guess as to what dose is likely to have a high probability of suppressing recurrent events, even without definitive knowledge of whether seizures will recur in specific patient. The temptation to use a low dose of medication thus seems ill advised. Most drugs should be started at a modest dose and then advanced over weeks to the target dose to avoid undue toxicity. Given the long-term nature of AED treatment, minor differences in the titration rates of available agents should not be a predominant factor in drug selection. After all, the goal is to establish an effective, well-tolerated treatment plan that will continue for years, so whether that takes 6 days or 6 weeks seems of little importance. In situations where the risk of early recurrence is high, patients can be covered with a rapidly titrated agent (often already the case after an ED visit) while titration of the ultimate treatment is underway.
Counseling The diagnosis of a new seizure disorder raises a series of issues that may be anxiety provoking and psychologically traumatic to consider for patients. Neurologist should have a calm, orderly, and systematic approach to discussing these issues with patients and their families. We begin by emphasizing that the goal of treatment is to allow the patient to live a normal life without undue restrictions. For example, unless there is a history of excessive alcohol consumption and abuse, we do not routinely prohibit the consumption of an occasional beer, glass of wine, or cocktail, although we do counsel moderation. We emphasize the importance of regular sleep habits and compliance with treatment schedules. Rules on driving and reporting vary by state. We advise patients of the rules in their home state and document that information has been provided and that the patient appears to understand. Driving laws in each state can Johnson: Current Therapy in Neurologic Disease (7/E)
First Generalized Seizure
41 Seizures
“Grand mal tonic clonic seizure”
History Examination EEG MRI
Epileptic
Non-epileptic
Classification Cardiac Unknown Primary (idiopathic) generalized epilepsy
Age > 30 and no previous history?
Partial seizure with secondary generalization
Vasovagal/ neurocardiogenic
Psychiatric/ behavioral
Refer/treat as appropriate
Yes
No
Review history, sleep-deprived EEG
2
Identifiable provocative factors?
Yes
No Rx: conservative management
No
Risk/benefit analysis for Rx: • EEG or MRI or exam abnl? • Patient unwilling to accept 20–40% risk of recurrence?
No
No Rx: observe
Yes
Partial seizures with or without secondary generalization: 1. Lamotrigine 300–500 mg/d 1. Levetiracetam 2000–3000 mg/d 1. Oxcarbazepine 600–1200 mg/d 2. Carbamazepine 400–800 mg/d 2. Phenytoin 300–00 mg/d 2. Topiramate 200–400 mg/d 2. Valproate 1000–1500 mg/d 3. Gabapentin 1500–2400 mg/d 3. Zonisamide 300–400 mg/d 4. Mysoline 500–750 mg/d 4. Phenobarbital 60–120 mg/d
Consider patient characteristics: • Age • Sex • Reproductive status • Body habitus • Medical co-morbidities • Psychiatric co-morbidities • Co-medications • Cognitive function • Financial concerns Select treatment
Primary (idiopathic) generalized epilepsy: 1. Lamotrigine 300–500 mg/d 1. Valproate 750–500 mg/d 2. Topiramate 200–400 mg/d 3. ?Levetiracetam 1500–3000 mg/d 3. ?Zonisamide 200–400 mg/d
FIGURE 1. Flowchart illustrating our approach to the evaluation and treatment of a first convulsion. Drugs are numbered as first-line, second-line, third-line, or fourth-line choices. Within category, drugs are listed alphabetically without implying a specific order of preference. Specific selections should be made based on individual patient characteristics. Dose ranges shown are approximate. All drugs should be titrated no faster than the manufacturer’s recommendations to avoid excessive initial toxicity. Johnson: Current Therapy in Neurologic Disease (7/E)
42
Recurrent Generalized and Partial Seizures
be accessed at http://epilepsyfoundation.org/answerplace/ Social/driving/statedrivinglaws.cfm. We discuss the effects of medications on the efficacy of oral contraceptives when appropriate, and we recommend supplemental folic acid, 1 mg daily, to all women of childbearing age, although the optimal dose has not been determined.
Treatment Monitoring We routinely see patients 2 to 3 months after treatment initiation or sooner if problems arise. Although there is little information available on optimal drug levels for many of the newer agents, we measure levels after a stable dose has been achieved to have an individual baseline against which comparisons can be made in the event problems arise in the future. We check routine laboratory tests (complete blood count, electrolytes, liver function tests, clotting parameters) at the initiation of treatment if recent values are unavailable, but we recheck these parameters only in specific cases (e.g., serum sodium in patients on oxcarbazepine, electrolytes in patients on topiramate, platelets and liver function tests in patients on valproate) unless there is a clinical indication. Some authors recommend measuring bone density at the initiation of treatment, but definitive studies supporting the value of this measurement are presently lacking. SUGGESTED READING French JA, Kanner AM, Bautista J, et al: Efficacy and tolerability of the new antiepileptic drugs: I. Treatment of new-onset epilepsy. Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004.
Recurrent Generalized and Partial Seizures Frank G. Gilliam, M.D., M.P.H.
Epilepsy is defined as two or more unprovoked seizures and has been described as a tendency toward recurrent seizures. The factors that determine whether a single seizure recurs, or whether recurrent seizures are preventable by medications, have not been clearly established. Understanding of both the genetic predisposition related to specific receptor/neurotransmitter system defects and characteristics of the acquired injury or dysfunction in a particular brain is required to explain a unique individual’s risk of epilepsy or pharmacoresistance. Although electroencephalography was developed in the 1930s, it remains the most accurate predictor of the probability of seizure recurrence, as well as epilepsy classification. After a single seizure, less than 30% of patients with a normal electroencephalogram (EEG) will have a second seizure. If the EEG shows an epileptiform
abnormality or focal slowing the probability of a second seizure is 40% to 60%. The EEG may not be a good predictor of pharmacoresistant epilepsy, and additional clinical biomarkers of treatment resistance are needed to improve the care of persons with recurrent seizures. Epilepsy is a chronic condition that requires years, if not lifelong, of treatment for most affected persons. The disability commonly associated with epilepsy begins on the day of the first seizure, because most adult and adolescent patients will receive a driving restriction. Work restrictions, social limitations, and public stigma significantly increase the disability experienced by many persons with epilepsy. Serious injuries such as fractures or burns may occur in up to 10% of patients with recurrent seizures per year. In addition, adverse antiepileptic drug (AED) side effects and the presence of comorbid depression have emerged as important predictors of poor quality of life with epilepsy.
Initial Treatment Considerations Based on available data from the Centers for Disease Control and Prevention and pharmacy registries, epilepsy care has changed very little during the past 30 years. Phenytoin remains the most frequently prescribed AED, and with carbamazepine, valproate, and phenobarbital, accounts for the large majority of prescriptions for epilepsy in the United States. The eight AEDs approved by the U.S. Food and Drug Administration (FDA) during the past 11 years account for less than 20% of prescriptions for epilepsy treatment in the United States. This may be considered surprising by some clinicians caring for persons with epilepsy, considering that the investigators in the largest randomized double-blind comparison of carbamazepine, phenobarbital, phenytoin, and primidone concluded: The outcome of this project underscores the unsatisfactory status of antiepileptic therapy with the medications currently available. Most patients whose epilepsy is reasonably controlled must tolerate some side effects. These observations emphasize the need for new AEDs and other approaches to treatment.
The characteristics of an optimal AED may be described based on pharmacokinetic properties, tolerability, and cost, as presented in Table 1. Considering that newer AEDs tend to have less hepatic enzyme induction and fewer drug interactions, but are generally more
TABLE 1 Optimal Attributes of an Antiepileptic Drug Simple, linear kinetics Minimal adverse side effects No drug-drug interactions (minimal hepatic enzyme induction and serum protein binding) Long half-life for once-a-day dosing and potential for extended seizure protection after a missed dose (>24-hour elimination half-life) Inexpensive Johnson: Current Therapy in Neurologic Disease (7/E)
42
Recurrent Generalized and Partial Seizures
be accessed at http://epilepsyfoundation.org/answerplace/ Social/driving/statedrivinglaws.cfm. We discuss the effects of medications on the efficacy of oral contraceptives when appropriate, and we recommend supplemental folic acid, 1 mg daily, to all women of childbearing age, although the optimal dose has not been determined.
Treatment Monitoring We routinely see patients 2 to 3 months after treatment initiation or sooner if problems arise. Although there is little information available on optimal drug levels for many of the newer agents, we measure levels after a stable dose has been achieved to have an individual baseline against which comparisons can be made in the event problems arise in the future. We check routine laboratory tests (complete blood count, electrolytes, liver function tests, clotting parameters) at the initiation of treatment if recent values are unavailable, but we recheck these parameters only in specific cases (e.g., serum sodium in patients on oxcarbazepine, electrolytes in patients on topiramate, platelets and liver function tests in patients on valproate) unless there is a clinical indication. Some authors recommend measuring bone density at the initiation of treatment, but definitive studies supporting the value of this measurement are presently lacking. SUGGESTED READING French JA, Kanner AM, Bautista J, et al: Efficacy and tolerability of the new antiepileptic drugs: I. Treatment of new-onset epilepsy. Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62:1252-1260, 2004.
Recurrent Generalized and Partial Seizures Frank G. Gilliam, M.D., M.P.H.
Epilepsy is defined as two or more unprovoked seizures and has been described as a tendency toward recurrent seizures. The factors that determine whether a single seizure recurs, or whether recurrent seizures are preventable by medications, have not been clearly established. Understanding of both the genetic predisposition related to specific receptor/neurotransmitter system defects and characteristics of the acquired injury or dysfunction in a particular brain is required to explain a unique individual’s risk of epilepsy or pharmacoresistance. Although electroencephalography was developed in the 1930s, it remains the most accurate predictor of the probability of seizure recurrence, as well as epilepsy classification. After a single seizure, less than 30% of patients with a normal electroencephalogram (EEG) will have a second seizure. If the EEG shows an epileptiform
abnormality or focal slowing the probability of a second seizure is 40% to 60%. The EEG may not be a good predictor of pharmacoresistant epilepsy, and additional clinical biomarkers of treatment resistance are needed to improve the care of persons with recurrent seizures. Epilepsy is a chronic condition that requires years, if not lifelong, of treatment for most affected persons. The disability commonly associated with epilepsy begins on the day of the first seizure, because most adult and adolescent patients will receive a driving restriction. Work restrictions, social limitations, and public stigma significantly increase the disability experienced by many persons with epilepsy. Serious injuries such as fractures or burns may occur in up to 10% of patients with recurrent seizures per year. In addition, adverse antiepileptic drug (AED) side effects and the presence of comorbid depression have emerged as important predictors of poor quality of life with epilepsy.
Initial Treatment Considerations Based on available data from the Centers for Disease Control and Prevention and pharmacy registries, epilepsy care has changed very little during the past 30 years. Phenytoin remains the most frequently prescribed AED, and with carbamazepine, valproate, and phenobarbital, accounts for the large majority of prescriptions for epilepsy in the United States. The eight AEDs approved by the U.S. Food and Drug Administration (FDA) during the past 11 years account for less than 20% of prescriptions for epilepsy treatment in the United States. This may be considered surprising by some clinicians caring for persons with epilepsy, considering that the investigators in the largest randomized double-blind comparison of carbamazepine, phenobarbital, phenytoin, and primidone concluded: The outcome of this project underscores the unsatisfactory status of antiepileptic therapy with the medications currently available. Most patients whose epilepsy is reasonably controlled must tolerate some side effects. These observations emphasize the need for new AEDs and other approaches to treatment.
The characteristics of an optimal AED may be described based on pharmacokinetic properties, tolerability, and cost, as presented in Table 1. Considering that newer AEDs tend to have less hepatic enzyme induction and fewer drug interactions, but are generally more
TABLE 1 Optimal Attributes of an Antiepileptic Drug Simple, linear kinetics Minimal adverse side effects No drug-drug interactions (minimal hepatic enzyme induction and serum protein binding) Long half-life for once-a-day dosing and potential for extended seizure protection after a missed dose (>24-hour elimination half-life) Inexpensive Johnson: Current Therapy in Neurologic Disease (7/E)
Recurrent Generalized and Partial Seizures
migraine is more common in persons with epilepsy than the general population; valproate and topiramate have received indications for migraine prophylaxis from the FDA and may be particularly useful in persons with both diagnoses. Lamotrigine at low to moderate doses has been found to have fewer adverse cognitive and fatigue effects compared with carbamazepine and may be advantageous to students and for people in professions requiring sustained concentration or mental vigilance. Valproate and lamotrigine are approved by the FDA for the treatment of bipolar disorder, and carbamazepine and oxcarbazepine may be effective as well. Some clinical trial data suggest that topiramate and zonisamide may facilitate weight loss, as opposed to a tendency toward weight gain with valproate. The lack of hepatic enzyme induction by gabapentin, levetiracetam, and lamotrigine is a consideration for women on
Seizures
expensive, the benefits of better pharmacokinetic properties and potential for improved tolerability must be weighed against greater monetary costs. In addition to pharmacokinetic properties, tolerability, and costs, the epilepsy syndrome being treated and clinically important comorbid conditions should be considered in the decision for initial AED treatment. As presented in Figure 1, partial seizures (with or without secondary generalizations), idiopathic generalized seizures, and symptomatic generalized seizures (secondary to prior brain injury) are the major categories that guide AED selection. Some drugs appear to have a broad spectrum of efficacy across multiple seizure categories and might be considered when the classification is not certain. Emerging evidence from clinical trials and aggregate clinical experience suggest that certain AEDs have efficacy for common comorbid conditions. For example,
43
Recurrent seizures (epilepsy)
Thorough history (including witness) + EEG
Seizure (epilepsy) classification
Generalized seizures
Symptomatic or cryptogenic
1. valproate 2. lamotrigine 3. topiramate 4. levetiracetam 5. zonisamide 6. phenobarbital 7. felbamate
Partial seizures (localization-related epilepsy)
Idiopathic (e.g., childhood absence, juvenile myoclonic epilepsy, etc.)
Absence only
Absence + GTC; or GTC only
1. ethosuxamide 2. valproate 3. lamotrigine 4. levetiracetam
Pregnancy
Headaches
1. topiramate 2. valproate 1. gabapentin 2. levetiracetam 3. lamotrigine
Consider patient preferences and comorbidity
Absence + GTC + myoclonic
1. valproate 2. topiramate 3. lamotrigine 4. levetiracetam
Oral contraception Avoid valproate and phenobarbital; consider lamotrigine
2
Cognition/fatigue
Cost
Overweight 1. lamotrigine 2. oxcarbazepine 1. topiramate 2. zonisamide
Generic carbamazepine valproate phenobarbital phenytoin
FIGURE 1. Suggested sequence of medications for recurrent unprovoked seizures (i.e., epilepsy). EEG, Electroencephalogram; GTC, generalized tonic-clonic. Johnson: Current Therapy in Neurologic Disease (7/E)
44
Recurrent Generalized and Partial Seizures
hormonal birth control. However, recent study data indicate that lamotrigine metabolism is significantly affected by hormonal birth control. Early results of systematic birth registries indicate that valproate and phenobarbital should be avoided in women who are considering pregnancy if medically feasible. The long half-life of zonisamide and phenobarbital may provide benefit to persons whose schedule or motivation limit compliance. The recommended maintenance doses of most AEDs are derived from clinical studies performed before optimal dosing strategies were determined. Recent evidence suggests that most people whose seizures can be controlled by AEDs will require doses in the lower end of a recommended range. For example, most persons with epilepsy will require less than 1000 mg/day of carbamazepine, 2000 mg/day of valproate, 400 mg/day of lamotrigine, or 300 mg/day of topiramate. Most AEDs require two- or three-times-a-day dosing, and the package insert should be consulted for specific recommendations. Fewer daily doses improve compliance, but multiple doses during the day may reduce peak serum concentrations and subsequent adverse effects. In general, the starting dose should be approximately one fourth of the initial target dose
with increases every 1 to 2 weeks by one fourth of the target dose. Lamotrigine has a slower titration rate due to the risk of rash, and topiramate has a slower rate to improve tolerability of adverse cognitive effects; the FDA-approved dosing information should be consulted for both of these AEDs. Systematic screening with a reliable and valid instrument, such as the Adverse Events Profile, may be necessary after each dosage adjustment to accurately identify significant side effects.
Treatment of Pharmacoresistant Epilepsy Most patients will be controlled by moderate doses of their first AED, but approximately 40% will not be controlled or will relapse after an initial response. There is no clear consensus in the epilepsy community about the treatment approach after failure of the initial AED, and as previously emphasized, the treatment decisions should be made in consideration of the individual patient’s unique situation. A suggested stepwise approach to epilepsy care is shown in Figure 2.
Two or three failed optimal antiepileptic drug (AED) regimens
1. Video/EEG 2. High-resolution MRI
Localized EEG or MRI abnormality
Yes
No
Consider presurgical evaluation: 1. Neuropsychological testing. 2. Functional neuroimaging?
Sensitivity to AED side effects
Good surgical candidate
Yes
Yes
No
Consider vagus nerve stimulator
Additional AEDs as mono or dual therapy
Seizure-free without adverse AED effects
No
Surgical resection* No
Yes
Consider vagus nerve stimulator or If injurious tonic or atonic seizures: Consider corpus callosotomy or Additional testing to attempt to localize a focal epileptogenic region
Continue AEDs
* Some patients may need additional testing such as intracarotid amobarbital test or intracranial EEG monitoring
FIGURE 2. Comprehensive approach to epilepsy care. EEG, Electroencephalogram. Johnson: Current Therapy in Neurologic Disease (7/E)
Status Epilepticus
SUGGESTED READING Engel J Jr, Wiebe S, French J, et al: Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society; American Association of Neurological Surgeons, Neurology 4:538–47, 2003. Gilliam F: Optimizing health outcomes in active epilepsy, Neurology 58(Suppl 5):S9-S19, 2002. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures, N Engl J Med 313:145-151, 1985. Johnson: Current Therapy in Neurologic Disease (7/E)
Status Epilepticus
Seizures
If seizures recur after the initial target dose of an AED is achieved, the dose should be increased at a tolerable rate to the most effective dose. The decision to increase to the next dosage increment, versus titrating to the highest tolerated dose, should be made in consultation with the patient. If seizures recur on the highest tolerated dose, then a second AED should be added in a similar approach to the initial drug. Frequently the dose of the initial AED will need to be reduced to improve tolerability of increased doses of the adjunctive AED. If seizures do not occur on the combination of two AEDs, the option to wean the first AED for convenience and cost should be reviewed with the patient. The decision to wean to monotherapy versus continuing effective combination therapy can be made only by weighing the overall risks and benefits to the specific patient’s situation. Similarly, the decision to consider a third medication after two have failed, versus proceeding to a presurgical evaluation, can be made only in consultation with the patient. Some patients may want to know if they have unilateral mesial temporal sclerosis, which may have a 75% chance for surgical success, whereas other patients will want to consider additional AEDs regardless of their surgical candidacy. The most important consideration to ensure optimal epilepsy care is that the patient be fully informed regarding the details of their options at each stage of treatment. Available evidence indicates that after three medications have failed due to lack of efficacy, as opposed to tolerability, the probability of achieving long-term remission is less than 10%. Alternative treatments, such as resective surgery or the vagus nerve stimulator, should be discussed in detail with the patient at this juncture. Although most patients who have a potential for complete seizure control, and the subsequent opportunity to drive a car and return to a more normal lifestyle, will elect to proceed with a presurgical evaluation as outlined in Figure 2, some patients may elect to try additional AEDs or the vagus nerve stimulator (VNS). Patients who have not tolerated three or more AEDs due to adverse effects may find the option of the VNS appealing, although less than 10% of patients will have complete seizure control after VNS implantation. Evaluation of patients at a comprehensive epilepsy center with epilepsy surgery capability is required for all patients with pharmacoresistant epilepsy and disabling seizures, as recommended by the published practice guidelines of the American Academy of Neurology.
45
Jehuda Sepkuty, M.D.
Status epilepticus (SE) is a common neurologic emergency. There are approximately 100,000 to 200,000 episodes of SE in the United States annually. The term status epilepticus generally refers to the occurrence of a single unremitting seizure or frequent clinical seizures without an interictal return to normal consciousness. An operational definition as proposed by Lowenstein and Alldredge accords the diagnosis “after 5 minutes of continuous seizure activity or 2 or more seizures without full recovery of awareness between seizures.” Older definitions considered 30 minutes as the time criterion, based on experimental animal data suggesting that seizure activity of this length is associated with significant neuronal damage. The sooner treatment is initiated, the better the outcome; however, the treatment for prolonged seizures versus SE is essentially the same initially anyway, so that the exact definition is less important practically, as long as preparations for the worst-case scenario are carried out early. SE can cause injury due to the intense neuronal activity within the central nervous system (CNS) and due to the metabolic stress of repeated muscular convulsions. Respiratory failure, aspiration pneumonitis, neurogenic pulmonary edema, rhabdomyolysis, and lactic acidosis may complicate convulsions, and neuronal death can occur after 30 to 60 minutes of continuous seizure activity. Classification of the type of SE is crucial because it is a major factor in determining morbidity and therefore the aggressiveness of the required treatment; generalized tonic-clonic or partial-complex SE poses the greatest risk. The most common forms of SE are the following: • Simple partial: characterized by repeated or continuous focal seizures that could be motor (twitching of one extremity), sensory (the sensation of numbness and tingling of one extremity), or cognitive (aphasia, dyslexia, and so forth) without impaired consciousness • Complex partial: characterized by repeated or continuous episodes of focal motor, sensory, or cognitive symptoms as earlier, but with impaired consciousness, and can be associated with automatisms like swallowing, licking lips, staring, and so forth; could be difficult occasionally to differentiate from other acute confusional states • Generalized tonic-clonic: always associated with impaired consciousness; tonic-clonic seizures may be the initial manifestation of SE or may represent secondary generalization from a partial seizure The following are a number of less common but important forms that need to be recognized: • Absence: characterized by altered awareness, but not necessarily unconsciousness. Patients are typically confused or stuporous, and there may be associated eye blinking, perseveration, small automatism,
2
Status Epilepticus
SUGGESTED READING Engel J Jr, Wiebe S, French J, et al: Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society; American Association of Neurological Surgeons, Neurology 4:538–47, 2003. Gilliam F: Optimizing health outcomes in active epilepsy, Neurology 58(Suppl 5):S9-S19, 2002. Kwan P, Brodie MJ: Early identification of refractory epilepsy, N Engl J Med 342:314-319, 2000. Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures, N Engl J Med 313:145-151, 1985. Johnson: Current Therapy in Neurologic Disease (7/E)
Status Epilepticus
Seizures
If seizures recur after the initial target dose of an AED is achieved, the dose should be increased at a tolerable rate to the most effective dose. The decision to increase to the next dosage increment, versus titrating to the highest tolerated dose, should be made in consultation with the patient. If seizures recur on the highest tolerated dose, then a second AED should be added in a similar approach to the initial drug. Frequently the dose of the initial AED will need to be reduced to improve tolerability of increased doses of the adjunctive AED. If seizures do not occur on the combination of two AEDs, the option to wean the first AED for convenience and cost should be reviewed with the patient. The decision to wean to monotherapy versus continuing effective combination therapy can be made only by weighing the overall risks and benefits to the specific patient’s situation. Similarly, the decision to consider a third medication after two have failed, versus proceeding to a presurgical evaluation, can be made only in consultation with the patient. Some patients may want to know if they have unilateral mesial temporal sclerosis, which may have a 75% chance for surgical success, whereas other patients will want to consider additional AEDs regardless of their surgical candidacy. The most important consideration to ensure optimal epilepsy care is that the patient be fully informed regarding the details of their options at each stage of treatment. Available evidence indicates that after three medications have failed due to lack of efficacy, as opposed to tolerability, the probability of achieving long-term remission is less than 10%. Alternative treatments, such as resective surgery or the vagus nerve stimulator, should be discussed in detail with the patient at this juncture. Although most patients who have a potential for complete seizure control, and the subsequent opportunity to drive a car and return to a more normal lifestyle, will elect to proceed with a presurgical evaluation as outlined in Figure 2, some patients may elect to try additional AEDs or the vagus nerve stimulator (VNS). Patients who have not tolerated three or more AEDs due to adverse effects may find the option of the VNS appealing, although less than 10% of patients will have complete seizure control after VNS implantation. Evaluation of patients at a comprehensive epilepsy center with epilepsy surgery capability is required for all patients with pharmacoresistant epilepsy and disabling seizures, as recommended by the published practice guidelines of the American Academy of Neurology.
45
Jehuda Sepkuty, M.D.
Status epilepticus (SE) is a common neurologic emergency. There are approximately 100,000 to 200,000 episodes of SE in the United States annually. The term status epilepticus generally refers to the occurrence of a single unremitting seizure or frequent clinical seizures without an interictal return to normal consciousness. An operational definition as proposed by Lowenstein and Alldredge accords the diagnosis “after 5 minutes of continuous seizure activity or 2 or more seizures without full recovery of awareness between seizures.” Older definitions considered 30 minutes as the time criterion, based on experimental animal data suggesting that seizure activity of this length is associated with significant neuronal damage. The sooner treatment is initiated, the better the outcome; however, the treatment for prolonged seizures versus SE is essentially the same initially anyway, so that the exact definition is less important practically, as long as preparations for the worst-case scenario are carried out early. SE can cause injury due to the intense neuronal activity within the central nervous system (CNS) and due to the metabolic stress of repeated muscular convulsions. Respiratory failure, aspiration pneumonitis, neurogenic pulmonary edema, rhabdomyolysis, and lactic acidosis may complicate convulsions, and neuronal death can occur after 30 to 60 minutes of continuous seizure activity. Classification of the type of SE is crucial because it is a major factor in determining morbidity and therefore the aggressiveness of the required treatment; generalized tonic-clonic or partial-complex SE poses the greatest risk. The most common forms of SE are the following: • Simple partial: characterized by repeated or continuous focal seizures that could be motor (twitching of one extremity), sensory (the sensation of numbness and tingling of one extremity), or cognitive (aphasia, dyslexia, and so forth) without impaired consciousness • Complex partial: characterized by repeated or continuous episodes of focal motor, sensory, or cognitive symptoms as earlier, but with impaired consciousness, and can be associated with automatisms like swallowing, licking lips, staring, and so forth; could be difficult occasionally to differentiate from other acute confusional states • Generalized tonic-clonic: always associated with impaired consciousness; tonic-clonic seizures may be the initial manifestation of SE or may represent secondary generalization from a partial seizure The following are a number of less common but important forms that need to be recognized: • Absence: characterized by altered awareness, but not necessarily unconsciousness. Patients are typically confused or stuporous, and there may be associated eye blinking, perseveration, small automatism,
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Status Epilepticus
or other symptoms. Absence SE typically occurs in patients with chronic epilepsy and frequently requires electroencephalogram (EEG) for confirmation • Myoclonic: characterized by frequent myoclonic jerks in the setting of altered mental status. This typically occurs in patients with one of the generalized epilepsies, such as juvenile myoclonic epilepsy. This condition needs to be differentiated from the patient who has metabolic encephalopathy (particularly uremic or hepatic encephalopathy) and may have also some myoclonic activity. EEG recordings can differentiate the two • Psychogenic: should be considered in situations where there are bilateral motor movements with preserved consciousness or side-to-side head movements as part of the convulsion. An EEG recording without seizure activity during motor events can help establish this diagnosis, although the EEG may also appear relatively normal during simple partial SE. It is important to refrain from the whole SE protocol, which has inherent iatrogenic risks, if there is a clinical suspicion for this diagnosis. The nonconvulsive types of SE may pose a greater clinical problem: Patients with complex partial or absence SE may exhibit confusional states that are not easily recognized as seizures. Also, patients who have had recurrent seizures may be considered postictal rather than in nonconvulsive SE; in this situation, subtle signs of ongoing seizures such as rhythmic papillary dilation or breathing may be the only evidence of seizure activity. The patient with possible SE requires rapid evaluation and treatment. Although there are differences in efficacy and side effect profile among effective agents, it is important to become familiar with one reasonable treatment method and use it. In general, more convulsive activity is associated with more systemic complications. Neither focal nor nonconvulsive SE should be considered non-life threatening, because they can progress to full convulsive SE, but they can be treated somewhat slower to minimize iatrogenic side effects. I divide the initial management into three phases: assessment and supportive treatment, initial pharmacotherapy, and pharmacotherapy for refractory seizures.
Assessment and Support Once a situation of a prolonged seizure is encountered, it is important to begin with performing a rapid neurologic examination to establish a preliminary classification of the type of SE and its probable etiology. The patient should also undergo a rapid systemic evaluation, with particular attention to circulatory and respiratory status and the possible need for supportive therapy (oxygen, mechanical ventilation). During this time, intravenous (IV) catheters should be placed and blood obtained for electrolytes, serum calcium, magnesium, phosphorus, glucose, toxicology studies, a complete blood count with differential, liver and kidney function studies, prothrombin time, and partial thromboplastin time. Anticonvulsant levels should be obtained if the patient is
on medications for chronic epilepsy. A rapid “fingerstick” glucose should confirm hypoglycemia. Measurement of arterial blood gases is often valuable and may suggest a need for intubation and mechanical ventilatory support. Cardiac monitoring, frequent measurement of blood pressure, and pulse oximetry should be instituted. Before the administration of pharmacologic treatment, administer thiamine, 100 mg, followed by 50 mL of 50% dextrose by direct push into the IV line. This phase usually lasts approximately 5 to 10 minutes (see our suggested protocol in Figure 1).
Initial Pharmacologic Therapy Lorazepam, 0.02 to 0.03 mg/kg, should be administered IV, and its effect should be assessed after a minute. If seizures continue, additional doses of lorazepam (up to a cumulative dose of 0.1 mg/kg) should be infused at a maximum rate of 2 mg/min, and a second IV catheter should be placed (if not in yet) to begin a concomitant phenytoin (or fosphenytoin) loading infusion.* Even if seizures terminate after the initial lorazepam dose (which happens in more than half of the patients presenting with SE), therapy with phenytoin or fosphenytoin is generally indicated to prevent the recurrence of seizures. As many as half of cases of treated generalized convulsive SE show evidence of persistent seizures on continuous EEG monitoring performed after clinically detectable seizures were abolished. Thus, continuing with administration of a standard anticonvulsant agent such as phenytoin is indicated even if overt seizures stopped with lorazepam. Also, follow-up EEG should be obtained as soon as possible to rule out the presence of nonconvulsive SE. A phenytoin infusion of 20 mg/kg (or 20 mg/kg phenytoin equivalents [PE] for fosphenytoin) should be started at 50 mg/min (or 100 to 150 mg PE/minute for fosphenytoin) and reduced if significant adverse effects of the infusion are seen. Heart rate and blood pressure must be watched closely because phenytoin can cause cardiac arrhythmias and hypotension. Another possible complication is local phlebitis resulting from the sclerotic effect of extravasated phenytoin. Phenytoin must be administered in saline because fluids containing glucose can cause the precipitation of phenytoin. This phase of treatment usually lasts approximately 30 minutes. In specific cases where IV access is not immediately obtained, rectal diazepam in children and intramuscular (IM) fosphenytoin injection in adults is indicated as a first step till an IV access is available. The option of IM administration of fosphenytoin is one of the three major differences between fosphenytoin and phenytoin, the other two being the option of two or three times faster administration compared with phenytoin and the reduced likelihood of causing local vein irritation. The major obstacle to the use of fosphenytoin is the high cost.
*Phenytoin and any of the benzodiazepines are incompatible and will precipitate if infused through the same IV line. Johnson: Current Therapy in Neurologic Disease (7/E)
Status Epilepticus
Seizures
Ongoing seizure activity
0–5 min.
5–30 min.
History while watching seizure
47
Examination while placing intravenous lines
Basic ABC’s
Consider the diagnosis of SE and draw the necessary bloods. Initial pharmacologic therapy. Consider EEG if possible without delaying treatment unless necessary to verify diagnosis.
Lorazepam 0.1 mg/kg IV at 1–2 mg/min
Ongoing seizure activity?
No
Yes
Phenytoin 20 mg/kg IV (or 20 mg/kg phenytoin equivalents (PE) for fosphenytoin) at 50 mg/min (or 100–150 PE/min for fosphenytoin) and reduced if significant adverse effects of infusion seen.
Phenytoin 20 mg/kg IV (or 20 mg/kg phenytoin equivalents (PE) for fosphenytoin) over 2–3 hours then end of protocol
Ongoing seizure activity?
2 30–60 min.
No
Yes: treatment of refractory seizures (definite SE)
End of protocol Phenytoin: additional 10 mg/kg IV (or 10 mg/kg phenytoin equivalents (PE) of fosphenytoin) and consider another 0.05 mg/kg of lorazepam if pt. is stable. Correct metabolic derangements, intubate and get continuous EEG recording if possible.
Ongoing SE?
Yes
No
Phenobarbital 20 mg/kg IV at 50 mg/min
End of protocol
Ongoing SE? 60–120 min. Yes
If the patient is hemodynamically very unstable you may consider midazolam 0.2 mg/kg bolus, then 0.05–0.5 mg/kg per hour for 45 minutes trial prior to pentobarbital. If the patient is at high risk for prolonged mechanical ventilation you may consider propofol 2 mg/kg IV over 10 min. If seizure stops, discontinue bolus and continue infusion at 4–12 mg/kg/hour while closely monitoring EEG and blood pressure. If seizures do not stop within 45 minutes, stop and start pentobarbital 5–15 mg/kg rapid IV bolus, then 1–6 mg/kg/min IV. Continuous EEG monitoring until pattern is isoelectric.
No
End of protocol
Proceed with further evaluation
FIGURE 1. Evaluation and pharmacologic treatment of status epilepticus (SE). ABC, Airway, breathing, circulation; IV, intravenous; EEG, electroencephalogram. Johnson: Current Therapy in Neurologic Disease (7/E)
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Status Epilepticus
Treatment of Refractory Seizures Infuse another 10 mg/kg of phenytoin (or 10 mg/kg PE of fosphenytoin) and consider another 0.05 mg/kg of lorazepam if the patient is stable. Metabolic abnormalities from initial laboratory studies should be appropriately addressed. It is critical to provide adequate ventilatory and hemodynamic support: Patients with refractory seizures should be endotracheally intubated because the combination of benzodiazepines and barbiturates is likely to cause respiratory failure. The primary drugs used in this setting are pentobarbital, midazolam, and propofol; a systematic review of drug therapy for refractory SE assessed data on 193 patients from 28 trials in an attempt to clarify this issue. Overall mortality was 48%, but there was no association between drug selection and the risk of death. Pentobarbital was more effective than either propofol or midazolam in preventing breakthrough seizures (12% vs. 42%), but was associated with a significantly increased incidence of hypotension, defined as a systolic blood pressure below 100 mm Hg (77% vs. 34%). I select further pharmacologic therapy at this point according to the old school (phenobarbital followed by pentobarbital) but may modify treatment if the patient is very unstable hemodynamically or at great risk for prolonged mechanical ventilation (see Figure 1). Treatment with high-dose barbiturates remains the treatment of choice because of the greatest experience with its use. Continuous EEG monitoring should be instituted if possible, along with continuous pulse oximetry and blood pressure monitoring via an arterial catheter. Vasopressors should be available at the bedside. An initial dose of 20 mg/kg of phenobarbital should be infused at a maximum rate of 100 mg/min. If seizure activity continues, pentobarbital coma should be induced. A dose of 10 mg/kg of pentobarbital should be infused while careful attention is paid to the EEG and hemodynamic status. Additional doses of pentobarbital at rates of 1 to 6 mg/kg/min should be infused until seizures stop (and the EEG shows isoelectric pattern). Almost all patients at this point require vasopressor support (typically phenylephrine or dopamine) as well as crystalloid infusions. The mortality rate associated with barbiturate coma reaches 80% in patients older than 70 years of age because of adverse hemodynamic effects and the severity of the underlying neurologic process. If seizures are terminated with pentobarbital, then an infusion at 1 to 4 mg/kg/hr should be maintained for 48 to 96 hours and tapered over the following 24 hours. During this time therapeutic phenytoin and phenobarbital concentrations must be maintained. If EEG is not available emergently, the maintenance dose of pentobarbital should be increased until all visible evidence of seizure activity has been abolished, including subtle signs such as pupillary dilation. Recent studies on the use of pentobarbital coma for treatment of SE shows that patients treated with sufficient dosing to produce isoelectric EEG did better than those whose EEG pattern showed burst suppression only. Also, continuation of the barbiturate anesthesia for longer time, namely 4 days, resulted in better outcome.
HEMODYNAMICALLY UNSTABLE PATIENTS Treatment with barbiturates or propofol may significantly worsen the unstable patients. Therefore, in extreme cases of hemodynamic instability one may proceed with a midazolam infusion because it is the besttolerated treatment in this setting. Generally, therapy is initiated with a 0.2 mg/kg bolus, followed by a continuous infusion of 0.05 to 0.5 mg/kg/hr. If this is unsuccessful within 45 to 60 minutes, a pentobarbital infusion should be started. PATIENTS AT HIGH RISK FOR PROLONGED MECHANICAL VENTILATION Patients who are at high risk for prolonged mechanical ventilation (e.g., with chronic obstructive pulmonary disease, severe debilitation, or cancer) could be treated with propofol in an attempt to minimize the duration of sedation. Blood pressure and EEG should be monitored closely, and pressors should be ready at the bedside, while 2 mg/kg of propofol is administered over 10 minutes. If the seizures stop prior to the infusion of the entire bolus, the bolus should be discontinued and a continuous infusion begun at 4 to 12 mg/kg per hour. This infusion should be titrated over the next 20 to 60 minutes to maintain burst suppression on the EEG and a seizurefree state. If seizures are controlled with propofol, the effective infusion rate should be maintained for 24 hours and then tapered at a rate of 5 percent per hour. This prevents rebound seizures that commonly occur with too fast propofol taper. It is critical that high therapeutic levels of anticonvulsants are obtained prior to tapering the propofol to reduce the risk of seizure recurrence. If seizure activity does not stop within 45 minutes, then the treatment with propofol should be considered unsuccessful. In this case, pentobarbital coma should be considered. Propofol infusions for refractory SE are relatively new in comparison with midazolam or high-dose barbiturates. However, as clinical experience with propofol sedation in the intensive care setting grows, this agent is increasingly used in patients with refractory status persisting after intubation. It remains critical that propofol be employed cautiously and by individuals familiar with its use in this context.
Further Evaluation after Controlling Seizures Once seizures are under control, other causes of SE should be excluded. Noncontrast brain computed tomography (CT) scan should be obtained to rule out acute CNS hemorrhage and a subsequent lumbar puncture should be done if the CT scan is negative to rule out acute infection. Urinalysis, urine culture, and blood cultures should be obtained in all patients because it may be impossible to discern the cause of existing fever as infection versus seizure related. The cause of a given episode of SE is important to determine for prognosis as well as for acute management. The most common causes for SE in adults are stroke, low anticonvulsant levels in Johnson: Current Therapy in Neurologic Disease (7/E)
Psychogenic Nonepileptic Seizures
Psychogenic Nonepileptic Seizures Allan Krumholz, M.D., and Tricia Ting, M.D.
Psychogenic nonepileptic seizures (PNESs) are among the most common and serious of all psychogenic neurologic disorders. They account for approximately 20% of all intractable seizure disorders referred to comprehensive epilepsy centers and present with a reported annual incidence of about 4% of true epilepsy. Moreover, patients with PNESs are seriously ill. PNESs may not be “real” epilepsy, but their adverse consequences are very real, resulting in severe disability and even death. Compared with patients with real epilepsy, patients with PNES exhibit more frequent, severe, and disabling seizures and a poorer quality of life. Although advances in video-electroencephalogram (EEG) monitoring have much improved our ability to correctly diagnose PNESs, diagnosis and management remain major problems. Consequently, here we emphasize strategies for both correct diagnosis and proper therapy in the management of patients with PNES.
SUGGESTED READING Chapman MG, Smith M, Hirsch NP: Status epilepticus, Anaesthesia 56:648, 2001. Claassen J, Hirsch LJ, Emerson RG, Mayer SA: Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review, Epilepsia 43:146, 2002. DeLorenzo RJ, Hauser WA, Towne AR, et al: A prospective populationbased epidemiologic study of status epilepticus in Richmond, Virginia, Neurology 46:1029-1035, 1996. Krishnamurthy KB, Drislane FW: Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus, Epilepsia 37:863-867, 1996. Lowenstein DH: Status epilepticus: an overview of the clinical problem, Epilepsia 40(Suppl 1):53-58, 1999. Lowenstein DH, Alldredge BK: Status epilepticus, N Engl J Med 338:970, 1998. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus, JAMA 270:854, 1993. Treiman DM: Status epilepticus. In Resor SR Jr, Kutt H, editors: The medical treatment of epilepsy, New York, 1992, Marcel Dekker.
PATIENT RESOURCE Epilepsy Foundation of America 4351 Garden City Drive Landover, Maryland 20785-7223 Phone: 800-332-1000 http://www.epilepsyfoundation.org/
Terminology There is no uniform standardized definition or classification for psychogenic disorders such as PNESs. We prefer the currently popular term psychogenic nonepileptic seizures. The more general term nonepileptic seizures (NESs) is used to encompass both physiologic and psychological causes for disorders that are mistaken for epilepsy (Table 1). NESs are operationally defined as disorders that mimic epilepsy but are not due to abnormal electrical discharges in the brain; and there are two types, physiologic and psychogenic. Physiologic NESs are physical disorders that are confused or mistaken for epilepsy. The specific causes vary TABLE 1 Classification of Nonepileptic Seizures I. Physiologic Nonepileptic Seizures or Events* A. Pure B. Mixed (with psychological exaggeration or embellishment) II. Psychogenic Nonepileptic Seizures A. Somatoform disorders 1. Somatization disorders 2. Conversion disorder or reactions B. Dissociative disorders C. Factitious disorder (e.g., Munchausen’s syndrome) D. Malingering *Age dependent, e.g., night terrors or breath-holding spells in children; other syncopes, complicated migraine, and transient ischemic attacks in adults.
Johnson: Current Therapy in Neurologic Disease (7/E)
Seizures
chronic epilepsy patients, toxic or metabolic derangements, anoxia or hypoxia, infection, tumor, trauma, or drug withdrawal. These causes can be identified relatively by simple tests, and treatment of the underlying cause can shorten the duration of SE, thereby improving outcome. While the patient is in barbiturate coma, systemic metabolic abnormalities should be managed aggressively. In particular, blood pressure fluctuations require pressors for control, and maintenance of normoglycemia is vital. In addition, as mentioned before, blood levels of phenytoin and phenobarbital should be kept in the high therapeutic ranges before gradual withdrawal of phenobarbital. After several days of barbiturate anesthesia, of which at least 2 days should be free of epileptiform activity on EEG, a gradual pentobarbital taper should be initiated by decreasing 1 mg/min every 6 hours with continuous EEG monitoring. If at any point epileptiform activity is seen, the infusion should be increased back to achieving isoelectric pattern. If, however, infusion can be tapered to zero, EEG monitoring should be continued continuously or intermittently for at least 4 more days to monitor for possible relapse. Good prognostic factors in recovery from SE are history of epilepsy, infectious etiology, lack of multiorgan system failure, and age younger than 40 years. Anoxia, stroke, and tumor are less favorable prognostic factors.
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Psychogenic Nonepileptic Seizures
Psychogenic Nonepileptic Seizures Allan Krumholz, M.D., and Tricia Ting, M.D.
Psychogenic nonepileptic seizures (PNESs) are among the most common and serious of all psychogenic neurologic disorders. They account for approximately 20% of all intractable seizure disorders referred to comprehensive epilepsy centers and present with a reported annual incidence of about 4% of true epilepsy. Moreover, patients with PNESs are seriously ill. PNESs may not be “real” epilepsy, but their adverse consequences are very real, resulting in severe disability and even death. Compared with patients with real epilepsy, patients with PNES exhibit more frequent, severe, and disabling seizures and a poorer quality of life. Although advances in video-electroencephalogram (EEG) monitoring have much improved our ability to correctly diagnose PNESs, diagnosis and management remain major problems. Consequently, here we emphasize strategies for both correct diagnosis and proper therapy in the management of patients with PNES.
SUGGESTED READING Chapman MG, Smith M, Hirsch NP: Status epilepticus, Anaesthesia 56:648, 2001. Claassen J, Hirsch LJ, Emerson RG, Mayer SA: Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review, Epilepsia 43:146, 2002. DeLorenzo RJ, Hauser WA, Towne AR, et al: A prospective populationbased epidemiologic study of status epilepticus in Richmond, Virginia, Neurology 46:1029-1035, 1996. Krishnamurthy KB, Drislane FW: Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus, Epilepsia 37:863-867, 1996. Lowenstein DH: Status epilepticus: an overview of the clinical problem, Epilepsia 40(Suppl 1):53-58, 1999. Lowenstein DH, Alldredge BK: Status epilepticus, N Engl J Med 338:970, 1998. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus, JAMA 270:854, 1993. Treiman DM: Status epilepticus. In Resor SR Jr, Kutt H, editors: The medical treatment of epilepsy, New York, 1992, Marcel Dekker.
PATIENT RESOURCE Epilepsy Foundation of America 4351 Garden City Drive Landover, Maryland 20785-7223 Phone: 800-332-1000 http://www.epilepsyfoundation.org/
Terminology There is no uniform standardized definition or classification for psychogenic disorders such as PNESs. We prefer the currently popular term psychogenic nonepileptic seizures. The more general term nonepileptic seizures (NESs) is used to encompass both physiologic and psychological causes for disorders that are mistaken for epilepsy (Table 1). NESs are operationally defined as disorders that mimic epilepsy but are not due to abnormal electrical discharges in the brain; and there are two types, physiologic and psychogenic. Physiologic NESs are physical disorders that are confused or mistaken for epilepsy. The specific causes vary TABLE 1 Classification of Nonepileptic Seizures I. Physiologic Nonepileptic Seizures or Events* A. Pure B. Mixed (with psychological exaggeration or embellishment) II. Psychogenic Nonepileptic Seizures A. Somatoform disorders 1. Somatization disorders 2. Conversion disorder or reactions B. Dissociative disorders C. Factitious disorder (e.g., Munchausen’s syndrome) D. Malingering *Age dependent, e.g., night terrors or breath-holding spells in children; other syncopes, complicated migraine, and transient ischemic attacks in adults.
Johnson: Current Therapy in Neurologic Disease (7/E)
Seizures
chronic epilepsy patients, toxic or metabolic derangements, anoxia or hypoxia, infection, tumor, trauma, or drug withdrawal. These causes can be identified relatively by simple tests, and treatment of the underlying cause can shorten the duration of SE, thereby improving outcome. While the patient is in barbiturate coma, systemic metabolic abnormalities should be managed aggressively. In particular, blood pressure fluctuations require pressors for control, and maintenance of normoglycemia is vital. In addition, as mentioned before, blood levels of phenytoin and phenobarbital should be kept in the high therapeutic ranges before gradual withdrawal of phenobarbital. After several days of barbiturate anesthesia, of which at least 2 days should be free of epileptiform activity on EEG, a gradual pentobarbital taper should be initiated by decreasing 1 mg/min every 6 hours with continuous EEG monitoring. If at any point epileptiform activity is seen, the infusion should be increased back to achieving isoelectric pattern. If, however, infusion can be tapered to zero, EEG monitoring should be continued continuously or intermittently for at least 4 more days to monitor for possible relapse. Good prognostic factors in recovery from SE are history of epilepsy, infectious etiology, lack of multiorgan system failure, and age younger than 40 years. Anoxia, stroke, and tumor are less favorable prognostic factors.
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Psychogenic Nonepileptic Seizures
depending on age (see Table 1). If these episodes are uncomplicated by psychological or emotional features, they can be called “pure” physiologic nonepileptic events. However, sometimes a patient’s physiologic events are psychologically exaggerated, embellished, or misinterpreted and may be thought of as “mixed” physiologic nonepileptic events (see Table 1). Physiologic NESs account for only a small proportion of all patients with NESs. Most patients with NESs have PNESs (see Table 1). In general any patient with a psychological disorder that causes symptoms that are mistaken for epilepsy can be said to have PNESs. It is useful to classify psychogenic seizure patients into four major psychopathologic categories based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-4) system (see Table 1): A. Somatoform disorders B. Dissociative disorders C. Factitious disorders D. Malingering Somatoform disorders account for the great majority of patients and can be further subclassified (see Table 1). Dissociative disorders are increasing recognized as a significant psychopathology in some patients with PNES. Also, these categories are not mutually exclusive and may be associated with other psychological, physical, and sociologic comorbidities.
Diagnosis Historically, physicians have resorted to clinical observation, seizure semiology, and history for distinguishing NES from epileptic seizures. Today, clinical observation has been buttressed by video-EEG monitoring, now considered the “gold standard” in the differential diagnosis of seizures. Additional diagnostic techniques including seizure provocation, serum prolactin levels, single photon emission computed tomography (SPECT), and
neuropsychological assessments can be useful complements to video-EEG monitoring. Diagnosis may be particularly complicated in patients with both nonepileptic and epileptic seizures. Approximately 10 to 40 percent of patients diagnosed with PNES also have been reported to have true epileptic seizures. Fortunately, in most patients with coexisting epilepsy and PNES, the epileptic seizures are usually well controlled or of only historical relevance at the time PNES present. CLINICAL OBSERVATIONS Physicians have long noted that certain overt seizure characteristics are more likely associated with PNES, whereas other features appear more indicative of epilepsy. The most commonly reported characteristics include movements and vocalizations during seizures, seizure duration, and other seizure-related associations such as injury, incontinence, and amnesia. Although variability and overlap in PNES and epileptic seizure semiology preclude relying on any single clinical sign to distinguish between the two, some clinical observations can be useful diagnostically (Table 2). PNESs often persist considerably longer than epileptic seizures, which typically last less than 3 minutes, excluding the postictal state. Some prolonged PNESs may present with nonphysiologic waxing and waning convulsive activity, or the activity may appear distractible with external stimuli. In PNES with convulsions, movements may look purposeful or semipurposeful, asymmetrical, or asynchronous (i.e., thrashing or writhing), in contrast to the synchronous tonic-clonic activity of epileptic seizures. However, it may be difficult to distinguish the semipurposeful behaviors of PNES from the automatisms of complex partial epileptic seizures, particularly frontal lobe seizures. Other distinguishing features of PNES include preservation of consciousness and responsiveness, which are frequently altered in epileptic seizures. Crying and weeping are more common to PNES, as is having the
TABLE 2 Clinical Characteristics of Epileptic versus Psychogenic Nonepileptic Seizures Characteristics
Epileptic
Nonepileptic
Age at onset
All ages; children and adolescents more common Male and female about equal Occasionally present
All ages; 15-35 yr most common
Sex Previous psychiatric history Motor
In generalized convulsions, bilateral movements are usually synchronous
Vocalization
Cry at onset
Incontinence Duration of seizure Injury Amnesia
Frequent Usually < 2-3 min Frequent tongue biting Common, unconcious during seizure
Suggestion provokes seizure
No
Female more common: 3:1 Commonly noted Flailing, thrashing, and asynchronous movements more common, side to side head movements, pelvic thrusting Weeping, crying, or screaming more common Occasional Often prolonged, > 2-3 min Uncommon Variable, sometimes conscious during seizure Often Johnson: Current Therapy in Neurologic Disease (7/E)
Psychogenic Nonepileptic Seizures
VIDEO-EEG MONITORING A diagnosis of PNESs is most secure when a typical seizure is captured and shows no epileptic activity on simultaneous EEG and video monitoring. In contrast, generalized convulsive epileptic seizures invariably are associated with clear changes in the background EEG during ictal recordings. Similarly, complex partial seizures, potentially arising from small or deep seizure foci, are associated with significant ictal EEG abnormalities in perhaps 85% to 95% of such seizures. Even simple partial seizures that do not impair consciousness have associated ictal EEG abnormalities up to 60% of the time (or nearly 80% if one records multiple seizures). The ictal EEG recording is particularly important because interictal or routine EEGs occasionally may be misleading. Patients with epilepsy may have normal
interictal EEGs, whereas patients with PNES may have minor EEG abnormalities (Table 3). Clinical seizures may be captured for differential diagnosis with either outpatient or inpatient EEG monitoring. Outpatient “ambulatory” EEG monitoring with or without simultaneous video recording has become a more readily available option that allows patients to wear the EEG at home for several days. It is particularly useful for patients who have daily events. The advantage of home monitoring is the ability to capture typical events that may be triggered by the patient’s usual environment. However, physician-directed seizure provocation by suggestion is less feasible. Prolonged inpatient video-EEG monitoring may be more appropriate for patients with less frequent events, especially when antiepileptic drug tapering is considered. Simultaneous video-EEG recording offers the advantage of permitting careful observation and review of the clinical manifestations of seizures. This can be especially useful for distinguishing epileptic discharges from movement and muscle artifact when assessing patients with PNES. PROLACTIN LEVELS Detecting a rise in serum prolactin levels following a seizure can be helpful in differentiating epileptic seizures from PNES. Prolactin levels rise approximately fivefold to tenfold after generalized tonic-clonic seizures and somewhat less so but still significantly (typically at least twofold to threefold) after complex partial seizures. This increase in serum prolactin is maximum in the initial 20 minutes to 1 hour after a seizure. Although measurements of serum prolactin may be useful in distinguishing epileptic from NESs, false-negative and false-positive results do occur. Simple partial seizures or mild complex partial seizures, particularly those with little motor activity or those arising from extratemporal regions, may not significantly raise prolactin levels. In addition, serum prolactin elevations have been reported in rare instances to occur after syncope. Overall, a prolactin level elevation is fairly specific for epilepsy; however, lack of an elevation is not highly predictive of PNES. SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY Single-photon emission computed tomography (SPECT), though not a first-line choice to differentiate PNES and epileptic seizures, may provide helpful data in difficult diagnostic cases. Typically, patients with epilepsy will
TABLE 3 EEG Characteristics of Epileptic Versus Nonepileptic (Psychogenic) Seizures EEG
Epileptic
Nonepileptic
Interictal
Spikes and sharp waves common
Preictal Ictal Postictal
Spikes, sharp waves, or rhythmic ictal activity Spikes, sharp waves, or rhythmic ictal activity Slow activity
Normal or nonspecific abnormalities, e.g., mild slow activity (possibly medication related) Movement artifact Movement artifact Normal EEG, preserved alpha when apparently unconscious
EEG, Electroencephalogram.
Johnson: Current Therapy in Neurologic Disease (7/E)
Seizures
eyes closed during a seizure. Although patients with PNES may report incontinence and self-injury, they are rarely actually witnessed or documented. Similarly, patients with PNES may report having seizures in sleep or appear to be asleep at seizure onset. However, PNESs arising from true sleep as documented by EEG are exceedingly rare. Additionally, unlike epileptic seizures, PNESs characteristically do not respond well to antiepileptic drug treatment. PNESs are much more likely to be provoked by emotional stimuli and suggestion. Thus, provocation procedures may be particularly useful for reproducing PNES during EEG recording to enable confirmation of the diagnosis. Provoking or suggesting seizures can be done in several ways, such as injecting saline or placing a tuning fork on the body or head. Hypnosis has also been used. These procedures all are accompanied by strong suggestion by the physician that this procedure is likely to bring on a typical seizure. An important diagnostic consideration is whether a provoked event truly represents the patient’s “typical” seizure. Conclusions based on an atypical induced event or on only one of a variety of seizure types can lead to a misdiagnosis, particularly in patients with coexisting PNES and epilepsy. Seizure provocation by suggestion does raise some ethical controversies. Misleading and deceiving a patient when provoking a seizure can be harmful to the patient-physician relationship and should be avoided. Nonetheless, provocative testing can be done with honesty and benefit the patient, particularly when it facilitates a correct diagnosis.
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have increased cerebral blood flow in the area of the seizure focus ictally but focally decreased blood flow interictally. In contrast, patients with PNES should not show such abnormalities. NEUROPSYCHOLOGICAL TESTING The performance of PNES and epilepsy patients on various psychological and neuropsychological tests including the Minnesota Multiphasic Personality Inventory (MMPI and MMPI-2), the Weschler Adult Intelligence Scale (WAIS), and the Halstead-Reitan Test Battery have been studied. As compared to their epilepsy counterparts, PNES patients more frequently demonstrate a “conversion V” profile on the MMPI. A “conversion V” profile, defined by an elevated MMPI Scale 1 and 3 with a relative trough on Scale 2, is highly associated with somatoform disorders and conversion symptoms. Studies assessing performance on the WAIS and Halstead-Reitan Test Battery have shown that both PNES patients and epilepsy patients have more cognitive impairment compared to the normal population, but on many neuropsychological measures, there is no significant difference in performance between the two groups. These findings suggest that while neuropsychological testing may not help distinguish between patients with PNES and epilepsy, it may nevertheless provide clinically useful data by highlighting comorbid psychopathology or cognitive difficulties that could benefit from psychological or psychiatric interventions. Formal neuropsychological testing requires referral to mental health professionals who are experienced in psychometric assessment and psychotherapeutic intervention in patients with neurologic disorders. However, the distinction between PNES and epileptic seizures is best made by a neurologist, particularly one who has expertise in epilepsy, and should be based on consideration of both clinical data and neuropsychological assessments.
Treatment PHYSIOLOGIC NONEPILEPTIC SEIZURES For patients with physiologic causes for their NESs, such as syncope, complicated migraine, or transient ischemic attacks, the treatment, clinical course, and outcome vary depending on the etiology. For example, some patients with cardiac syncope may need placement of a pacemaker, and their prognosis depends on the cardiac disease. PSYCHOGENIC NONEPILEPTIC SEIZURES Even after a diagnosis of PNES is established, neurologists can and should continue to take an active role in the care of such patients (Table 4). It is important to consider the associated psychopathology in such patients, and when appropriate, to refer patients to mental health professionals. However, mental health professionals are often uncomfortable and inexperienced with seizures
and PNES, so neurologists need to maintain an active role in the care of such patients, even if that role is simply to provide support to the mental health professional or psychiatrist. Unfortunately PNES seizure patients often “fall in the cracks” between psychiatry and neurology. Neurologists can be reassured that they can and should continue to be involved with PNES patients and can follow some simple guidelines for managing these types of patients. Management of patients with PNES is similar to that for patients with other types of so-called abnormal illness behavior (see Table 4). Historically, “moral” therapy was advocated as recognition that psychological, social, and cultural factors play an important role in these types of disorders. More recently approaches have centered on concepts such as “supportive re-education.” The first consideration should be the manner in which the diagnosis of psychogenic seizures is presented to the patient and family. It is important to be honest with the patient and to demonstrate a positive approach to the diagnosis. The physician should emphasize as favorable the good news that the patient does not have epilepsy and should also stress that the disorder, although serious and real, does not require treatment with antiepileptic medications and that once stress or emotional issues are resolved, the patient has the potential to gain better control of these events. Nevertheless, not all patients readily accept the diagnosis of PNES or this type of approach. Some may seek other opinions, and this should not be discouraged. An adversarial relationship with the patient should be avoided. In fact, the patient should be encouraged to return as desired, and records should be made available to avoid duplication of services. After a diagnosis of PNES is presented, supportive measures should be initiated. Regular follow-up visits for the patient are useful even if a mental health professional is involved. This allows the patient to get medical attention without demonstrating illness behavior. Moreover, it also offers support to the involved mental health professional. Patient education and support are stressed at these visits. Since family issues are often important contributing factors, family members should be involved.
TABLE 4 Management of Nonepileptic Seizure Patients Present the diagnosis of nonepileptic seizures positively, emphasizing the potential for better seizure control. After patients are referred to mental health professionals, the diagnosing neurologist should provide some followup and support. Regular follow-up visits should be scheduled that are not contingent on persistent, new, or worsening symptoms. Give patients attention when they do well. Avoid prescribing unnecessary medications, unwarranted tests, and excessive referrals to specialists. Permit the continuation of some symptoms. A patient’s optimal well-being and function, rather than eradication of seizures, is the goal. Johnson: Current Therapy in Neurologic Disease (7/E)
Psychogenic Nonepileptic Seizures
Prognosis The outcomes of patients with psychogenic seizures vary. Outcome studies show that about half of all patients Johnson: Current Therapy in Neurologic Disease (7/E)
with psychogenic seizures function reasonably well after diagnosis. However, many have poor functional outcomes, and only about 30% completely stop having psychogenic seizures. When the diagnosis of psychogenic seizures is based on reliable criteria such a video-EEG monitoring, misdiagnosis is unlikely, but in patients, particularly those with unusual appearing frontal lobe seizures, it can occur. Instead, the usual cause for a poor outcome is related to a patient’s chronic psychological and social problems. It is noteworthy that children with psychogenic seizures appear to have a much better prognosis than adults. Children may have psychogenic seizures more related to transient stress and coping disorders, whereas adults are more likely to have psychogenic seizures within the context of more chronic psychological maladjustment, such as personality disorders. Another factor accounting for the better outcomes in children is that they are usually diagnosed earlier. Patients without evidence of serious psychiatric or personality disorders but rather symptoms more suggestive of stress and coping disorders respond relatively well to supportive, educational, or behavioral therapeutic approaches. In contrast, patients with somatoform disorders and factitious disorders more often have associated chronic personality problems and, correspondingly, a poorer prognosis. In addition, recent evidence suggests that patients with PNES may benefit from structured treatment programs and continued support by epilepsy specialists or centers. As knowledge about the nature of psychogenic seizures and their associated psychopathology is gained, better treatment strategies can be developed that will improve the care and prognosis of these difficult and challenging patients. SUGGESTED READING Barry E, Krumholz A, Bergey C, et al: Nonepileptic posttraumatic seizures, Epilepsia 39:427-431, 1998. Bowman ES: Etiology and clinical course of pseudoseizures: relationship to trauma, depression, and dissociation, Psychosomatics 34:333-342, 1993. Cragar DE, Berry DTR, Fakhoury TA, et al: A review of diagnostic techniques in the differential diagnosis of epileptic and nonepileptic seizures, Neuropsychol Rev 12:31-64, 2002. Krumholz A: Nonepileptic seizures: diagnosis and management, Neurology 53(Suppl):S76-S83, 1999. Rueber M, Pukrop T, Bauer J, et al: Outcome in psychogenic nonepileptic seizures: one- to ten-year follow-up in 164 patients, Ann Neurol 53:305-311, 2003. Wyllie E, Friedman D, Luders H, et al: Outcome of psychogenic seizures in children and adolescents compared to adults, Neurology 41:742-744, 1991.
PATIENT RESOURCE Epilepsy Foundation of America 4351 Garden City Drive Landover, MD 20785-7223 Phone: 800-332-1000 http://www.epilepsyfoundation.org/
Seizures
If symptoms worsen or new ones develop, patients should get appropriate attention. However, it is important to avoid unnecessary testing, uncalled-for medication, or excessive referral to specialists. In addition, we advise that sometimes symptoms, even some PNESs, should be tolerated. Indeed, the goal of therapy should be to maximize the patient’s function, well-being, and quality of life—not just to eliminate seizures. It is also important to look beyond the patient’s physical symptoms and apparent psychopathology. Indeed one needs to consider such factors as personality structure, coping mechanism, related psychosocial stressors, and associated cognitive problems. This approach is supported by current psychiatric theory, as emphasized in the DSM-4 classification system. For patients with coexisting epileptic and nonepileptic seizures, proper treatment is dependent on defining the nature of the seizures that are causing problems. In many patients with coexisting epileptic and nonepileptic seizures, the events are really sequential rather than truly actively coexisting or simultaneous. This means that a patient may have a history of epileptic seizures, often in the distant past or in the case of some adults, in childhood, and may be on antiepileptic medications for these, but then the patient develops different types of events that prove to be PNES. In such cases, the active problem is really not epilepsy, because the patient’s epileptic seizures are well controlled. Therefore, attention and treatment should be directed to the PNES, and the patient and family reassured that the epileptic seizures are controlled. Patients who present with both epileptic and nonepileptic seizures simultaneously demand more complex management. In such patients, we have found it particularly helpful to focus on the semiology of seizure manifestations as recorded by video-EEG monitoring to distinguish the NESs from the epileptic ones. We then direct our treatment of the patient according to the semiology manifesting at that time. We also have found it useful to show such epileptic or nonepileptic seizures to family members to help them understand how to respond best to a specific patient’s symptoms when epileptic and nonepileptic seizures coexist as active problems. A history of sexual or physical abuse is often reported among patients diagnosed with PNES. NESs occur with greater frequency in women. The exact incidence varies, but women generally account for about 70% to 80% of all individuals with NESs. In addition head injury, particularly mild head injury, is noted as a potential precipitant in a substantial proportion of these patients. These factors may represent specific psychological risk factors or the more general risk of trauma in a susceptible individual. In regard to sexual and physical abuse, these issues should be investigated and treatment directed as appropriate.
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SECTION 3 ●
Pain Chronic Pain Management: General Principles Charles E. Argoff, M.D.
Nearly 80 million Americans suffer from one or more types of chronic painful disorders, including chronic headache, chronic neuropathic pain, pain secondary to degenerative spinal disorders, pain secondary to nonspinal degenerative joint disease, fibromyalgia, soft tissue pain disorders such as chronic myofascial pain, cancer-related pain, and others. The pain experienced by millions of Americans is frequently associated with profound restrictions of vocational as well as nonvocational activities with devastating effects on one’s quality of life. Chronic pain disables more people and adds more costs to our health care economy on an annual basis than do heart disease and cancer combined. Unlike in acute painful states such as postoperative pain or pain associated with an ankle sprain, in which the cause of the pain may be relatively easily determined, for patients with chronic pain, the exact cause of the pain may be difficult to identify even many years after the original acute injury or painful event. The term chronic pain is often defined as pain that lasts 3 months or more; however, in reality, chronic pain is pain that persists beyond the time of normal healing. By this definition, patients in certain settings might begin to experience chronic pain 1 month after the initial onset of acute pain. This is important to recognize for early treatment intervention and for the prevention of lifelong pain for the affected individual. Evaluating chronic pain poses numerous challenges to the neurologist. Although many pain assessment tools exist (see later) and new ones are being developed, the lack of a specific pain measurement tool that can prove or disprove the presence and/or the intensity of the pain may allow some practitioners to dismiss a person’s complaint of pain as “subjective.” There are also limitations in the interpretation of available test results such as imaging and electrophysiologic tests. For example, it is well known that the degree of abnormality seen on Johnson: Current Therapy in Neurologic Disease (7/E)
magnetic resonance imaging (MRI) of the lumbar spine does not routinely correlate with the degree of pain experienced by an individual. Patients with severe low back pain may have little or no structural abnormalities seen by MRI, whereas asymptomatic individuals may be noted to have disk herniations or other obvious structural problems with such imaging tools. Electrophysiologic tests may be normal in patients with severe pain, prompting some to question the legitimacy of the pain as opposed to acknowledging the limitations of the diagnostic test. Psychosocial and other factors often play a role in the “chronic pain experience,” adding an additional layer of complexity for both assessment and treatment. Despite these challenges, advances in our understanding of the pathophysiology of various chronic pain problems have been made that in turn have led to new pharmacotherapeutic and other treatment options for the management of chronic pain. Numerous therapeutic approaches are available that hold great promise for reducing the amount of pain that an individual has to endure, hopefully leading to functional restoration as well. The purpose of this chapter is to review the general principles of chronic pain management for the practicing neurologist. The success of the assessment and treatment of chronic pain may be enhanced by the recognition of the difference between nociceptive and neuropathic pain. Nociceptors are specialized nerve endings that are able to respond to typical “normal” pain producing stimuli such as thermal, chemical, mechanical, and other potential causes of tissue damage. An activated nociceptor, through C and A-delta nerve fibers, transmits its pain-producing information from the peripheral to the central nervous system, where it is processed further at spinal cord and brain levels. Nociceptive input does not become experienced by a person as pain unless the nociceptive information reaches appropriate areas of the brain. In the absence of nociceptive input, the normal nervous system does not experience pain. In contrast, neuropathic pain results from injury to the peripheral and/or central nervous system and represents abnormalities in transmission that have developed as the result of the injury. Ongoing injury is not required for these abnormalities to be expressed. There is clear evidence that neuropathic pain appears to result from the manner in which the nervous system is reorganized following injury. Peripheral and central sensitization are 55
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Chronic Pain Management: General Principles
key mechanisms that many lead in a neuropathic state to this reorganization such that lowered threshold to nociceptive processing that may now occur. Stimuli that may normally not be painful are, in neuropathic pain states, experienced as painful (allodynia). Stimuli that are normally painful may be more painful than usual (hyperalgesia). Any sensory stimuli, painful or otherwise, may be perceived in a more exaggerated manner (hyperesthesia). These clinical findings are the hallmark of neuropathic pain and reflect a nervous system that is now able to facilitate pain production because it is more easily excited than in a normal state. It must be emphasized that neuropathic pain may therefore be experienced even when the affected individual is not subjected to a tissue-damaging stimulus. It is important as well to recognize that a persistent nociceptive pain state may, through peripheral and central sensitization, develop into a neuropathic pain state. Although certainly not all chronic pain states are neuropathic, central nervous system changes that facilitate pain transmission have been postulated in chronic pain as well. Factors underlying this transformation are being actively studied and hold the key to the treatment and hopefully the prevention of many different chronic pain states, including postherpetic neuralgia, complex regional pain syndrome, chronic headache, chronic pain related to degenerative joint disease, chronic low back pain, and fibromyalgia, to name a few. To minimize the effect of the chronic pain on one’s quality of life, it is imperative that a patient with chronic pain be assessed as early as possible. I must emphasize that chronic pain may have significant negative impact on a patient’s ability to function from both a physical as well as cognitive viewpoint. Work, recreational, and normal activities of daily living all may be adversely affected. Patients with chronic pain frequently develop or have exacerbation of depression, anxiety, sleep disturbances, and loss of self-esteem as the result of the pain. Lost workdays, impaired job performance, and frank absence/disability are some of the ways in which employment is often limited by the presence of chronic pain. The goals of chronic pain management must be realistic: (1) reduce pain and (2) improve quality of life and functioning—each to the fullest extent possible. The evaluation and treatment of chronic pain are not only about finding the proper medicine, nerve block, or new exercise to “cure” the pain: this is not likely to happen in most cases. Rather, the management of chronic pain involves a detailed assessment of the problem, including both medical and nonmedical aspects, and the development of a comprehensive treatment plan. Medical, physical rehabilitative, and psychosocial treatment strategies all are appropriate to consider in this plan. The clinical assessment is the first step in the management of any neurologic disorder, including chronic pain. The goals of the clinical assessment include not only making the diagnosis of chronic pain but also attempting to make as specific a diagnosis as possible. The clinical assessment includes obtaining the following information: • When did the pain start? Was the specific onset of the pain remembered (as for example, with postherpetic
•
• • • • • • •
neuralgia or trauma)? Was there a specific cause to the pain (e.g., injury, surgery)? Are there already known medical or surgical conditions for the patient (e.g., diabetes, osteoarthritis, osteoporosis, connective tissue disease) that can provide clues regarding the cause of the chronic pain? For how long has the pain existed? Where is the pain? What does the pain feel like? Is it sharp, stabbing, dull, throbbing, aching, burning, knifelike, or a combination of these? What impact on physical function is associated with the pain? What makes it better? What makes it worse? Are there past medical, neurologic, or psychosocial factors that help you, the treatment provider, to understand the pain better? What diagnostic testing is required to assist in the assessment?
The clear purpose of diagnostic testing is to help make as specific a diagnosis as possible. It is not to be used nor can it be used to validate or invalidate the complaint of pain. A normal result does not suggest there is not a chronic pain problem. In my experience, I have encountered too many instances in which a negative test result, particularly a normal electrophysiologic examination (e.g., electromyography, nerve conduction velocity) or MRI was equated to the absence of legitimate pain. This practice is not only scientifically invalid but also ethically inappropriate. The assessment of pain is aided by the use of several pain questionnaires currently available. Individual patients with chronic pain often report widely different pain levels even for similar conditions and similar degrees of functional impairment. It is, therefore, important to always assess pain intensity levels as well as the degree of functional impairment in a person with chronic pain. The Brief Pain Inventory addresses not only the pain level but also the impact of that pain on various functional domains. It is a validated tool, takes only minutes to complete, and is a practical way to assess chronic pain as well as the results of treatment in a busy practice. Use of other tools, such as the Visual Analogue Scale or the Pain Intensity Scale, assess pain solely and not function. Use of the Faces scale may be appropriate for patients who are cognitively impaired or speak a foreign language that you are not conversant in. Longer and more detailed tools also are available but are not as practical or easy to use. Other tools are being developed for specific conditions such as neuropathic pain. After completing a comprehensive assessment of the chronic pain problem, an effective treatment plan needs to be developed that provides acceptable analgesia with an acceptable side effect profile. This may include pharmacologic, interventional, rehabilitative, and cognitivebehavioral approaches singly or in combination. With respect to pharmacotherapy, there is growing empirical evidence that “rational” polypharmacy may be most successful for patients with chronic pain. No matter how effective a single agent may be, it rarely if ever reduces pain completely; therefore, various medications Johnson: Current Therapy in Neurologic Disease (7/E)
Chronic Pain Management: General Principles
57
of valdecoxib daily, whereas another may require a 30-mg dose. Each treatment that you offer a patient (medical or otherwise) should be considered a trial therapy. Even if you just read the latest article stating that drug X is the best choice for diabetic neuropathy, you must individually assess and reassess the effect of that drug on each individual patient. If, after a period of treatment, you and the patient believe that it is both safe and effective, then continue. If not, then either amend how the treatment is offered (increase the dose, change the route of delivery) or change the treatment. Treatment goals need to be shared between you and your patient, and they need to include understanding that your patients may need to be titrated and managed with more than one agent and one type of treatment. Patients need to know that you are not “married” to the same treatment forever even if it does not work. They need to expect that the treatment will be altered if it is not effective. For this reason, you must have, even as you begin treatment, a plan for treatment discontinuation or an exit strategy. Whatever you are treating your patient with: an antidepressant, anticonvulsant, muscle relaxant, opiate analgesic, NSAID, topical analgesic, or any other agent, the patient and you both should have a rational sense of what treatment success or treatment failure are. A complete lack of any pain relief or functional improvement clearly constitutes treatment failure, and the patient’s report following treatment of minimal pain and return to work certainly suggests treatment success. Most of what we experience with our patients lies somewhere in between. In fact, this matter has been carefully studied recently in patients with postherpetic neuralgia treated with gabapentin. Substantial improvement, as reported by patients, was associated with not 100%, or even 50%, pain reduction, but with “only” 30% pain reduction. These data emphasize that successful treatment outcomes as defined by the patient’s experiences occur without absolute pain cessation and, perhaps even more important, that in chronic pain treatment it is not realistic to expect total or even 50% pain reduction.
*For example, doubling the dose of the transdermal fentanyl patch daily until comfort is achieved is likely to be associated with significant side effects, because it takes far longer than 1 day to determine the effect of the patch on the patient.
Finally, NEVER GIVE UP. There are numerous options for the treatment of chronic pain. If you believe that all treatment strategies have been exhausted, it is
Johnson: Current Therapy in Neurologic Disease (7/E)
Conclusions The management of chronic pain should be viewed in the same way as any other chronic disease. • Determine the cause to the fullest extent possible, and institute a treatment plan that has established efficacy and acceptable side effects. • Assess and reassess not only the benefit of the treatment but also the possibility of adverse effects. • Do not continue treatments that are ineffective or have unacceptable side effects; always be ready to exit one treatment and begin another if needed. • Reduce pain and improve function as much as possible.
Pain
most often based on complementary mechanisms of action may need to be combined in a rational fashion. As in other areas of medical care (e.g., cancer, hypertension, and coronary artery disease management), combinations of therapies are often believed to be more effective than a single agent. As an example, a recent open label study demonstrated that for three painful conditions (low back pain, postherpetic neuralgia, and painful diabetic neuropathy), the addition of the lidocaine 5% patch to a treatment regimen that already included gabapentin reduced pain further in all three conditions. A randomized, controlled study examining the potential benefit of combining the lidocaine 5% patch with gabapentin for postherpetic neuralgia compared with each alone is being completed. So how do you start to develop a comprehensive treatment plan? Ideally you would consider established and accepted guidelines, based on consensus unbiased expert opinion, for the condition(s) that you are treating. Regrettably, such guidelines are not uniformly available; for example, an international panel has just published guidelines for the treatment of neuropathic pain, but similar guidelines do not exist for the treatment of chronic low back pain, an even more common set of disorders. Truly “whole-istic” care means integrating medical care with appropriate interventional, physical rehabilitative, and behavioral pain management approaches. When considering any type of pharmacologic therapy, treatment goals need to balance efficacy, tolerability, cost, and safety. Choose among agents that have efficacy established through a variety of means, including published multicenter, randomized, controlled studies as well as significant clinical experience. Assess the tolerability of initiating and maintaining treatment, short- and long-term side effects, the likelihood of drug-drug interactions, the ease of dosage timing, and other medication use. Consider also the severity of the side effects. For example, the nonsteroidal antiinflammatory (NSAID) agent, piroxicam, although effective in reducing symptoms associated with inflammation, is also associated with potentially fatal gastrointestinal complications, thereby making it less than ideal for conditions in which an NSAID would be appropriate. Wherever possible, you should choose the approach (assuming equal efficacy and toxicities) that requires the least laboratory monitoring (e.g., to check drug levels, monitor for hepatic, renal, or bone marrow effects). Using one agent at a time, titrate for therapeutic efficacy versus side effect(s) in a manner consistent with the pharmacokinetics of the agent.* Increase the dose of the agent until acceptable analgesia is experienced or adverse effects limit further use of the agent. Remember that each patient is different. Even if both have similar radiologic findings and the same pain level, one patient with chronic low back pain may benefit from 10 mg
3
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Failed Back Syndrome
almost certain that one of your colleagues may be able to help with a new approach. Therefore, referral to a specialized center should be considered for the difficultto-manage patient—there is always something more to be done in controlling chronic pain. PATIENT RESOURCES American Pain Society 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4715 http://www.ampainsoc.org/ American Academy of Pain Medicine 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4731 http://www.painmed.org/ International Association for the Study of Pain 909 NE 43rd Street, Suite 306 Seattle, WA 98105 Phone: 206-547-6409 http://www.iasp-pain.org/
Failed Back Syndrome Jacob P. Schwarz, M.D., and Neal J. Naff, M.D. The imprecise term failed back syndrome refers broadly to the pain and disability experienced by patients whose back and/or leg pain remains refractory to surgical therapy. The frustration that these patients and their physicians experience when therapy fails can sour the patient-physician relationship and discourages many physicians from accepting the therapeutic challenge that these patients present. In every case, it is essential to determine the following about the patient’s prior surgical treatment: (1) Was surgical intervention indicated? and (2) Did the surgical intervention adequately treat the offending pathology? The answers to these questions will direct the appropriate work-up and treatment (Figure 1). We present here our therapeutic strategy for patients with failed back syndrome.
Initial Evaluation Many patients who suffer from failed back syndrome have not received the diagnosis or treatment most appropriate for their constellation of symptoms. A thorough review of the patient’s initial history, physical examination, past imaging studies, and previous therapeutic interventions are crucial to developing the most effective treatment plan for these patients. The physical examination should include observation of muscle bulk and tone; symmetry of strength; sensation to light touch, pain, temperature, and joint position; reflexes; gait; posture; tension signs; and the range of motion of the back and legs. Perineal sensation,
a postvoid residual, and rectal tone should be examined if the history suggests injury to the sacral roots. Data regarding the onset of the pain, the circumstances provoking it, its distribution, any patterns of radiation, the effect of various postures, and ameliorating factors are particularly important aspects of the history. Pain originating in the hip joint may radiate to the low back, buttock, and groin. Hip pathology is a frequent mimic of low back pain associated with leg pain. An assessment of hip motion and tenderness should be part of every examination to evaluate back and leg pain. In the case of hip pathology, the examiner can usually provoke the patient’s pain with abduction, flexion, and external rotation of the hip. Tenderness over the trochanteric bursa should also be evaluated. Pain in the legs that occurs at a reproducible duration of leg activity and disappears immediately on rest is indicative of vascular disease. Neurogenic claudication from lumbar stenosis occurs at a less reproducible duration of leg activity in an erect posture. The pain may not occur at all if the patient is in a flexed posture. Typically patients with neurogenic claudication report they can walk for much longer distance if they are pushing a grocery cart. Less frequently, they may report that stationary biking does not cause the leg pain they experience when walking. Peripheral neuropathy occurs frequently in the same patient population susceptible to neurogenic claudication but is not activity dependent. Appropriate consultations should be made for those patients suspected of having vascular claudication, peripheral neuropathy, or hip pathology. These are the most frequently missed diagnosis in patients with failed back syndrome. If the commonly missed diagnoses are ruled out by history and physical examination, then sources of pain other than might not have been addressed by the patient’s surgical intervention should be sought. A commonly misapplied surgical intervention is lumbar laminectomy for the treatment of back pain. Patients with lumbar facet arthritis, by definition, have some radiographic evidence of lumbar stenosis. Many of those patients, however, do not have any leg pain consistent with neurogenic claudication. All too frequently, those patients may have a lumbar laminectomy for their back pain in spite of the fact that there is no anatomic reason to expect that decompressing asymptomatic compressed nerve roots will reduce the back pain associated with inflamed and degenerative facet joints. Weight loss and physical therapy, particularly water aerobics, may relieve the inciting stress on the affected facets. Failing these, more appropriate therapy for facet arthropathy would be facet joint injections with cortisone and facet median nerve rhizotomy. Psychological evaluation is critical to successful therapy in many cases. The use of psychotherapy must be introduced carefully and with sensitivity. Certainly there are patients with underlying psychopathology who develop back pain. In these circumstances, awareness of certain psychiatric vulnerabilities, such as drug dependency, may help tailor an appropriate treatment plan for each patient. The sequelae of failed back syndrome can have devastating results to the patient’s psyche. Appropriate psychotherapy can improve the chances Johnson: Current Therapy in Neurologic Disease (7/E)
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Failed Back Syndrome
almost certain that one of your colleagues may be able to help with a new approach. Therefore, referral to a specialized center should be considered for the difficultto-manage patient—there is always something more to be done in controlling chronic pain. PATIENT RESOURCES American Pain Society 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4715 http://www.ampainsoc.org/ American Academy of Pain Medicine 4700 W. Lake Avenue Glenview, IL 60025 Phone: 847-375-4731 http://www.painmed.org/ International Association for the Study of Pain 909 NE 43rd Street, Suite 306 Seattle, WA 98105 Phone: 206-547-6409 http://www.iasp-pain.org/
Failed Back Syndrome Jacob P. Schwarz, M.D., and Neal J. Naff, M.D. The imprecise term failed back syndrome refers broadly to the pain and disability experienced by patients whose back and/or leg pain remains refractory to surgical therapy. The frustration that these patients and their physicians experience when therapy fails can sour the patient-physician relationship and discourages many physicians from accepting the therapeutic challenge that these patients present. In every case, it is essential to determine the following about the patient’s prior surgical treatment: (1) Was surgical intervention indicated? and (2) Did the surgical intervention adequately treat the offending pathology? The answers to these questions will direct the appropriate work-up and treatment (Figure 1). We present here our therapeutic strategy for patients with failed back syndrome.
Initial Evaluation Many patients who suffer from failed back syndrome have not received the diagnosis or treatment most appropriate for their constellation of symptoms. A thorough review of the patient’s initial history, physical examination, past imaging studies, and previous therapeutic interventions are crucial to developing the most effective treatment plan for these patients. The physical examination should include observation of muscle bulk and tone; symmetry of strength; sensation to light touch, pain, temperature, and joint position; reflexes; gait; posture; tension signs; and the range of motion of the back and legs. Perineal sensation,
a postvoid residual, and rectal tone should be examined if the history suggests injury to the sacral roots. Data regarding the onset of the pain, the circumstances provoking it, its distribution, any patterns of radiation, the effect of various postures, and ameliorating factors are particularly important aspects of the history. Pain originating in the hip joint may radiate to the low back, buttock, and groin. Hip pathology is a frequent mimic of low back pain associated with leg pain. An assessment of hip motion and tenderness should be part of every examination to evaluate back and leg pain. In the case of hip pathology, the examiner can usually provoke the patient’s pain with abduction, flexion, and external rotation of the hip. Tenderness over the trochanteric bursa should also be evaluated. Pain in the legs that occurs at a reproducible duration of leg activity and disappears immediately on rest is indicative of vascular disease. Neurogenic claudication from lumbar stenosis occurs at a less reproducible duration of leg activity in an erect posture. The pain may not occur at all if the patient is in a flexed posture. Typically patients with neurogenic claudication report they can walk for much longer distance if they are pushing a grocery cart. Less frequently, they may report that stationary biking does not cause the leg pain they experience when walking. Peripheral neuropathy occurs frequently in the same patient population susceptible to neurogenic claudication but is not activity dependent. Appropriate consultations should be made for those patients suspected of having vascular claudication, peripheral neuropathy, or hip pathology. These are the most frequently missed diagnosis in patients with failed back syndrome. If the commonly missed diagnoses are ruled out by history and physical examination, then sources of pain other than might not have been addressed by the patient’s surgical intervention should be sought. A commonly misapplied surgical intervention is lumbar laminectomy for the treatment of back pain. Patients with lumbar facet arthritis, by definition, have some radiographic evidence of lumbar stenosis. Many of those patients, however, do not have any leg pain consistent with neurogenic claudication. All too frequently, those patients may have a lumbar laminectomy for their back pain in spite of the fact that there is no anatomic reason to expect that decompressing asymptomatic compressed nerve roots will reduce the back pain associated with inflamed and degenerative facet joints. Weight loss and physical therapy, particularly water aerobics, may relieve the inciting stress on the affected facets. Failing these, more appropriate therapy for facet arthropathy would be facet joint injections with cortisone and facet median nerve rhizotomy. Psychological evaluation is critical to successful therapy in many cases. The use of psychotherapy must be introduced carefully and with sensitivity. Certainly there are patients with underlying psychopathology who develop back pain. In these circumstances, awareness of certain psychiatric vulnerabilities, such as drug dependency, may help tailor an appropriate treatment plan for each patient. The sequelae of failed back syndrome can have devastating results to the patient’s psyche. Appropriate psychotherapy can improve the chances Johnson: Current Therapy in Neurologic Disease (7/E)
Failed Back Syndrome
59 Pain
Review initial history and diagnostic imaging
Yes
No
Was the initial surgery indicated?
Is there lumbar pathology that was not addressed?
Did the surgery adequately address the pathology?
Yes
Yes
No Re-operate
No
Address pathology: Facet arthropathy → blocks, rhizotomy Lumbar instability → spinal fusion Lumbar stenosis → spinal decompression
Is there additional pathology?
Is extra-spinal pathology present?
Yes Address pathology: Arachnoiditis → spinal cord stimulator Lumbar instability → spinal fusion
No Nonoperative pain management
Yes Address pathology: Hip arthritis Vascular disease Peripheral neuropathy
No Nonoperative pain management
Consider: Nerve/nerve root injury ↓ Spinal cord stimulator Implantable drug pump FIGURE 1. Flowsheet synopsis of our approach to the work-up of failed back surgery syndrome.
that this patient will successfully comply with other treatment strategies and learn the coping mechanisms necessary to regain a reasonable quality of life. A careful review of the initial and most recent diagnostic imaging is also necessary. Plain radiographs provide important information about bone density, spinal alignment, and fractures. Standing, sitting, supine, standing flexion, and standing in extension radiographs provide invaluable information about the spine and how it changes in response to stress that is not available from any other studies. A spine that appears to have a normal radiographic appearance when the patient is standing erect may move out of alignment on flexion or extension. Disk spaces may collapse under different stresses evoked by differences in posture. In such cases mechanical instability may be provoking pain that would respond to surgical intervention. Computed tomography (CT) scans provide similar information to plain radiographs but allow for three-dimensional reconstruction and investigation. This illuminates problems related to joint hypertrophy, calcified ligaments, and osteophytes in the spinal canal or foramen that cannot be seen on plain radiograph. Finally, magnetic resonance imaging (MRI) captures data about connective tissues such as disk material, ligaments, and abnormal masses that Johnson: Current Therapy in Neurologic Disease (7/E)
might change the architecture of the spinal column and provoke pain. It is important that all patients with failed back syndrome have an MRI with and without contrast. The contrast component of the imaging is necessary to distinguish between recurrent disk herniation and postsurgical scarring. Contrast administration is also important for the thorough evaluation for arachnoiditis.
Treatment Options SURGICAL INTERVENTION: OPERATION AND REOPERATION Was the Surgical Intervention Indicated? To determine if the patient’s initial surgery was indicated, the following factors should be present. First, the patient should have had a complaint that is reliably attributable to a structural problem. Second, there should be a structural abnormality on the initial diagnostic imaging that explained the patient’s complaint. Third, the surgical procedure performed must have been appropriate to treat the responsible structural abnormality. In the absence of these criteria, the patient’s surgical intervention was misguided and was destined
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to fail. It is also a near certainty that a repeat of the same operation in this situation will also be destined to fail. If Surgery Was Indicated, Did the Surgical Intervention Adequately Treat the Pathology? It might be the case that the previous surgery failed in the presence of a surgically correctable abnormality because the wrong surgery was performed or because the appropriate surgical procedure failed or partly failed to treat the offending pathology. Common examples of the latter are residual herniated lumbar disk material or foraminal stenosis that continues to compress one or more nerve roots. In these situations the most reasonable intervention would be another operative attempt to correct the offending pathology. In these cases, repeat surgery, when properly directed at specific findings and complaints, is often successful. Success rates for reoperation vary with each report. Large series report success rates in the range of 30% to 50%. Certain features predict better outcomes. Females do better than males. Those with fewer prior surgeries are more likely to benefit from reoperation than those with multiple unsuccessful attempts. Those who have evidence of epidural scarring from previous operations are more likely to encounter bad outcomes as are those involved in litigation related to their back pain. The patient must be made aware that the risk of perioperative complications increases with reoperation and the efficacy slightly decreases. A more complicated situation is persistent lumbar instability after a lumbar fusion operation. Lumbar fusions have a mixed history of success. Most wellconducted clinical studies demonstrate no better than a 60% success rate. Therefore, 4 of 10 patients that have that operation will not benefit regardless of the technical “success of the procedure.” Reoperation for persisting back pain following a fusion procedure should be cautiously considered, particularly if there is no clear technical problem with the fusion construct. NO SURGICALLY CORRECTABLE PATHOLOGY PRESENT: OPTIONS WHEN NO SURGERY IS INDICATED If the determination is made that surgical intervention was not indicated, the etiology of the patient’s initial complaint must be determined through a careful history and physical examination. The history should reveal the specific features about the original pain that the patient had suffered and the pain that the patient experienced subsequent to each surgical intervention. This information will give important insights to the original etiology of the back pain and help to direct nonoperative therapies that might be of benefit. Physical Therapy and Rehabilitation All patients with chronic disabling back pain should be referred for physical therapy and rehabilitation regardless of other concordant therapies. Physical therapy is
important for strengthening, increasing flexibility, and helping patients learn strategies to more efficiently and safely increase their activity. Reasonable exercise has been shown not only to be safe for patients with chronic back pain but to lead to reduction in pain magnitude of 10% to 50%. Lumbar Facet Denervation Among patients whose pain is consistent with lumbar facet joint disease, facet denervation can provide measurable relief. As facet joints degenerate with time, arthritis, or instability, they gradually endure more stress and wear. This is often noticeable on diagnostic imaging where one or both facet joints demonstrate hypertrophy. These enlarged facets may cause stenosis of the lateral recess of the spinal canal and the neural foramen that contributes to radiculopathy from nerve root compression. In other cases, no radiculopathy is present, but instead severe axial back pain with radiation to the flank and hip. If this pain is worst with standing and lumbar extension, it may be that irritation of the nerves of the affected facet joints is responsible for the offending pain. When appropriately used, radiofrequency ablation of the median nerve of the facet can provide 45% to 50% of patients at least a 50% reduction in pain. Spinal Cord Stimulation Spinal cord stimulation provides pain relief by “confusing” the pain signaling pathways. A stimulator electrode placed over the dorsal columns of the spinal cord causes a mild vibratory sense over the dermatomes it stimulates. When targeted to the region afflicted by pain, a discomforting sensation can be overwhelmed by the vibrating sensation triggered by the stimulator. In this fashion, a constant unbearable sensation is replaced by a pleasing tingling sensation. Stimulator electrodes are designed in such a fashion that selected contact points along the electrode surface may have varying intensity. This allows the effect of the stimulator to be targeted to specific regions of the spinal cord and for the intensity of that effect to be modulated selectively. To ensure that a spinal cord stimulator will be worthwhile and to identify the ideal settings for the stimulator, surgeons conduct a temporary trial of stimulation prior to implanting it permanently. The trial uses a percutaneously placed epidural electrode that is then attached to an external computer. Over the course of the next few days, the patient is able to modulate the stimulator intensities and stimulation pattern. If an efficacious and tolerable combination arises, the surgeon then implants a permanent system. If the patient does not experience any benefit from the temporary stimulator, the electrode is simply removed and no surgery is necessary. Although this technique works best for lower extremity pain, there are many clinical series that report success with the treatment of axial back pain. Again, with careful selection, most patients receive significant pain relief from spinal cord stimulation, and as many as 78% would have the procedure again and recommend it Johnson: Current Therapy in Neurologic Disease (7/E)
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neurosurgeons, a thoughtful methodical evaluation and treatment plan may provide benefit and ensure that all that can be done is offered for these patients.
Implantable Drug Pumps
SUGGESTED READING
Intrathecal or epidural administration of opioids and other pharmaceuticals has been used in the treatment of chronic low back pain with mixed success. Although the use of intrathecal drug therapy has been shown to be cost effective in the long term, patient satisfaction has been erratic from one study to the next. Most studies of implantable drug delivery are retrospective and most success has been anecdotal. Further investigation is necessary to establish which patients with failed back syndrome are most likely to benefit from this therapy.
Kumar K, Hunter G, Demeria DD: Treatment of chronic pain by using intrathecal drug therapy compared with conventional pain therapies: a cost-effectiveness analysis, J Neurosurg 97:803-810, 2002. Loubser PG, Akman NM: Effects of intrathecal baclofen on chronic spinal cord injury pain, J Pain Symptom Manage 12:241-247, 1996. North RB, Han M, Zahurak M, Kidd DH: Radiofrequency lumbar facet denervation: analysis of prognostic factors, Pain 57:77-83, 1994. North RB, Wetzel FT: Spinal cord stimulation for chronic pain of spinal origin: a valuable long-term solution, Spine 27:2584-2591, 2002. Ohnmeiss DD, Rashbaum RF: Patient satisfaction with spinal cord stimulation for predominant complaints of chronic, intractable low back pain, Spine J 1:358-363, 2001. Rainville J, Hartigan C, Martinez E, et al: Exercise as a treatment for chronic low back pain, Spine J 4:106-115, 2004. Royal M, Wienecke G, Movva V, et al: Retrospective study of efficacy of radiofrequency neurolysis for facet arthropathy, Pain Med 2:249-250, 2001. Schwarz J, Naff N: The management of neuropathic pain, Neurosurg Clin North Am 15:231-239, 2004. van Kleef M, Barendse GA, Kessels A, et al: Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain, Spine 24:1937-1942, 1999. Yoshida GM, Nelson RW, Capen DA, et al: Evaluation of continuous intraspinal narcotic analgesia for chronic pain from benign causes, Am J Orthop 25:693-694, 1996.
Conclusions Failed back syndrome is an all-too-common problem that is disabling, demoralizing, and disruptive to a patient’s quality of life. A careful history of the patient’s initial presentation and review of the initial diagnostic studies are necessary to determine the pathology that led to the initial symptoms. Every attempt should be made to identify the initial source of the pain, and if it is determined that the initial intervention was not indicated, appropriate treatment should be offered. This may require investigation and treatment for hip pathology, vascular disease, or peripheral neuropathy. If it is determined that the patient did have a surgically remediable problem, then it must be determined if the surgical intervention adequately treated that problem. If the wrong surgical intervention was chosen initially, the best course would be to offer the patient the appropriate surgical intervention. A frequent example of this situation is the use of lumbar laminectomy for back pain when facet joint injections or median facet nerve rhizotomy would be more appropriate. If the correct surgical intervention was performed initially, then it must be determined if that intervention adequately treated the offending pathology. If the initial procedure did not adequately treat the offending pathology, then a second attempt at the same procedure would likely be the most appropriate treatment. A frequent example of this situation would be residual disk herniation or foraminal stenosis compressing a nerve root. A repeat diskectomy or foraminotomy in this situation has a high likelihood of success. If it is determined that the initial operation was indicated and that there is no residual pathology that is surgically remediable, it is then advisable that the patient pursue a comprehensive pain management program under the direction of a physician with experience in chronic pain management. A frequent example of this last situation is patients with radiculitis from pathologic or iatrogenic intrinsic nerve root injury. If these patients are inadequately treated by pharmaceutical pain management strategies, they may be ideal candidates for spinal cord stimulation or implantable morphine pumps. Although failed back syndrome is one of the more frustrating problems that confronts neurologists and Johnson: Current Therapy in Neurologic Disease (7/E)
CERVICAL SPONDYLOSIS Erick Scott, M.D., and Douglas Kerr, M.D., Ph.D. Cervical spondylosis is defined as a degenerative condition compromising the spinal canal. It is an inevitable consequence of aging and is present in more than 90% of individuals older than 65 years of age. As such, it is a natural consequence of a bipedal existence and is not a disease state. However, this degenerative process may cause symptoms in up to 10% to 15% of the population and therefore is among the most common causes of patient visits to health care providers. Cervical spondylosis may cause symptoms of neck pain and restricted movement due to mechanical limitation, radicular pain and paresthesias due to compression of nerve roots, or myelopathic symptoms due to compression of the spinal cord itself. This chapter reviews the most recent advances in the diagnosis and treatment of cervical spondylosis.
Definition and Clinical Manifestations Cervical spondylosis may cause one of three syndromes: radiculopathy, myelopathy, or mechanical neck pain. Radiculopathy is due to nerve root compression, usually from the progressive narrowing of a neural foramen, caused by hypertrophic bony changes in the anterior
Pain
to another patient. Spinal cord stimulation is an increasingly valuable long-term solution for chronic low back pain.
3
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61
neurosurgeons, a thoughtful methodical evaluation and treatment plan may provide benefit and ensure that all that can be done is offered for these patients.
Implantable Drug Pumps
SUGGESTED READING
Intrathecal or epidural administration of opioids and other pharmaceuticals has been used in the treatment of chronic low back pain with mixed success. Although the use of intrathecal drug therapy has been shown to be cost effective in the long term, patient satisfaction has been erratic from one study to the next. Most studies of implantable drug delivery are retrospective and most success has been anecdotal. Further investigation is necessary to establish which patients with failed back syndrome are most likely to benefit from this therapy.
Kumar K, Hunter G, Demeria DD: Treatment of chronic pain by using intrathecal drug therapy compared with conventional pain therapies: a cost-effectiveness analysis, J Neurosurg 97:803-810, 2002. Loubser PG, Akman NM: Effects of intrathecal baclofen on chronic spinal cord injury pain, J Pain Symptom Manage 12:241-247, 1996. North RB, Han M, Zahurak M, Kidd DH: Radiofrequency lumbar facet denervation: analysis of prognostic factors, Pain 57:77-83, 1994. North RB, Wetzel FT: Spinal cord stimulation for chronic pain of spinal origin: a valuable long-term solution, Spine 27:2584-2591, 2002. Ohnmeiss DD, Rashbaum RF: Patient satisfaction with spinal cord stimulation for predominant complaints of chronic, intractable low back pain, Spine J 1:358-363, 2001. Rainville J, Hartigan C, Martinez E, et al: Exercise as a treatment for chronic low back pain, Spine J 4:106-115, 2004. Royal M, Wienecke G, Movva V, et al: Retrospective study of efficacy of radiofrequency neurolysis for facet arthropathy, Pain Med 2:249-250, 2001. Schwarz J, Naff N: The management of neuropathic pain, Neurosurg Clin North Am 15:231-239, 2004. van Kleef M, Barendse GA, Kessels A, et al: Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain, Spine 24:1937-1942, 1999. Yoshida GM, Nelson RW, Capen DA, et al: Evaluation of continuous intraspinal narcotic analgesia for chronic pain from benign causes, Am J Orthop 25:693-694, 1996.
Conclusions Failed back syndrome is an all-too-common problem that is disabling, demoralizing, and disruptive to a patient’s quality of life. A careful history of the patient’s initial presentation and review of the initial diagnostic studies are necessary to determine the pathology that led to the initial symptoms. Every attempt should be made to identify the initial source of the pain, and if it is determined that the initial intervention was not indicated, appropriate treatment should be offered. This may require investigation and treatment for hip pathology, vascular disease, or peripheral neuropathy. If it is determined that the patient did have a surgically remediable problem, then it must be determined if the surgical intervention adequately treated that problem. If the wrong surgical intervention was chosen initially, the best course would be to offer the patient the appropriate surgical intervention. A frequent example of this situation is the use of lumbar laminectomy for back pain when facet joint injections or median facet nerve rhizotomy would be more appropriate. If the correct surgical intervention was performed initially, then it must be determined if that intervention adequately treated the offending pathology. If the initial procedure did not adequately treat the offending pathology, then a second attempt at the same procedure would likely be the most appropriate treatment. A frequent example of this situation would be residual disk herniation or foraminal stenosis compressing a nerve root. A repeat diskectomy or foraminotomy in this situation has a high likelihood of success. If it is determined that the initial operation was indicated and that there is no residual pathology that is surgically remediable, it is then advisable that the patient pursue a comprehensive pain management program under the direction of a physician with experience in chronic pain management. A frequent example of this last situation is patients with radiculitis from pathologic or iatrogenic intrinsic nerve root injury. If these patients are inadequately treated by pharmaceutical pain management strategies, they may be ideal candidates for spinal cord stimulation or implantable morphine pumps. Although failed back syndrome is one of the more frustrating problems that confronts neurologists and Johnson: Current Therapy in Neurologic Disease (7/E)
CERVICAL SPONDYLOSIS Erick Scott, M.D., and Douglas Kerr, M.D., Ph.D. Cervical spondylosis is defined as a degenerative condition compromising the spinal canal. It is an inevitable consequence of aging and is present in more than 90% of individuals older than 65 years of age. As such, it is a natural consequence of a bipedal existence and is not a disease state. However, this degenerative process may cause symptoms in up to 10% to 15% of the population and therefore is among the most common causes of patient visits to health care providers. Cervical spondylosis may cause symptoms of neck pain and restricted movement due to mechanical limitation, radicular pain and paresthesias due to compression of nerve roots, or myelopathic symptoms due to compression of the spinal cord itself. This chapter reviews the most recent advances in the diagnosis and treatment of cervical spondylosis.
Definition and Clinical Manifestations Cervical spondylosis may cause one of three syndromes: radiculopathy, myelopathy, or mechanical neck pain. Radiculopathy is due to nerve root compression, usually from the progressive narrowing of a neural foramen, caused by hypertrophic bony changes in the anterior
Pain
to another patient. Spinal cord stimulation is an increasingly valuable long-term solution for chronic low back pain.
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Cervical Spondylosis
wall. Although the foraminal compromise is gradual, symptoms may be of sudden onset, often precipitated by a particular event such as a motor vehicle accident, a fall, or an exercise-induced injury. It is likely that the sudden nature of symptom onset is due to microtrauma, stretching or tethering of a nerve root, or inflammation within an already compromised neural foramina. Symptoms usually consist of neck pain and stiffness that evolve to include pain, paresthesias, numbness, and weakness in one arm. Neurologic examination usually reveals sensory loss and weakness in a nerve root distribution and may reveal an accompanying decrease in a deep tendon reflex (biceps reflex for C6 radiculopathy, triceps reflex for C7 radiculopathy). Cervical spondylitic myelopathy results from compression of the spinal cord, anteriorly by bony structures of the vertebral body and facets, or posteriorly by ligamentum flavum hypertrophy. Symptoms usually progress insidiously and can often be present for years prior to seeking medical attention. Occasionally, a relatively minor trauma, such as a hyperextension injury from a fall or a motor vehicle accident, precipitates sudden and severe myelopathic symptoms. Symptoms usually consist of gait difficulty and “stiffness.” Gait dysfunction may result from abnormal proprioceptive input due to compression of ascending sensory pathways or may be due to evolving spasticity due to compression of descending motor pathways. Bowel and bladder involvement, usually consisting of urgency, is associated with inconsistent symptoms and, if present, suggests a more advanced myelopathy. Examination findings usually consist of spasticity, hyperreflexia, and Babinski’s response. Since cervical spondylitic myelopathy typically affects C6 or C7, there may be relative sparing of arm function and there may be a discord between the reflexes and tone of the upper and lower extremities. Mechanical pain due to cervical spondylosis is the most common of the three syndromes, though it is the least clearly understood and defined. In part, this is because there is poor correlation between radiologically defined spondylosis and neck pain. Also, there is no examination finding (e.g., paraspinalis spasm, limitation of neck motion or reflex asymmetry) that defines this syndrome. Typically, patients describe localized pain in the neck without radiation and often limitation in range of motion of the neck or “clicks” during neck movement. The pain itself likely comes from a variety of sources: new bone generation in the facets or vertebral bodies, myofascial changes, muscular spasm or the degenerating disk (diskogenic pain).
Classification Several classification schemes exist to quantify the degree of cervical spondylosis. These stages are defined as follows: • Stage 1: diskogenic phase without osteophyte formation • Stage 2: spondylosis with disk degeneration and osteophyte formation
• Stage 3: bridging osteophytes with immobilization of the involved segment • Stage 4: compression of the spinal cord Recent studies have suggested that the dynamic nature of the cervical spinal cord is an important predictor of disability and that flexion and extension studies must be incorporated into this scheme. Magnetic resonance imaging (MRI) studies and plain radiographs done in the neutral position often do not effectively define spinal canal compromise in either the flexed or extended positions. In this study, 27% of patients in the extended position and 5% of patients in the flexed position experienced worsened spinal canal compromise compared to a neutral-position MRI. Therefore, we recommend a dynamic MRI or computed tomography (CT) myelogram to accurately evaluate cervical spondylosis.
Pathophysiology of Cervical Spondylosis Cervical spondylosis occurs in response to dehydration or degeneration of intervertebral disks that begins in young adulthood. As a result of this degeneration, adjacent bony structures acquire new stresses as the spinal column is subjected to the dynamic movement of normal life. The disks themselves become less capable of load bearing and transfer this load to facet joints and vertebral bodies. In places where the degeneration is most advanced, adjacent bony structures contact each other, generating new bone. This results in osteophytes, bony ridges, and spurs. Additionally, the ligamentum flavum hypertrophies posterior to the spinal cord. The consequence is narrowing of the spinal canal with impingement of nerve roots or the spinal cord. If the spinal cord is compressed, myelopathic symptoms develop. If nerve roots are compressed, radicular symptoms develop. Pain may be a prominent symptom of cervical spondylosis even in the absence of neural compromise due to mechanical dysfunction.
Pathophysiology of Spondylitic Myelopathy In some cases of spondylitic myelopathy, a dynamic compression of the spinal cord occurs. During flexion or extension of the spinal cord, a spondylitic spur compresses the spinal cord, resulting either in a direct contusion or in impaired venous drainage out of the spinal cord. Many patients demonstrate a central, high T2-weighted signal intensity on MRI. Recent studies have demonstrated that this central spinal cord abnormality represents cystic necrosis resulting from venous hypertension. Venous drainage of the spinal cord occurs via both intrinsic and extrinsic spinal cord veins. The intrinsic spinal cord veins consist of an anterior median group and a radial group. Blood in the anterior third of the spinal cord drains to the segmental central vein, then to the longitudinally oriented anterior median spinal vein, which lies on the pial surface of the spinal Johnson: Current Therapy in Neurologic Disease (7/E)
Cervical Spondylosis
Diagnosis The diagnosis of cervical spondylitic myelopathy or radiculopathy is dependent on the clinical symptoms confirmed by a detailed neurologic examination. The diagnosis of spondylitic radiculopathy can be confirmed by cervical spine radiographs. Oblique views, which are aimed to “look down” the neural foramina, demonstrate the encroachment by osteophytes from the anterior wall. Spiral CT scanning, especially with two-dimensional sagittal reconstructions, can also confirm foraminal stenosis. MRI images are less helpful in spondylitic radiculopathies. For spondylitic myelopathy, an MRI of the neck in neutral, extended, and flexed position is recommended (no gadolinium needed). If the anterior and posterior cerebrospinal fluid (CSF) spaces remain patent in all sequences, then conservative management is likely warranted. If the anterior and/or the posterior CSF space is impinged, especially if there is a “pincer” effect (anterior and posterior compression at nearby levels), then neurosurgical consultation is warranted. Cord signal change necessitates urgent neurosurgical referral.
Treatment CONSERVATIVE MANAGEMENT For spondylitic radiculopathy, conservative measures should be attempted first. Simple soft collar immobilization often is helpful because it decreases repetitive motion and microtrauma that have precipitated the symptoms. The most effective method is the use of “over-the-door” cervical traction. Patients can do this at home with the use of a head halter attached to a rope that passes through a pulley set over the top of a door and is connected to a water bag for weight (5 to 10 lb). Patients should sit facing the door (to avoid hyperextension) for 30 minutes twice a day. Nonsteroidal anti-inflammatory agents and localized massage should also be employed in patients with spondylitic radiculopathy. Patients often are offered selective nerve root block for spondylitic radiculopathy. However, this approach usually results in only temporary improvement in Johnson: Current Therapy in Neurologic Disease (7/E)
symptoms. In a recent study, only 20% of patients experienced significant relief of symptoms. Mechanical pain from cervical spondylosis should be treated by heating pads and by stretching range-ofmotion exercises. Most patients respond well to “no-no” stretching of the neck for five seconds at each limit; “yes-yes” stretching of the neck for 5 seconds at each limit; and “ear-to shoulder” stretching of the neck for 5 seconds at each limit. Chiropractic therapy is often used by patients with cervical spondylosis, though there are no controlled studies that warrant this approach. Recent uncontrolled reports suggest that chiropractic manipulations may be beneficial. However, though chiropractic manipulation may be appropriate for uncomplicated mechanical pain associated with cervical spondylosis, chiropractic manipulations are not recommended for either radicular or myelopathic symptoms and may cause adverse outcomes in such patients. Shiatsu (deep massage) and acupuncture therapies are often employed by patients with anecdotally excellent response and little risk.
Pain
cord in the midline. The radial veins form in the peripheral gray matter or white matter and drain radially to the coronal plexus of veins on the pial surface. The anterior median spinal vein and the coronal plexus (termed the extrinsic venous drainage) are drained by the medullary veins that travel with nerve roots. Anterior medullary veins travel with the ventral roots, while posterior medullary veins travel with the dorsal roots. In the intervertebral foramen, a number of veins, including the anterior and posterior medullary veins, veins from the vertebral plexus, and the radicular veins, coalesce to form a plexus surrounding the spinal nerve. Appreciation of this anatomy is critical to understand how spondylitic myelopathy develops.
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SURGICAL APPROACH Patients with spondylitic myelopathy or radiculopathy are often offered surgical treatment that typically consists of either anterior cervical decompressions with fusion and/or instrumentation or posterior cervical laminectomy or laminoplasty. The data to support surgical intervention remain mixed. In a nonrandomized, prospective study of patients with cervical spondylitic myelopathy, surgically treated patients had a significant improvement in functional status and pain, whereas medically treated patients were worse in these areas. In a separate report, cervical laminectomy or laminoplasty was successfully used to decrease symptoms in patients with spondylitic myelopathy. Although patients younger than 65 years of age did well in the short term, they had significant deterioration between 3 and 10 years after surgery. A randomized study designed to define whether patients with mild-to-moderate spondylitic myelopathy did better with conservative or surgical treatment revealed no clear difference between the groups at 3 years’ follow-up. A recent Cochrane review suggested that there was not sufficient evidence from controlled trials to support surgical treatment of patients with spondylitic radiculopathy or myelopathy. Patients with persistent cord signal change after surgery had worse outcomes. T1-weighted hypointensities predicted a worse outcome.
Outcomes Although the outcomes from cervical spondylosis vary and the treatment of choice remains uncertain, the following guidelines apply: Patients with mechanical pain from spondylosis should have conservative therapy as defined earlier. Patients with spondylitic radiculopathy should be given conservative therapy, including cervical traction and
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soft collar immobilization, and only later should be offered a surgical treatment. Patients with rapidly progressive spondylitic myelopathy and a clearly defined compressive etiology (either direct compression or impaired venous drainage) should be rapidly offered surgical decompression. The optimal surgical technique (laminectomy, laminoplasty, or anterior decompression with fusion/instrumentation) depends on the dynamic compressive states present. Long-term consequences of surgery remain unknown and depend on the degree of destabilization/compression of other segments of the spinal column. SUGGESTED READING Epstein NE: Laminectomy for cervical myelopathy, Spinal Cord 41:317-327, 2003. Fouyas IP, Statham PF, Sandercock PA: Cochrane review on the role of surgery in cervical spondylitic radiculomyelopathy, Spine 27:736-747, 2002. Gillilan LA: Veins of the spinal cord: anatomic details, suggested clinical applications, Neurology 20:860-868, 1970. Handal JA, Knapp J Poletti S. The structural degenerative cascade: the cervical spine, 1995. Kirkaldy-Willis WH, Bernard TN, editors: Managing low back pain, ed 4, Philadelphia, 1999, Churchill-Livingstone. Kukurin GW: The amelioration of symptoms in cervical spinal stenosis with spinal cord deformation through specific chiropractic manipulation: a case report with long-term follow-up, J Manipulative Physiol Ther 27:E7, 2004. Mizuno J, Nakagawa H, Inoue T, Hashizume Y: Clinicopathological study of “snake-eye” appearance in compressive myelopathy of the cervical spinal cord, J Neurosurg 99(Suppl):162-168, 2003. Muhle C, Metzner J, Weinert D, et al: Classification system based on kinematic MR imaging in cervical spondylitic myelopathy, AJNR Am J Neuroradiol 19:1763-1771, 1998. Sampath P, Bendebba M, Davis JD, Ducker TB: Outcome of patients treated for cervical myelopathy: a prospective, multicenter study with independent clinical review, Spine 25:670-676, 2000. Slipman CW, Lipetz JS, DePalma MJ, Jackson HB: Therapeutic selective nerve root block in the nonsurgical treatment of traumatically induced cervical spondylitic radicular pain, Am J Physical Med Rehabil 83:446-454, 2004.
associated with nonspecific symptoms and signs such as altered skin color, temperature, or sudomotor activity, allodynia, disuse atrophy, or edema; and, in contrast with CRPS type 2 (formerly called causalgia), occurs in a distribution different from that resulting from injury to a single peripheral nerve. In many cases CRPS syndromes resolve over weeks or months. Even so, the unexpected finding of persistent, worsening pain, often after seemingly minor trauma or brief limb immobilization, poses a significant psychological challenge that the clinician must keep in mind from the beginning of treatment to avoid a vicious circle of pain, distress, guarding, muscle atrophy, and increased pain susceptibility. At all stages of treatment (Figure 1), effective management of CRPS depends on a threepronged approach—rehabilitation, psychological support, and medicinal agents—probably in descending order of importance. The cornerstone of management of CRPS is physical and occupational therapy. Improvement often requires a closely supervised program of continued and increasing activity of the affected limb, while the patient is under the influence of an analgesic if necessary. In additional to active exercise of the limb, physical therapy approaches can include “desensitization,” where progressively coarser objects are rubbed across the skin of the affected limb; spinal manipulation; myofascial
CRPS Physical therapy (e.g., active mobilization, desensitization, myofascial release) NSAID Lidocaine patch/capsaicin (local only) Corticosteroids (early only)
Resolved
Unresolved Sympathetically maintained?
Yes
No
Sympatholytic trial e.g., clonidine, terazosin, tizanidine
Complex Regional Pain Syndromes
Resolved
Gabapentin Opiate Mexiletine (if acute benefit from i.v. lidocaine)
Unresolved
Resolved
Opiate tricyclic
David S. Goldstein, M.D., Ph.D. Resolved
Complex regional pain syndromes (CRPSs) come under the classification of neuropathic pain, along with entities such as postherpetic neuralgia and painful diabetic neuropathy. Distinguishing characteristics of CRPS are onset after physical trauma or limb immobilization and spread of involvement. CRPS type 1, formerly called reflex sympathetic dystrophy, refers to post-traumatic pain that spreads from the site of injury; exceeds in magnitude and duration the expected clinical course of the inciting event; progresses variably over time; is
Unresolved
Unresolved Spinal cord stimulation trial
Acute improvement
Unresolved
Spinal cord stimulator
FIGURE 1. Treatment algorithm for complex regional pain syndromes. CRPS, Complex regional pain syndrome; NSAID, nonsteroidal anti-inflammatory drug; i.v., intravenous. Johnson: Current Therapy in Neurologic Disease (7/E)
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Complex Regional Pain Syndromes
soft collar immobilization, and only later should be offered a surgical treatment. Patients with rapidly progressive spondylitic myelopathy and a clearly defined compressive etiology (either direct compression or impaired venous drainage) should be rapidly offered surgical decompression. The optimal surgical technique (laminectomy, laminoplasty, or anterior decompression with fusion/instrumentation) depends on the dynamic compressive states present. Long-term consequences of surgery remain unknown and depend on the degree of destabilization/compression of other segments of the spinal column. SUGGESTED READING Epstein NE: Laminectomy for cervical myelopathy, Spinal Cord 41:317-327, 2003. Fouyas IP, Statham PF, Sandercock PA: Cochrane review on the role of surgery in cervical spondylitic radiculomyelopathy, Spine 27:736-747, 2002. Gillilan LA: Veins of the spinal cord: anatomic details, suggested clinical applications, Neurology 20:860-868, 1970. Handal JA, Knapp J Poletti S. The structural degenerative cascade: the cervical spine, 1995. Kirkaldy-Willis WH, Bernard TN, editors: Managing low back pain, ed 4, Philadelphia, 1999, Churchill-Livingstone. Kukurin GW: The amelioration of symptoms in cervical spinal stenosis with spinal cord deformation through specific chiropractic manipulation: a case report with long-term follow-up, J Manipulative Physiol Ther 27:E7, 2004. Mizuno J, Nakagawa H, Inoue T, Hashizume Y: Clinicopathological study of “snake-eye” appearance in compressive myelopathy of the cervical spinal cord, J Neurosurg 99(Suppl):162-168, 2003. Muhle C, Metzner J, Weinert D, et al: Classification system based on kinematic MR imaging in cervical spondylitic myelopathy, AJNR Am J Neuroradiol 19:1763-1771, 1998. Sampath P, Bendebba M, Davis JD, Ducker TB: Outcome of patients treated for cervical myelopathy: a prospective, multicenter study with independent clinical review, Spine 25:670-676, 2000. Slipman CW, Lipetz JS, DePalma MJ, Jackson HB: Therapeutic selective nerve root block in the nonsurgical treatment of traumatically induced cervical spondylitic radicular pain, Am J Physical Med Rehabil 83:446-454, 2004.
associated with nonspecific symptoms and signs such as altered skin color, temperature, or sudomotor activity, allodynia, disuse atrophy, or edema; and, in contrast with CRPS type 2 (formerly called causalgia), occurs in a distribution different from that resulting from injury to a single peripheral nerve. In many cases CRPS syndromes resolve over weeks or months. Even so, the unexpected finding of persistent, worsening pain, often after seemingly minor trauma or brief limb immobilization, poses a significant psychological challenge that the clinician must keep in mind from the beginning of treatment to avoid a vicious circle of pain, distress, guarding, muscle atrophy, and increased pain susceptibility. At all stages of treatment (Figure 1), effective management of CRPS depends on a threepronged approach—rehabilitation, psychological support, and medicinal agents—probably in descending order of importance. The cornerstone of management of CRPS is physical and occupational therapy. Improvement often requires a closely supervised program of continued and increasing activity of the affected limb, while the patient is under the influence of an analgesic if necessary. In additional to active exercise of the limb, physical therapy approaches can include “desensitization,” where progressively coarser objects are rubbed across the skin of the affected limb; spinal manipulation; myofascial
CRPS Physical therapy (e.g., active mobilization, desensitization, myofascial release) NSAID Lidocaine patch/capsaicin (local only) Corticosteroids (early only)
Resolved
Unresolved Sympathetically maintained?
Yes
No
Sympatholytic trial e.g., clonidine, terazosin, tizanidine
Complex Regional Pain Syndromes
Resolved
Gabapentin Opiate Mexiletine (if acute benefit from i.v. lidocaine)
Unresolved
Resolved
Opiate tricyclic
David S. Goldstein, M.D., Ph.D. Resolved
Complex regional pain syndromes (CRPSs) come under the classification of neuropathic pain, along with entities such as postherpetic neuralgia and painful diabetic neuropathy. Distinguishing characteristics of CRPS are onset after physical trauma or limb immobilization and spread of involvement. CRPS type 1, formerly called reflex sympathetic dystrophy, refers to post-traumatic pain that spreads from the site of injury; exceeds in magnitude and duration the expected clinical course of the inciting event; progresses variably over time; is
Unresolved
Unresolved Spinal cord stimulation trial
Acute improvement
Unresolved
Spinal cord stimulator
FIGURE 1. Treatment algorithm for complex regional pain syndromes. CRPS, Complex regional pain syndrome; NSAID, nonsteroidal anti-inflammatory drug; i.v., intravenous. Johnson: Current Therapy in Neurologic Disease (7/E)
Complex Regional Pain Syndromes
Johnson: Current Therapy in Neurologic Disease (7/E)
Even in patients with repeated, temporary improvement with ganglion blocks, surgical sympathectomy does not necessarily guarantee long-term pain relief. On the contrary, patients can fail to obtain relief, the pain can recur months or years later, and the pain can spread to other limbs and body regions. By the time of establishment of chronic CRPS, mechanisms relatively independent of postganglionic sympathetic nerve traffic maintain the pain in most patients. In patients without sympathetically maintained pain, the anticonvulsant gabapentin (Neurontin) has become a first-line drug. Gabapentin can be effective to treat postherpetic neuralgia and painful diabetic neuropathy, and some uncontrolled studies have touted its value to treat CRPS. The drug has a relatively low toxicity profile, but there is a wide range of employed dosages, and no randomized, placebo-controlled trial of gabapentin for CRPS has been published yet. The same lack of controlled trials obtains for retrograde local IV injection of sympatholytic drugs, periganglionic injection of local anesthetics, systemically administered alpha-adrenoceptor antagonists, clonidine, tricyclic antidepressants, selective serotonin reuptake inhibitors, other antiepileptic drugs, ganglion blockers, mexiletine (the oral analog of lidocaine), and surgical sympathectomy; studies of these treatments have yielded disappointingly inconsistent results. Tricyclic antidepressants are often tried in CRPS. They not only can relieve pain but also can exert other beneficial effects, such as improving sleep and inducing sedation. Clinical use of tricyclics is often limited by orthostatic intolerance, dry mouth, constipation, or decreased concentration. There is recent interest in serotonin-norepinephrine reuptake inhibitors such as duloxetine in neuropathic pain, but no data are available for CRPS. Most patients with severe, chronic CRPS receive treatment with some type of opiate. Even with highdose opiate treatment, the pain, while more bearable, rarely disappears. Treatment on a continuous rather than an as-needed basis is preferred, and so long-acting agents are used, such as sustained-release oxycodone (Oxycontin), sustained-release morphine (MS Contin), methadone, and a transdermal fentanyl patch (Duragesic). Most authorities now believe that, in the absence of a history of substance abuse, neither tolerance nor addiction is an issue when opiates are prescribed for CRPS. Calcium channel blockers, beta-adrenoceptor blockers, or classic anticonvulsants are not recommended, because of lack of positive clinical experiences and frequent intolerable side effects. Stimulation of the dorsal spinal cord, via an electrode placed in the epidural space, constitutes a different treatment strategy, based on interference with transmission of impulses from the nociceptors. This approach has been used for many years in other painful conditions. A variety of ascending and descending pain pathways converge in or near the dorsal spinal cord, including a descending inhibitory noradrenergic pathway from the pontine locus ceruleus. Exactly how spinal cord stimulation relieves pain remains unclear,
Pain
release; and massage with moist heat. It is important to emphasize to the patient that physical therapy, while painful, does not worsen the injury. The distress associated with prolonged, painful treatment can exacerbate comorbid depression or anxiety; supportive psychological counseling and psychiatric drug treatments may be essential for the patient to cope with the condition and continue the rehabilitation. Psychological treatments such as relaxation, imagery, self-hypnosis, cognitive behavioral therapy, and biofeedback may help. Throughout treatment the patient should be reassured that the condition does not progress to a neurodegenerative or lethal disease and that most people with CRPS improve if they adhere to the rehabilitation program. For local pain and allodynia, topical lidocaine can be effective. Capsaicin, the alkaloid that makes red chili peppers “hot,” stimulates transient receptor potential vanilloid (TRPV1)-1 receptors on cutaneous nociceptor C-fibers. It is thought that prolonged stimulation of the TRPV-1 receptors suppresses hyperactive nociceptors to alleviate pain without loss of sensation. Although accepted treatment for other neuropathic painful conditions, capsaicin has not yet been established as effective for CRPS. Patients may find the burning sensation produced by capsaicin to be unacceptable. Mysteriously, the pain in CRPS can spread to the opposite limb or the ipsilateral other limb, which were not traumatized. Spread of pain over a relatively large area at sites distant from that of trauma mitigates benefits of local treatments such as with topical lidocaine or capsaicin. Chronic CRPS syndromes constitute miserable, frustrating disorders—for patients and clinicians. Pathophysiologic bases for the pain remain unclear; and since CRPS is a relatively rare consequence of physical trauma, the trauma itself might interact importantly with as yet unidentified predisposing or reactive factors. Recent reviews have emphasized traumatic sympathetic denervation, followed subacutely or chronically by secondary pathologic responses such as aberrant sprouting of regenerant sympathetic nerves. A variable proportion of patients with CRPS have “sympathetically maintained pain,” where the pain improves temporarily with local stellate ganglion block for an upper limb or lumbar sympathetic block for a lower limb; intravenous (IV) infusion or local injection of the alpha-adrenoceptor blocker, phentolamine; or IV infusion of the ganglion blocker trimethaphan. The finding of sympathetically maintained pain rationalizes a trial of a sympatholytic drug such as clonidine or tizanidine. These alpha2-adrenoceptor agonists act in the brain to decrease sympathetic nervous system outflows and also act at alpha2-adrenoceptors on sympathetic nerves to inhibit release of the sympathetic neurotransmitter, norepinephrine, for a given amount of sympathetic nerve traffic. The main limitation of treatment with alpha2-adrenoceptor agonists is sedation. Alpha1-adrenoceptor blockers such as terazosin may also be tried; however, these can produce substantial orthostatic intolerance or hypotension, headache, flushing, and reflexive tachycardia.
65
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Complex Regional Pain Syndromes
and several possible mechanisms are not mutually exclusive. Previous studies have reported positive results of dorsal spinal cord stimulation in alleviating pain in CRPS, especially in patients with successful trial stimulation. A recent report provides reassuring information about the long-term efficacy of spinal cord stimulation. Briefly, in a 2-year follow-up study of a randomized, controlled trial of spinal cord stimulation with physical therapy versus physical therapy alone in patients in whom conventional treatment had failed but who had had a successful test stimulation, there was long-term improvement in pain and health-related quality of life, although functional status did not change. The results confirmed and extended those from a previously reported trial that lasted 6 months. Spinal cord stimulation, therefore, seems to be an effective long-term treatment for CRPS, in patients in whom a trial stimulation alleviates the pain.
SUGGESTED READING Backonja MM: Anticonvulsants (antineuropathics) for neuropathic pain syndromes, Clin J Pain 16:S67-S72, 2000. Davis KD, Treede RD, Raja SN, et al: Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain, Pain 47:309-317, 1991. Drummond PD: Mechanism of complex regional pain syndrome: no longer excessive sympathetic outflow? Lancet 358:168-170, 2001. Hord ED, Cohen SP, Cosgrove GR, et al: The predictive value of sympathetic block for the success of spinal cord stimulation, Neurosurgery 53:626-632, 2003; discussion 632-633. Kemler MA, De Vet HC, Barendse GA, et al: The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial, Ann Neurol 55:13-18, 2004. Kingery WS: A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes, Pain 73:123-139, 1997. Kumar K, Nath RK, Toth C: Spinal cord stimulation is effective in the management of reflex sympathetic dystrophy, Neurosurgery 40:503-508, 1997; discussion 508-509. Oakley JC, Prager JP: Spinal cord stimulation: mechanisms of action, Spine 27:2574-2583, 2002.
Johnson: Current Therapy in Neurologic Disease (7/E)
SECTION 4 ●
Headache and Facial Pain Migraine and Cluster Headache B. Todd Troost, M.D.
The classification of migraine and cluster headache is presented in the second edition of the International Headache Classification published in 2004 (see Suggested Reading).
Treatment of Migraine ACUTE THERAPY A variety of acute medications may be prescribed for migraine, including the triptans, ergotamines, and analgesic medication. I avoid, as much as possible, the use of class II narcotics or excessive dependence on acetaminophen or nonsteroidal anti-inflammatory drugs. If a patient just has one headache per month that readily responds to an NSAID or two extra-strength acetaminophen, that may be sufficient. However, for more frequent acute migraine headaches, up to three per month, acute therapies may be used such as listed in Tables 1 and 2. The choice of acute treatment depends on the severity and frequency of headaches, the pattern of associated symptoms, comorbid illness, and the patient treatment response profile. The most simple treatment is with nonprescription or prescription analgesics. Most of the patients I see, however, are beyond the stage of one or two headaches per month and frequently present with chronic daily headache. I take a detailed history and attempt to verify it with a significant other of the number of analgesic medications the patient is taking. If patients are using analgesic medication more than twice a week, they tend to get rebound headache and transform their migraine into chronic daily headache. Therefore, it is imperative to determine how many extra-strength acetaminophen tablets, NSAIDs, or barbiturate-containing compounds the patient is actually consuming. Frequently, patients are taking more than 200 doses of analgesic medication per week. A determined Johnson: Current Therapy in Neurologic Disease (7/E)
effort must be made to reduce the intake of all analgesic medication. I usually start out with a request that there be a 10% reduction each week, up to 6 weeks, when the medication is to be discontinued entirely. During this time, I prescribe a preventive therapy such as that discussed later. If patients have more than two headaches per month or are not responding well to simple analgesics, I begin one of the triptrans (Table 3). The usual dosing of triptans is one as soon as possible during the onset of a migraine attack, followed by a second, if needed, in 2 hours. The nature of the attack also makes a difference. If it is an entirely predictable migraine, a slow-onset triptan, such as frovatriptan, may be appropriate versus a faster occurring attack, when sumatriptan or rizatriptan may be the preferred triptan. Patients respond differently to the triptans, and if one does not work after two or three trials, it is appropriate to shift to another triptan. The triptans that I personally use most often are (1) eletriptan, 40 mg to repeat in 2 hours, and (2) sumatriptan, 100 mg to repeat in 2 hours. As an off-label use, if I find that patients are frequently needing a second dose, I may have them double-up on the initial dose of eletriptan and take 80 mg at the onset of the migraine. It is clear, from recent studies, that the earlier into an attack that a person takes a triptan, the more likely it is that the attack can be abolished along with cutaneous allodynia. Occasionally, patients with status migrainosus may require a variety of outpatient abortive procedures, as follows, and these are listed with doses: Valproate sodium injection (Depacon 500 mg and 50 mL saline) given intravenously (IV) over 5 minutes and repeated a single time in 1 hour. Dihydroergotamine (DHE) protocol in which patients are given, first, 10 mg of metoclopramide by slow IV push followed in 15 minutes by 0.5 mg of DHE, and this can be repeated in 1 hour. If this does not break the headache, the patient may need to be admitted for the standard IV DHE protocol. Another possibility that patients can try at home, before coming to the outpatient clinic or emergency department, is subcutaneous sumatriptan in a stat dose pack such as listed in Table 3. PREVENTIVE THERAPY The decision to use preventive therapy depends on the degree of disability and the frequency and the intensity 67
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Migraine and Cluster Headache
TABLE 1 Symptomatic Therapy for Migraine
Drug
Route of Administration
NSAIDs Naproxen
PO
Ibuprofen
PO
Antiemetics* Promethazine Prochlorperazine Trimethobenzamide Metoclopramide Dimenhydrinate Mixed barbiturate analgesics Butalbital, aspirin or acetaminophen, and caffeine; butalbital and acetaminophen Narcotics (codeine-containing compounds, oxycodone, propoxyphene, meperidine)
Dosage 550-750 mg with repeat in 1-2 hr; limit three times per wk 200-300 mg with repeat in 1-2 hr; limit three times per wk
PO, IM PO Suppository IM/IV PO Suppository PO IM IV PO
50-125 mg/day 1-25 mg/day 2.5-25 mg/day 5-10 mg/day 250 mg/day 200 mg/day 5-10 mg/day 10 mg/day 5-10 mg slowly 50 mg
PO
1 or 2 tablets q 4-6 hr; limit 4 tablets per day up to twice per wk Sparingly and infrequently, if at all, in patients with chronic headaches
PO
*Given 10-20 min before ingestion of oral abortive migraine medication. NSAID, Nonsteroidal anti-inflammatory drug.
of headaches in a given patient. My current regimens are listed in Table 4. Anticonvulsants I usually begin with topiramate 25 mg, increasing weekly up to 50 to 100 mg twice a day with careful monitoring of efficacy. The primary side effects are cognitive dysfunction (∼10% to 15%), weight loss, and paresthesias (usually mild and disappearing within a few weeks).
Rare complications include hair loss, dry eyes, kidney stones, and an idiopathic form of glaucoma occurring in roughly 8 patients per 1 million. The next anticonvulsant I prescribe is levetiracetam (Keppra), and with slow titration, as described in Table 5, the main side effect of drowsiness is avoided. Levetiracetam is an excellent anticonvulsant with no significant drug-drug interactions. It is weight neutral, and in one study we performed, we found that 70% of patients with chronic daily headache had some level of improvement.
TABLE 2 Abortive Therapy for Migraine
Drug Serotonin receptor agonists Dihydroergotamine Ergotamine derivatives Ergotamine and caffeine*
Route of Administration
Dosage
IM, SC, IV
0.5-1 mL
PO
2 tablets, repeat in 1 hr if necessary; limit 4 per attack 1 tablet (let dissolve), may repeat in 30 min; limit 2 per attack 1 /2-1 suppository, repeat in 1 hr if necessary; limit two doses
Ergotamine*
Sublingual
Ergotamine and caffeine*
Suppository
Sympathomimetic agents Isometheptene, acetaminophen, dichloralphenazone Corticosteroids Dexamethasone
PO
2 capsules, may repeat in 1 hr; limit three times per wk
PO† IM†
2-6 mg; may repeat in 3 hr if necessary
*Wait 3 days between dosing with ergotamine in patients with frequent migraine or daily headache. †For protracted migraine.
Johnson: Current Therapy in Neurologic Disease (7/E)
Migraine and Cluster Headache
Drug
Trade Name
Sumatriptan
Imitrex
Naratriptan Zolmitriptan
Amerge Zomig
Rizatriptan
MaxAlt
Frovatriptan Eletriptan Almotriptan
Frova Relpax Axert
TABLE 4 Migraine Preventive Therapy
Dosage 25, 50, 100 mg PO 25 mg nasal spray and 6 mg SC 2.5 mg PO 2.5, 5 mg PO (oral melting tablet also available) 2.5 mg nasal spray 5, 10 mg PO (oral melting tablet also available) 2.5 mg PO 40 mg PO 12.5 mg PO
I use zonisamide at the dosage described in Table 5, lamotrigine, and gabapentin, in that order. I generally do not use divalproex sodium (Depakote) because of a significant tendency for weight gain, hair loss, and tremor. Botulinum Toxin Type A Mounting clinical evidence supports the use of botulinum type A (BoNT-A) in migraine and tension headache, particularly when there is a history or physical examination finding of neck muscle spasm. The discovery of the efficacy of BoNT-A in headache was serendipitous. Migraineurs who received BoNT-A injections for cosmetic reasons reported significant improvement in headache symptoms, and thereafter, an open-label multicenter trial suggested a high level of migraine relief. In prior studies, when we used a five-point categorical scale based on 1 = no effect to 5 = excellent improvement (90% reduction in headache) when we analyzed 436 patients, we found that most patients, who had previously failed three or more preventive pharmacologic therapies for migraine, had significant improvement after three or four injection cycles. Patients who were administered two treatments noted significantly greater improvement than those who were administered just a single treatment. We have now treated more than 650 patients with 2500 injection cycles and found that 75% to 80% reported improvement as good or excellent. It also
Anticonvulsants Botulinum toxin type A injections Calcium channel blockers Beta blockers Methysergide Nonsteroidal anti-inflammatory drugs Lithium Antidepressants
appeared that there was a major reduction of other analgesic medication on BoNT-A therapy. Therefore, we believe BoNT-A is a significantly promising treatment for the management of severe headache. Major placebo-controlled, double-blind studies are required to obtain U.S. Food and Drug Administration approval, and these are the results of the trials currently being analyzed. ADDITIONAL THERAPY Additional preventive therapies include calcium channel blockers and beta blockers (Table 6). For patients who have concurrent comorbidity such as Raynaud’s phenomenon, a calcium channel blocking drug may be efficacious. The dose can be gradually increased with verapamil or diltiazem as described in Table 6. Patients must be warned about the possibility of constipation (less with diltiazem) and should be evaluated for the possibility of cardiomyopathy or the history of congestive heart failure because these are both contraindications of the use of a calcium channel blocking drug. Beta blockers (see Table 6) such as propranolol and timolol have had the longest trial of preventive use; however, there is a significant incidence of depression in women, and I personally find the efficacy not as good as with the anticonvulsants.
Cluster Headache The characteristics of cluster headache, now classified as one of the autonomic cephalalgias, is discussed in the International Headache Society publication listed in the Suggested Reading. Cluster headache is extremely
TABLE 5 Anticonvulsants for Migraine Therapy Generic Name Topiramate Levetiracetam Zonisamide Lamotrigine Gabapentin Divalproex sodium
Trade Name
Dosage
Topamax Keppra Zonegran Lamictal Neurontin Depakote
25 mg daily times 1 wk, increasing to 200 mg/day, average 100 mg/day 500 mg,1/2 qhs increased by 1/2 pill each week, to 11/2 pills bid, may increase up to 3000 mg 100 mg daily times 1 wk, then 200 mg/day, to be increased to 300 mg/day in single dose 25 mg, 2 tablets at night for 2 wk, then increase by 25 mg q 1-2 wk to ≥100-200 mg 100-300 mg, 1-3/day to ≥1200 mg 250 mg, 1 tablet tid to 1.5 gm/day
Johnson: Current Therapy in Neurologic Disease (7/E)
Headache and Facial Pain
TABLE 3 Triptans
69
4
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Chronic Daily Headache
TABLE 6 Additional Pharmacologic Migraine Therapy Generic Name Calcium channel blockers Verapamil Diltiazem Beta blockers Propranolol Timolol
Trade Name
Dosage
Inderal Cardizem
120 mg/day, increasing to 600 mg/day 120 mg bid, increasing to 720 mg/day
Verelan Blocadren
10 mg tid, increasing to 180 mg/day 5 mg bid, increasing to 40 mg/day
difficult to treat. I use most of the standard preventive therapies such as calcium channel blocking drugs or anticonvulsants as initial starting therapy. Nasal oxygen (8 to 10 L/min) may be helpful at the start of a series of cluster headaches. However, I have found that most patients with recurrent cluster headache do not respond to these therapies and need to be treated with other agents such as methysergide (Sansert). The methysergide dosage should be 2 mg once to three times per day, and the patient should be given a drug-free month once every 6 months to reduce the likelihood of retroperitoneal fibrosis. Rarely, I have also used lithium in the form of Lithobid 300 mg one or two times per day. Patients may experience tremor and should have lithium levels checked at least monthly and not be on concurrent therapy with calcium channel blocking drugs. Finally, in selected patients, I have used BoNT-A with modest success in approximately 25% of the patients. SUGGESTED READING Headache Classification Subcommittees of the International Headache Society: The international classification of headache disorders: 2nd edition, Cephalalgia 24(Suppl 1):9-160, 2004. Troost BT: Botulinum toxin type A (Botox) in the treatment of migraine and other headaches, Expert Rev Neurother 4:27-31, 2004. Goadsby PJ, Lipton RB, Ferrari MD: Migraine: current understanding and treatment, N Engl J Med 346:257-270, 2002.
PATIENT RESOURCE http://www.imigraine.net/
Chronic Daily Headache Jonathan P. Gladstone, M.D., and David W. Dodick, M.D.
Chronic daily headache (CDH) is a significant public health problem affecting 3% to 5% of the population worldwide. The treatment of patients with CDH can be both challenging and immensely rewarding. Effective management requires a systematic approach to diagnosis and treatment.
Definition What is CDH? CDH is a symptom rather than a diagnosis. CDH simply refers to the presence of headache on 15 or more days per month for more than 3 months. There are many primary and secondary causes of CDH. The International Headache Society (IHS) classification of headache disorders recently developed operational diagnostic criteria for primary and secondary CDH disorders (see Suggested Reading).
Epidemiology The population prevalence of CDH is 3% to 5%, whereas the prevalence within U.S. headache centers approaches 80%. The annual incidence of CDH in the general population is approximately 3%. The disability associated with primary forms of CDH is substantial. These patients experience significant impairment in health-related quality of life and in physical and mental health, as well as decreased social and occupational functioning.
Approach to the Patient with Chronic Daily Headache In most cases, CDH is attributable to primary headache disorders. However, clinicians need to be vigilant in excluding secondary causes of headaches in this population (Table 1). A thorough history is the most critical aspect of the evaluation and provides the diagnosis or guides the evaluation in most cases. Clinical evaluation should always address the possibility of elevated or low intracranial pressure, a chronic infectious or inflammatory disease, a space-occupying lesion, or symptomatic medication overuse. In the absence of red flags in the history or physical examination, a secondary cause can usually be eliminated (Table 2). Next, the question “How long do the patient’s individual headaches last if left untreated?” narrows the primary CDH subtypes into two discrete categories—short lasting (4 hours) (Figure 1). By recognizing the distinctive clinical features of the common primary CDH subtypes, a specific diagnosis can be made and appropriate treatment initiated in most patients. Johnson: Current Therapy in Neurologic Disease (7/E)
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Chronic Daily Headache
TABLE 6 Additional Pharmacologic Migraine Therapy Generic Name Calcium channel blockers Verapamil Diltiazem Beta blockers Propranolol Timolol
Trade Name
Dosage
Inderal Cardizem
120 mg/day, increasing to 600 mg/day 120 mg bid, increasing to 720 mg/day
Verelan Blocadren
10 mg tid, increasing to 180 mg/day 5 mg bid, increasing to 40 mg/day
difficult to treat. I use most of the standard preventive therapies such as calcium channel blocking drugs or anticonvulsants as initial starting therapy. Nasal oxygen (8 to 10 L/min) may be helpful at the start of a series of cluster headaches. However, I have found that most patients with recurrent cluster headache do not respond to these therapies and need to be treated with other agents such as methysergide (Sansert). The methysergide dosage should be 2 mg once to three times per day, and the patient should be given a drug-free month once every 6 months to reduce the likelihood of retroperitoneal fibrosis. Rarely, I have also used lithium in the form of Lithobid 300 mg one or two times per day. Patients may experience tremor and should have lithium levels checked at least monthly and not be on concurrent therapy with calcium channel blocking drugs. Finally, in selected patients, I have used BoNT-A with modest success in approximately 25% of the patients. SUGGESTED READING Headache Classification Subcommittees of the International Headache Society: The international classification of headache disorders: 2nd edition, Cephalalgia 24(Suppl 1):9-160, 2004. Troost BT: Botulinum toxin type A (Botox) in the treatment of migraine and other headaches, Expert Rev Neurother 4:27-31, 2004. Goadsby PJ, Lipton RB, Ferrari MD: Migraine: current understanding and treatment, N Engl J Med 346:257-270, 2002.
PATIENT RESOURCE http://www.imigraine.net/
Chronic Daily Headache Jonathan P. Gladstone, M.D., and David W. Dodick, M.D.
Chronic daily headache (CDH) is a significant public health problem affecting 3% to 5% of the population worldwide. The treatment of patients with CDH can be both challenging and immensely rewarding. Effective management requires a systematic approach to diagnosis and treatment.
Definition What is CDH? CDH is a symptom rather than a diagnosis. CDH simply refers to the presence of headache on 15 or more days per month for more than 3 months. There are many primary and secondary causes of CDH. The International Headache Society (IHS) classification of headache disorders recently developed operational diagnostic criteria for primary and secondary CDH disorders (see Suggested Reading).
Epidemiology The population prevalence of CDH is 3% to 5%, whereas the prevalence within U.S. headache centers approaches 80%. The annual incidence of CDH in the general population is approximately 3%. The disability associated with primary forms of CDH is substantial. These patients experience significant impairment in health-related quality of life and in physical and mental health, as well as decreased social and occupational functioning.
Approach to the Patient with Chronic Daily Headache In most cases, CDH is attributable to primary headache disorders. However, clinicians need to be vigilant in excluding secondary causes of headaches in this population (Table 1). A thorough history is the most critical aspect of the evaluation and provides the diagnosis or guides the evaluation in most cases. Clinical evaluation should always address the possibility of elevated or low intracranial pressure, a chronic infectious or inflammatory disease, a space-occupying lesion, or symptomatic medication overuse. In the absence of red flags in the history or physical examination, a secondary cause can usually be eliminated (Table 2). Next, the question “How long do the patient’s individual headaches last if left untreated?” narrows the primary CDH subtypes into two discrete categories—short lasting (4 hours) (Figure 1). By recognizing the distinctive clinical features of the common primary CDH subtypes, a specific diagnosis can be made and appropriate treatment initiated in most patients. Johnson: Current Therapy in Neurologic Disease (7/E)
Chronic Daily Headache
TABLE 2 Daily Headache: Red Flags for Secondary Causes
Primary Short lasting (4 hr) Chronic migraine Chronic tension type Hemicrania continua New daily persistent type
Factor
Comments
Onset age >50 years
Consider giant cell arteritis, brain tumor (primary or secondary), or subdural hematoma Chronic meningitis (tubercular, fungal, or parasitic infection) Sinusitis (sphenoid sinusitis may occur without nasal symptoms) Vasculitis (primary CNS or secondary to other inflammatory/rheumatologic conditions) Giant cell arteritis —
Secondary Medication related Medication overuse Drug side effects Vascular Giant cell arteritis Subdural hematoma Ischemic or hemorrhagic stroke Venous sinus thrombosis Arterial dissection Severe arterial hypertension Infectious Meningitis (viral, bacterial, tubercular, fungal, parasitic) Sinusitis (sphenoid) Disorders of intracranial pressure Increased intracranial pressure (primary or secondary tumor, idiopathic intracranial hypertension, hydrocephalus) Decreased intracranial pressure (spontaneous intracranial hypotension, post-lumbar puncture headache) Structural Attributable to cervical spine disorders Attributable to TMJ/dental pathology Post-traumatic Attributable to head injury Attributable to neck injury or whiplash Metabolic Hypoxia, hypercarbia Obstructive sleep apnea Carbon monoxide Thyroid disease TMJ, Temporomandibular joint; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
Primary CDH
Presence of fever or systemic symptoms
Focal neurologic symptoms or signs Precipitated by positional changes, Valsalva maneuver, bending or coughing
History of cancer, immunocompromise, or HIV infection Progressive headache or escalating medication requirements
If worse when standing, consider spontaneous intracranial hypotension If worse when supine, consider increased intracranial pressure and/or posterior fossa pathology Be wary of metastatic disease or intracranial infection Re-evaluate original diagnosis, and consider a secondary cause Always be on the lookout for caffeine or medication overuse headache
CNS, Central nervous system; HIV, human immunodeficiency virus.
distribution of the pain and the accompanying cranial autonomic features. These syndromes must be differentiated from each other because they are each treated in a different manner (Table 3). The important treatment implications are the exquisite response of chronic paroxysmal hemicrania to indomethacin, and the preferred use of second- or third-generation anticonvulsants (gabapentin, lamotrigine, topiramate) for SUNCT syndrome.
SHORT-DURATION ( 4 hours)
Short duration (< 4 hours)
• Chronic cluster headache (CCH) • Chronic paroxysmal hemicrania (CPH) • Hypnic headache (HH) • SUNCT syndrome
• Chronic migraine (CM) • Chronic tension type headache (CTTH) • New daily persistent headache (NDPH) • Hemicrania continua (HC)
– Autonomic
+ Autonomic
– Autonomic
+ Autonomic
• Hypnic Headache
• CCH • CPH* • SUNCT
• CM • CTTH • NDPH
• HC*
Onset < 3 days
Gradual onset
• NDPH
• CM • CTTH
See Table 3
* Indomethacin responsive Autonomic – cranial autonomic symptoms
FIGURE 1. Approach to chronic daily headache: narrowing the differential diagnosis based on the duration of individual headaches. SUNCT, Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
cluster headache. Recently, trials in patients with episodic cluster headache demonstrated good efficacy with intranasal sumatriptan (20 mg) and intranasal zolmitriptan (5 mg). Inhalational oxygen, administered via face mask at 10 to 15 L/min for at least 15 minutes, is effective in up to 70% of patients. Practically, the need for an oxygen canister and regulator makes this modality cumbersome for some patients. Dihydroergotamine (DHE) administered intravenously (IV), subcutaneously, or intranasally is also effective, although there are few data from randomized, controlled trials. For some patients, especially those who cannot use or tolerate
vasoconstrictive drugs such as triptans or DHE, intranasal lidocaine 4% may be effective. Prescription analgesics or opioids are not effective and may lead to medication overuse headache and central nervous system side effects. An effective preventive regimen for patients with cluster headache is crucial because attacks often occur daily for months or years (Table 4). Corticosteroids usually provide swift relief from attacks. Prednisone can be initiated at 60 mg/day for 3 days followed by 10-mg decrements every 3 days. Blockade of the ipsilateral occipital nerve can suppress attacks for up to 2 weeks in as many
TABLE 3 Differentiating Features of the Trigeminal Autonomic Cephalalgias Feature
Cluster
CPH
SUNCT
Gender (male/female) Attack duration Attack frequency Autonomic features Alcohol ppt First-line treatment
4:1 15-180 min 1-8/day ++ ++ Verapamil
1:3 2-45 min 1-40/day ++ + Indomethacin
4:1 5-250 sec 1/day-30/hour ++ + Lamotrigine gabapentin
CPH, Chronic paroxysmal hemicrania; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
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Chronic Daily Headache
Transitional (1-2 wk) Prednisone 60 mg qd for 3 days, then 10-mg decrements q 3 days (18 days) Ergotamine tartrate 1-2 mg PO/suppository qd (qhs or divided dosage) D.H.E-45 0.5-1 mg SC/IM q 8-12 hr Occipital nerve blockade (e.g., 3-5 mL 0.5% bupivacaine + 10-20 mg Depo-Medrol) Maintenance (duration of cluster period, usually 2-3 mo) Verapamil 80 mg tid or 240 mg SR; up to 720 mg/day Methysergide 2 mg tid; up to 12 mg/day Lithium carbonate 150-300 mg tid or 450 mg SR Valproic acid 500-2000 mg/day in divided dosages Topiramate 50-150 mg in divided daily dosages Adjunctive Melatonin 10 mg PO qhs Indomethacin 25-50 mg tid Gabapentin 300-1200 mg tid
as two thirds of patients and avoid the potential side effects associated with oral corticosteroids. Occipital nerve blockade can be achieved with 3 mL of 0.5% bupivacaine combined with 10 to 20 mg of methylprednisolone or another long-acting corticosteroid. IV DHE with repetitive infusions every 8 to 12 hours over a 1- to 2-day period can provide significant relief; however inpatient admission or an outpatient infusion center is required. Verapamil should be considered the first-line preventive agent for both episodic and chronic cluster headache. After a baseline electrocardiogram (ECG) the initial starting dose is 80 mg three times a day, or one can titrate to this dose over 3 to 5 days. Titration, as needed, should occur in 80-mg intervals every 3 to 7 days. For doses above 480 mg/day, an ECG is required prior to each dose escalation. If partial benefit is obvious at this dose, some patients may become cluster free at higher dosages (≤720 mg). If side effects occur (significant constipation, fatigue, gastrointestinal symptoms, hypotension, edema), we recommend decreasing the dose and adding a second-line agent such as melatonin, topiramate, or gabapentin. Although two open-label studies with divalproic acid for chronic cluster headache were encouraging, a recent placebo-controlled study failed to show a significant difference (though the placebo response in this study was unusually high). Beta blockers and tricyclic antidepressants have no role in the treatment of chronic cluster headache. Although quite effective, lithium carbonate and methysergide are typically reserved as third-line agents due to their potential for significant side effects and systemic toxicity, difficulty with dose titration, and access issues (methysergide is no longer available in the United States). Patients on methysergide require a 1-month “drug holiday” every 6 months and regular screening for retroperitoneal/ pleural/pericardial fibrosis. Testing usually requires an echocardiogram, computed tomographic scan of the chest and abdomen, serum creatinine, erythrocyte sedimentation rate, and urinalysis. Johnson: Current Therapy in Neurologic Disease (7/E)
A number of other agents have been reported in small open-label studies or within case reports to have demonstrated efficacy in patients with cluster headache. These include methylphenidate, pizotifen, indomethacin, antispasticity drugs (tizanidine and baclofen), clonidine, diltiazem, flunarizine, histamine, somatostatin, and intranasal capsaicin. There is a paucity of clinical experience with most of these drugs in patients with cluster headache, and because of the lack of data, further evidence is needed before recommendations can be made to support their routine use in cluster headache. However, consideration of all medical options should be given in patients with treatment-resistant cluster headache before an ablative surgical procedure is attempted. For individuals who fail medical management or develop unacceptable side effects and are psychologically stable, surgical options are available. Multiple surgical interventions have been proposed, but the results are best and experience is greatest with those procedures directed at the sensory portion of the trigeminal nerve. These include percutaneous radiofrequency, glycerol or balloon rhizolysis, and trigeminal root sectioning. Each of these procedures is irreversibly destructive with the potential for significant neurologic morbidity. Two emerging surgical options for patients with refractory chronic cluster headache are available in select research centers—deep brain stimulation and occipital nerve stimulation. Ipsilateral posteroinferior hypothalamic stimulation has been found to be relatively safe and effective in patients with medically intractable chronic cluster headache. However, fatal iatrogenic cerebral hemorrhage occurred in one patient, reminding us of the potential for serious neurologic morbidity and mortality associated with this procedure. Occipital nerve stimulation may represent an effective and minimally invasive procedure for patients with chronic cluster headache. Thus far, only two patients with chronic cluster headache have been treated, both with good results, and further investigation into the effectiveness of occipital nerve stimulation for patients with chronic migraine and cluster headache is under way. Chronic Paroxysmal Hemicrania and Hemicrania Continua Chronic paroxysmal hemicrania and hemicrania continua are typically responsive to indomethacin in dosages ranging between 25 and 75 mg three times a day. Hemicrania continua is a continuous exclusively unilateral headache that is punctuated by severe exacerbations lasting hours to days. These patients also experience one or more cranial autonomic symptoms, often during painful exacerbations. Patients typically notice complete relief within 48 hours, and once a stable dose is obtained, patients can be switched to a once-daily dosage with the slow-release formulation. If indomethacin is not effective, the diagnosis should be revisited. If indomethacin is poorly tolerated or contraindicated, alternative treatment options include other nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen, sulindac, diclofenac, aspirin, cyclooxygenase-2 inhibitors, and verapamil, and brief courses of corticosteroids.
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TABLE 4 Treatment for Cluster Headache
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SUNCT Until recently, SUNCT syndrome has been notoriously difficult to treat effectively. An initial trial of indomethacin, especially if there is diagnostic uncertainty, is warranted. Lamotrigine should be considered first-line therapy. Second-line therapies include gabapentin and topiramate. Hypnic Headache Hypnic headache is a unique headache entity occurring mainly in the elderly and exclusively during sleep. The headache is generally bilateral, moderately severe, and lasts between 15 and 120 minutes. Patients generally feel better upright, and there are no cranial autonomic symptoms—features that distinguish this disorder from cluster headache, which can also awaken patients from sleep. Paradoxically, caffeine before bed is often effective and should be tried initially either in the form of a caffeinated beverage or tablet. Lithium, melatonin, and indomethacin all have demonstrated benefit in patients with hypnic headache. LONG-DURATION (>4 HOURS) CHRONIC DAILY HEADACHES Chronic Migraine and Transformed Migraine Chronic migraine is characterized by headaches fulfilling the criteria for migraine without aura on more than 15 days per month for more than 3 months in the absence of medication overuse. Most headache specialists in North America use the Silbsertein-Lipton criteria for transformed migraine (TM) since they are more sensitive and relevant to the CDH patients seen in U.S. clinics (Table 5). Patients with transformed migraine usually have a history of episodic migraine that gradually transforms to chronic migraine, although this transformation may be abrupt in up to 15% of patients.
TABLE 5 Transformed Migraine: Silberstein-Lipton Criteria Type
Description
A
Daily or almost daily (>15 days/mo) head pain for > 1 mo Average headache duration of > 4 hr/day (if untreated) At least one of the following: (1) History of any form of episodic migraine meeting IHS criteria 1.1-1.6* (2) History of increasing headache frequency with decreasing severity of migrainous features over at least 3 mo (3) Headache at some time meets HIS criteria for migraine other than duration Does not meet criteria for new daily persistent headache or hemicrania continua
B C
D
*”IHS criteria” refers to International Headache Society classification (see Suggested Reading).
Patients with transformed migraine often require aggressive management with both nonpharmacologic and pharmacologic treatment modalities. Migraineurs are often exquisitely sensitive to internal and external stimuli. Therefore, regulating daily activities (e.g., regular mealtimes and sleep schedules) and avoiding identifiable triggers are important. Anxiety and attention to pain results in inhibition of antinociceptive brainstem structures such as the periaqueductal gray matter. Therefore, training in relaxation, biofeedback, stress management, and cognitive-behavioral therapy allow patients to exert control over physiologic responses that may influence pain modulation. The efficacy of these techniques has been demonstrated in multiple welldesigned clinical trials in patients with episodic migraine and received a grade A recommendation in the U.S. Headache Consortium Guidelines and American Academy of Neurology Practice Parameter. Preventive therapy should be considered for patients with transformed migraine whether or not symptomatic medication overuse is present. Although the most frequently prescribed preventive medications for episodic migraine in North America continue to be the beta blockers and tricyclic antidepressants, evidence has emerged over the last decade for novel formulations of older anticonvulsants (divalproic acid extended-release); for newer, second-generation anticonvulsants (e.g., topiramate, gabapentin); and for botulinum toxin type A (BoNT-A) for the treatment of both episodic and chronic migraine. Although most studies have been with episodic migraine, these agents are, and will continue to be, widely used in practice to treat patients with chronic migraine in the absence of evidence from randomized, controlled data to the contrary. Medication Overuse Headache Medication overuse headache (rebound headache) is a common and disabling headache disorder characterized by the generation, perpetuation, or maintenance of CDH, caused by the frequent and excessive use of immediaterelief (symptomatic) medications. Patients with medication overuse headache frequently have a history of episodic migraine that has been transformed into CDH as a result of symptomatic medication overuse. In susceptible individuals the frequent, neardaily, or daily use of simple analgesics (aspirin or acetaminophen), combination analgesics (containing caffeine, codeine, or barbiturates), opioids, ergotamine, or triptans may transform an episodic pattern of headache into one that occurs daily. Characteristic features of medication overuse headache have been well described (Table 6) and the IHS has developed operational criteria for the diagnosis of medication overuse headache (Table 7). Medication overuse headache is a retrospective diagnosis made when the offending agent is withdrawn and the headache pattern ceases to be daily. This process generally takes weeks to months. However, daily headache is not synonymous with analgesic overuse, and many patients with transformed migraine, chronic tensiontype headache, and new daily persistent headache do not overuse symptomatic medications. It is these patients Johnson: Current Therapy in Neurologic Disease (7/E)
Chronic Daily Headache
Frequency of headaches increases insidiously over time Patients often awake in the early morning with headache A proportion of individual headache attacks may become nondescript (lose the characteristic “migrainous” features) Lowered threshold for precipitating headache exacerbations (concentration, minimal exertion, anxiety) Escalating doses of symptomatic medications required for headache relief Headaches occur within a predictable period after the last consumption of symptomatic medication, usually with reduced efficacy
who continue to have daily headache even after analgesics are discontinued. Familiarity and comfort with drug withdrawal and detoxification strategies are essential for the treatment of patients with medication overuse headache (Table 8). Patients with CDH who overuse acute symptomatic medications must discontinue or taper the overused medication due to the possibility of tolerance; habituation and dependence; the potential for renal, hepatic, or gastrointestinal side effects; and the possibility that medication overuse may neutralize the effectiveness of prophylactic medications. In the absence of prospective, placebo-controlled, randomized studies evaluating the different treatment modalities for medication overuse headache or the efficacy of medication withdrawal alone, treatment strategies are based on case reports, case series, retrospective chart reviews, and expert opinion. Treatment of medication overuse headache may occur in the outpatient setting or at an infusion center, or it may require hospitalization. Hospitalization is
TABLE 7 Headache Attributed to Medication Overuse: IHS Criteria* Type
Comments
A
Headache present on >15 days/mo, fulfilling criteria C and D Characteristics depend on drug Regular overuse of a medication for > 3 mo Ergotamine, triptans, opioids, and combination analgesics ≥ 10 days/mo Simple analgesics ≥ 15 days/mo Total exposure to symptomatic medications ≥ 10 days/mo Headache has developed or markedly worsened during medication overuse Headache resolves or reverts to its previous pattern within 2 mo after discontinuation of overused medication
B
C D
*”IHS criteria” refers to International Headache Society classification (see Suggested Reading).
Johnson: Current Therapy in Neurologic Disease (7/E)
typically reserved for patients overusing opioids, barbiturates, or benzodiazepines; those with severe psychiatric comorbidity; or those who have failed previous withdrawal attempts as an outpatient (Table 9). Most patients can be managed as outpatients. The first stage of treatment involves headache education, particularly regarding the role of medication overuse in the patient’s CDH. Comorbid depression and anxiety need to be addressed concurrently. Biobehavioral education with training in relaxation techniques and biofeedback is often helpful to allow patients to achieve an internal locus of control. Modifications of lifestyle habits must be made including, but not limited to, decreasing caffeine consumption, increasing exercise, incorporating stress management strategies, and improving sleep hygiene. Patients should always be provided with support and close follow-up and provided with the realistic expectation that they may feel worse before they feel better. In parallel, simple analgesics, ergotamines, triptans, and most combination analgesics can be abruptly discontinued, whereas opioids and butalbital containing analgesics should be gradually tapered. To alleviate potential side effects from barbiturate withdrawal, a long-acting barbiturate alternative (phenobarbital) may be substituted and tapered; similarly to avoid complications from opioid withdrawal, low doses of clonidine may be considered. Patients should be provided with
TABLE 8 Treatment of Medication Overuse Headache Education and support with follow-up Encourage healthful behavior (smoking, exercise, meals, sleep, caffeine) Biobehavioral therapy (relaxation therapy, biofeedback) Abrupt withdrawal of overused acute medications except barbiturates, opioids, or benzodiazepines Butalbital overuse (taper over 2-4 wk; if concern for withdrawal syndrome, provide tapering course of phenobarbital 30 mg bid for 2 wk followed by 15 mg bid for 2 wk) Opioid overuse (taper over 2-4 wk; if concern for withdrawal, clonidine transdermal patch for 1-2 wk) Relief of worsening/breakthrough headache Prednisone 60 mg for 3 days; decrease by 10 mg q 3 days NSAIDs (ketoprofen 50-100 mg; naproxen sodium 550 mg; ibuprofen 600-800 mg) Antiemetics (metoclopramide 10-20 mg, prochlorperazine 10 mg or 25 mg suppository) SC or IM DHE 1 mg Triptans (if not drug being overused ) Preventive drug therapy Amitriptyline 25-100 mg qhs Divalproex sodium ER 500-2000 mg Topiramate 50-200 mg Gabapentin 900-3600 mg Botulinum toxin type A Tizanidine 4-16 mg qhs Fluoxetine 20-60 mg NSAID, Nonsteroidal anti-inflammatory drug; DHE, dihydroergotamine.
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TABLE 6 Features of Medication Overuse Headache
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TABLE 9 Treatment of Medication Overuse Headache Indications Failure of outpatient treatment High consumption of opioids, butalbital, or benzodiazepines Significant psychological or behavioral disturbances Significant coexistent medical illnesses Protocols Repetitive IV infusions q 8 hr for 2-4 days Dihydroergotamine 0.5-1 mg plus metaclopramide 10-20 mg or prochlorperazine 10 mg Prochlorperazine 10 mg Divalproex sodium 6.4 mg/kg Methylprednisolone 250-500 mg q 12 hr Initiate taper/withdrawal symptomatic medications overused (clonidine, phenobarbital) Initiate preventive therapy
symptomatic agents in limited doses (e.g., long-acting NSAIDs, DHE, triptans, or steroids) from drug classes other than those which they are overusing to alleviate withdrawal symptoms (headache, nausea, vomiting, arterial hypotension, tachycardia, sleep disturbances, restlessness, and nervousness). Withdrawal symptoms typically last from 2 to 10 days. For patients requiring more aggressive treatment, various strategies have been advocated including parenteral DHE, methylprednisolone, neuroleptics, or divalproex sodium acid. After initial detoxification, alternative acute medications to treat breakthrough attacks are provided in strictly limited doses. Prophylactic pharmacotherapy is initiated from the outset. There is no evidence base on which to make prophylactic therapy decisions in the medication overuse headache population, but reasonable options include amitriptyline, divalproex sodium, topiramate, botulinum toxin type A, fluoxetine, and tizanidine (see Table 4). The goal of withdrawal or detoxification therapy for medication overuse headache is to eliminate daily or neardaily medication use, to restore an episodic pattern of headache, and to establish an effective preventive and acute (symptomatic) treatment strategy. In patients with a long-standing history of near-daily or daily headache, it may be unrealistic to expect restoration of pain-free intervals. In these patients, the objective becomes to reduce the intensity of daily pain, to restore the patient’s ability to function, and to provide an effective strategy for acute management of severe headaches. Significant relapse rates estimated at 1 (20%) and 5 years (50%) highlights the need for ongoing follow-up care. Chronic Tension-Type Headache Chronic tension-type headache is seen much less commonly in neurologic practice than chronic migraine. Typically the syndrome evolves after years of episodic tension-type headache. First-line treatments for chronic tension-type headache include nonpharmacologic therapy such as relaxation, stress reduction, and biofeedback
as well as pharmacologic therapy with tricyclic antidepressants. New Daily Persistent Headache New daily persistent headache is characterized by a constant and unremitting headache of acute onset (developing over 1–3 months after resolution of skin lesions
• Acyclovir 10 mg/kg q8h (adults) or 500 mg/m2 body surface (children) for 7 days. • Prednisone 60–80 mg/day for 3–5 days • Stop treatment if negative zoster PCR in the CSF.
Systemic
Acyclovir: PO: 800 mg five times daily for 7 to 10 days IV: 10 mg/kg every 8 hours for 7 to 10 days or Famciclovir: 500 mg orally three times daily for 7 days or Valacyclovir: 1,000 mg orally three times daily for 7 days ± Prednisone: 30 mg orally twice daily for 7 days then 15 mg twice daily for 7 days then 7.5 mg twice daily for 7 days ± Amitriptyline: elderly: 10 mg qhs, others 20 mg qhs. Titrate up to 100–150 mg/day qd if needed and tolerated
Chronic pain postherpetic neuralgia (PHN)
• Lidocaine patch 5%, 12h on, 12h off; up to 3 patches at a time (minimum of 2 weeks trial) • Capsaicin 0.075%. Initial exacerbation of pain limits its use.
Systemic
NSAIDs + adjuvants: Gabapentin: 300 mg/day for 3 days, then b.i.d. for 3 days, then t.i.d., then double. If additional benefit then continue titration up to 3600 mg/day. • If side effects Tiagabine: 150–300 mg/day • If no effect Amitriptyline (if already on it, titrate) elderly: 10 mg qhs, others 20 mg qhs. Titrate up to 100–150 mg/day q.d. if needed and tolerated • If no effect or side effects Newer anticonvulsants (topiramate, levetiracetam, lamotrigine, oxcarbazepine) or other antidepressants (desipramine, nortriptyline) ± Opioids: May use at initiation of treatment for intense pain. Oxycodone 5 mg tabs q 4h. Once taking >20 mg q.d. introduce long-acting form.
No response or intolerable side effects
• Nerve blocks • Spinal cord stimulation • Intrathecal methylprednisolone
FIGURE 1. Algorithm for approach to the treatment of herpes zoster. PCR, Polymerase chain reaction; CSF, cerebrospinal fluid; CNS, central nervous system; NSAIDs, nonsteroidal anti-inflammatory drugs.
has been elusive for many years, recently it has been shown to bind to the alpha2-delta subunits of the voltage-sensitive calcium channels. Its pharmacokinetic profile (with renal excretion) makes it safe in patients taking a variety of medications. Since only 10% binds to plasma proteins, the drug has little effect on the Johnson: Current Therapy in Neurologic Disease (7/E)
Headache and Facial Pain
Herpes zoster ophthalmicus (keratitis/retinitis) Early referral to ophthalmology IV acyclovir 10 mg/kg every 8 h for 7 to 14 days Prevention of corneal exposure
Herpes zoster (shingles)
CNS involvement (myelitis/angiitis)
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international normalized ratio in patients on warfarin (Coumadin) anticoagulation. The liver does not metabolize gabapentin; hence, it does not compete for the P-450 with the selective serotonin receptor inhibitors. The dose may need to be reduced in patients with elevated creatinine.
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Pregabalin In a double-blind, placebo-controlled clinical trial, pregabalin in doses ranging from 150 to 300 mg/day reduced pain scores by more than 50% in patients with PHN. The mechanism of action and side effect profile are similar to those of gabapentin. However, since it has a linear pharmacokinetic profile, there is less interindividual variability and the dose range is more narrow and predictable. It also may have fewer side effects than gabapentin. Other Anticonvulsants When an adequate response is not achieved or in the presence of unacceptable side effects, trials with other anticonvulsants can be attempted. Topiramate, lamotrigine, levetiracetam, zonegram, and tiagabine have been shown to be of help in certain forms of neuropathic pain, and they may be helpful in the treatment of PHN. Both carbamazepine and phenytoin have been used in the past with some degree of success, but their use has been relegated to second- or third-line agents due to the high incidence and severity of side effects. ANTIDEPRESSANTS Amitriptyline Among the tricyclic antidepressants, amitriptyline is the most extensively studied. In a double-blind, placebocontrolled clinical study, amitriptyline showed significant pain relief in patients with PHN. Unfortunately the tricyclics may cause dose-limiting side effects due to their anticholinergic activity. Side effects (dry mouth, impotence, constipation, urinary retention, tachycardia, confusion) may be ameliorated by starting at low doses, slow titration, and night administration when possible. Side effects are more prominent in the elderly. The starting dose is 10 to 20 mg and because of potential somnolence and sedation, it should be given at bedtime. This side effect may be of help in patients with insomnia, a common comorbidity in chronic pain patients. On occasion, doses of 100 to 150 mg a day may be necessary. When dosing above 75 to 100 mg a day (or lower if side effects are observed), blood levels should be determined to avoid toxicity. Desipramine, a tricyclic with less severe anticholinergic effects, and nortriptyline have also been shown to be effective in controlled studies for the treatment of PHN. OPIOIDS Depending on the intensity of the pain, opioids may need to be introduced early in the treatment plan for both herpes zoster and PHN. A placebo-controlled clinical study with the extended form of oxycodone has shown significant pain relief in patients with PHN. The opioids, when used in the right context, can be a valuable tool. The patient must be warned of the potential side effects, which include physical dependence, constipation, nausea/vomiting, sedation, and the potential for addiction. If certain guidelines are followed (patient
cannot change dosing on his or her own, only one practitioner writes the prescriptions, utilization of only one pharmacy, frequent assessments), they are safe to use. Patients with a history of drug abuse can represent a unique challenge. When treating patients who are attending a methadone program, it is advisable to discuss the plan with the methadone maintenance treatment program clinic counselor and use methadone for the treatment of pain. Methadone is an interesting drug that, due to its low cost and long half-life, has been advocated for the treatment of chronic pain. The formulation available in the United States is a racemic form. While the L-enantiomer activates mu opioid receptors inducing analgesia, the D-enantiomer blocks (weakly) N-methyl-D-aspartate–mediated excitatory responses, believed to be exacerbated in neuropathic pain. Urine toxicology, pill counting, and contracts are useful tools that have to be tailored to the patient. LOCAL ANESTHETICS Topical Lidocaine Double-blind, placebo-controlled trials with lidocaine 5% in a patch form have been shown to alleviate pain in PHN. Up to three patches can be used at a given time. The patches should be used 12 hours on and 12 hours off. No significant side effects have been observed with this regimen. The patch can be used alone or in combination with other adjuvants (e.g., gabapentin). The combination of the lidocaine patch with gabapentin has proved to be more effective than the two agents separately. Intravenous Lidocaine The pain crisis may be managed with intravenous (IV) administration of lidocaine. This procedure can be done on an outpatient basis. When pain scores improve more than 50%, oral mexiletine can be initiated. The IV dose is converted into an equivalent oral dose, and the titration up can be continued by 150 mg at a time every 3 to 4 days if tolerated. Patients may require up to 400 to 500 mg a day to experience relief. Capsaicin Capsaicin 0.075% cream has been shown to decrease pain. The initial application may temporarily exacerbate pain possibly due to depletion of substance P or activation of nociceptors, which frequently results in abandonment of treatment.
Conclusion Although the literature is not conclusive, it is recommended to treat herpes zoster infection aggressively to decrease PHN. No single best treatment for PHN is known. Both topical and systemic therapies can be initiated simultaneously. If the pain is very intense, opioids can be initiated early into the regimen. Johnson: Current Therapy in Neurologic Disease (7/E)
Herpes Zoster and Postherpetic Neuralgia
Davis PS, Gailor BS: Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia, Drugs 64:937-947, 2004. Dworkin RH, Schmader KE: Epidemiology and natural history of herpes zoster and postherpetic neuralgia. In Watson CPN, Gershon AA, editors: Herpes zoster and postherpetic neuralgia, ed 2, New York, 2001, Elsevier, 39-64. Helgason S, Petursson G, Gudmundsson S, et al: Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long-term follow-up, BMJ 321:794-796, 2000. Raja SN, Haythornthwaite JA, Pappagallo M, et al: Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebocontrolled trial, Neurology 59:1015-1021, 2002. Rowbotham M, Harden N, Stacey B: Gabapentin for the treatment of postherpetic neuralgia: a randomized, controlled trial, JAMA 280:1837-1842, 1998.
Sabatowski R, Galvez R, Cherry DA, et al, and the 1008-045 Study Group: Pregabalin reduces pain and improves sleep and mood disturbances in patients with postherpetic neuralgia: results of a randomized, placebo-controlled clinical trial, Pain 109:26-35, 2004. Tyring S, Barbarash RA, Nasklik JE: Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group, Ann Intern Med 123:89-96, 1995. Watson CP, Vernich L, Chipman M: Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial, Neurology 51:1166-1171, 1998. Whitley RJ, Shukla S, Crooks RJ: The identification of risk factors associated with persistent pain following herpes zoster, J Infect Dis 178(Suppl 1):S71-S75, 1998.
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SECTION 5 ●
Developmental Disorders Neonatal Encephalopathy Steven P. Miller, M.D., C.M., F.R.C.P.C.
Neonatal encephalopathy is a major cause of neurodevelopmental disability in term infants, occurring in 1 to 6 per 1000 live term births. Neonatal encephalopathy is a serious condition: 15% to 20% of affected infants will die during the newborn period, and an additional 25% will sustain permanent clinical deficits. Hypoxic-ischemic encephalopathy certainly accounts for a substantial proportion of these patients, yet many cases of neonatal encephalopathy have no documented hypoxic-ischemic insult. Furthermore, there is continuing controversy as to whether neonatal encephalopathy is primarily related to insults sustained in the antepartum or intrapartum period. For the purpose of this article, the term neonatal encephalopathy is used instead of hypoxic-ischemic encephalopathy, in recognition of the many variables in the etiology and timing of this syndrome. As many causes of neonatal encephalopathy have specific therapies, a critical part of management is to determine the diagnosis. The diagnosis is made through careful history taking and neurologic examination, with laboratory studies to exclude conditions with specific therapy. Metabolic abnormalities (including inborn errors of metabolism), infection, trauma, and malformations of cerebral development all can result in neonatal encephalopathy. The history should elicit indicators of intrauterine distress: fetal heart tracing abnormalities, passage of meconium, or difficulty in labor or delivery that may have contributed to decreased placental or fetal blood flow. Hypoxicischemic brain injury is frequently accompanied by a history of difficult resuscitation including cardiopulmonary resuscitation, medications in the delivery room, intubation, and assisted ventilation at birth. Seizures, apneic episodes, jitteriness, and abnormal cry all are indicators of brain injury but do not identify the etiology of the injury. Because the clinical signs are often not specific for an etiology, laboratory tests are critical to exclude reversible causes of neonatal encephalopathy. Metabolic complications such as hypoglycemia, Johnson: Current Therapy in Neurologic Disease (7/E)
hypocalcemia, hyponatremia, hypoxemia, and acidosis are frequently seen and should be identified and treated. Lumbar puncture should be performed if the history is not typical for hypoxic-ischemic encephalopathy to rule out intracranial infections. Neuroimaging has become increasingly important for the accurate diagnosis of neonatal encephalopathy in the term newborn. The American Academy of Neurology practice parameter suggests that a noncontrast computed tomography (CT) scan should be performed to detect hemorrhagic lesions with a history of birth trauma, low hematocrit, or coagulopathy. If CT findings are inconclusive, magnetic resonance (MR) imaging should then be performed (on days 2 and 8 of life) to establish the pattern of injury and predict neurologic outcome. Other observations suggest that CT scan is not often helpful in making a diagnosis since it is relatively insensitive to changes in water content and because injury in the posterior fossa can be obscured by bony artifact. Given this, CT is best used to determine the extent of bleeding in an emergency situation where MR imaging is not available. MR imaging has proved to be a sensitive technique to determine injury in term neonatal encephalopathy and can help establish the diagnosis of hypoxic-ischemic injury. MR imaging helps to narrow the differential diagnosis in the evaluation of an encephalopathic neonate who might have an underlying metabolic, neurogenetic, neurovascular, or inflammatory disease requiring intervention. As the first step in caring for an encephalopathic newborn is establishing the diagnosis, MR imaging should be performed in the first week of life as the diagnostic test of choice. Additionally, MR imaging, particularly in combination with MR spectroscopy, can provide important prognostic information. Regardless of the specific etiology, the importance of the immediate management of neonatal encephalopathy cannot be overestimated. The management of moderate or severe encephalopathy should occur in a neonatal intensive care unit in close collaboration with a neonatologist. Immediate management requires securing an appropriate airway and maintaining adequate ventilation and circulation. As discussed earlier, an important component of the diagnostic work-up is to identify treatable conditions causing neonatal encephalopathy that require specific therapy. Blood tests obtained routinely are serum glucose, arterial or capillary blood gas, 89
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electrolytes (including calcium and magnesium), and a complete blood count with differential. Determinations of liver enzymes and serum creatinine are performed to detect injury in other end organs. If the history or examination is atypical for hypoxic-ischemic injury, a lumbar puncture is performed to rule out intracranial infections, and serum ammonia and lactate levels are obtained to expedite the investigation of an inborn error of metabolism. If infection is suspected, ampicillin and gentamicin are empirically started in addition to acyclovir if herpes simplex virus infection is suspected. If an inborn error of metabolism is suspected based on the history, examination, and the initial laboratory investigations, early treatment is crucial. Management in this situation, in consultation with a biochemical geneticist, includes stopping feeds, correcting acidosis and hypoglycemia, and considering hemodialysis based on the specific metabolic disorder. Additional diagnostic tests such as serum amino acids and urine organic acids are required to identify the specific disorder. The diagnosis of a severe intracranial hemorrhage on neuroimaging should prompt consultation with a neurosurgeon to manage raised intracranial pressure from mass effect or hydrocephalus and confirmation of platelet levels and coagulation function. In cases where neonatal encephalopathy is caused by hypoxic-ischemic injury, it is important to point out that at this time there is no specific treatment for the injury. The specific management of neonatal hypoxic-ischemic brain injury, therefore, focuses on preventing secondary brain injury. Since the clinical syndrome evolves considerably over the first 72 hours of life, management of specific complications can often be anticipated. As the clinical signs and symptoms depend on the severity, timing, and duration of the insult, it is extremely helpful to perform serial neurologic examinations. The severity of the encephalopathy can be measured daily for the first 3 days of life using a simple bedside encephalopathy score (Table 1). Not only is this score helpful in determining prognosis but it allows the management team to monitor the evolution of the clinical syndrome. The evolution of the clinical syndrome associated with hypoxic-ischemic injury is described in detail by Volpe (see “Suggested Reading”). The first 12 hours after birth are dominated by a depressed level of consciousness and
breathing abnormalities, including apnea. Ventilatory support with mechanical ventilation or continuous positive airway pressure is often required. Significant bradycardia and hypotension may require treatment with agents such as dopamine. Cerebral cortical involvement may present as hypotonia with decreased movement or as jitteriness. Seizures are seen in 50% of severely affected infants by 6 to 12 hours after birth. Seizures at this stage are often subtle, manifesting as ocular movements such as tonic horizontal eye deviation, tongue or lip smacking, bicycling movements of the extremities or as recurrent apnea. It is therefore important to alert the nursing staff to identify and document paroxysmal behaviors. Multifocal or focal clonic seizures may also occur, and they often indicate focal cerebral infarction. The management of neonatal seizures is outlined later. During the 12- to 24-hour period after the injury there is an apparent increase in the level of alertness that is not accompanied by other signs of improvement in neurologic function. This should not be falsely reassuring because it is frequently accompanied by more seizures and apneic episodes. An electroencephalogram (EEG) is helpful on the first day to assess background activity and determine the presence of electrographic seizures. After 24 to 72 hours following severe brain injury the infant’s level of consciousness deteriorates again, often accompanied by brainstem and respiratory depression requiring ventilatory support. During this period cerebral edema resulting from hypoxia-ischemia is maximal and can further impair cerebral blood flow secondary to increased vascular pressure. Most investigators avoid treatment of cerebral edema in this setting, because many interventions such as corticosteroids, hyperventilation (PaCO2 of 20 to 25 mm Hg), furosemide, or mannitol may be harmful. Follow-up EEG during this period is used primarily to determine the progression of background activity. Infants surviving beyond 72 hours often have an improvement in level of consciousness, needing less intensive care but requiring attention to feeding because suck and swallow often remain impaired. Neonatal seizures require treatment to prevent secondary brain injury, either from the seizures themselves or from the associated impairments in respiration and hemodynamics. Anticonvulsant medication should be
TABLE 1 Neonatal Encephalopathy Score* Encephalopathy Feature
Abnormal Signs
Score if Abnormal
Feeding Alertness Tone Respiratory status Reflexes Seizure Total
Gavage feeds, gastrostomy tube, or not tolerating oral feeds Irritable, poorly responsive, or comatose Hypotonia or hypertonia Respiratory distress (need for CPAP or mechanical ventilation) Hyperreflexia, hyporeflexia, or absent reflexes Suspected or confirmed clinical seizure
1 1 1 1 1 2 0 -7
*Because the duration of an abnormal neurologic examination is usually helpful in predicting long-term neurologic disability, newborns are scored daily for the first 3 days of life and the maximum score is considered. CPAP, Continuous positive airway pressure.
Johnson: Current Therapy in Neurologic Disease (7/E)
Neonatal Encephalopathy
• Ensure adequate ventilation and perfusion. • Correct metabolic disturbances, in particular hypoglycemia, hyponatremia, hypocalcemia, and hypomagnesemia. • Begin anticonvulsant therapy. The three main anticonvulsants for use in the newborn are the following: Phenobarbital: 20 mg/kg intravenously (IV); if necessary, administer additional 10 to 20 mg/kg IV in 10 mg/kg aliquots. Monitor blood pressure and respiration. A therapeutic drug level of 40 microgram/ml or greater is targeted. Maintenance dose is 4 to 6 mg/kg per 24 hours IV or orally (PO). Lorazepam: 0.05 to 0.1 mg/kg IV over several minutes. Again, monitor closely for respiratory depression. The half-life of lorazepam in asphyxiated newborns can be as long as 40 hours, with duration of action from 6 to 24 hours. Lorazepam can be repeated at this dose (0.05 to 0.1 mg/kg IV) every 6 to 8 hours as short-term maintenance if necessary. Phenytoin: 20 mg/kg IV (diluted in 0.9% NaCl); maximal rate is 1 mg/kg/min. Monitor cardiac rate and rhythm. Maintenance dose is 5 mg/kg IV per 24 hours. Note that phenytoin is poorly absorbed orally in the newborn and is not recommended as oral maintenance therapy. Pyridoxine deficiency is a rare cause of neonatal seizures and should be considered in any newborn with intractable seizures. The diagnosis is made by pyridoxine IV with concurrent EEG. The literature supports the use of phenobarbital as the first-line agent and phenytoin as a second-line agent for seizures associated with neonatal encephalopathy. These medications, especially phenobarbital, are frequently associated with electroclinical dissociation, with control of clinical seizures but not electrographic ones. Lorazepam may be more effective in the acute setting, particularly for control of both clinical and electrographic seizures. Lorazepam can often be used as a single agent because seizures associated with neonatal encephalopathy are often limited to the first 3 days of life. If seizures are not controlled by lorazepam, phenobarbital can be added. If seizures are not controlled after the addition of phenobarbital, phenytoin can be started. Before giving a second dose or a second medication, it is important to consider the following: • Is the diagnosis correct? • Are ventilation and perfusion optimal? • Are metabolic disturbances recognized and corrected? The optimal duration of therapy for neonatal seizures is controversial, given the potential detrimental effects of these medicines on longer-term brain development.
Johnson: Current Therapy in Neurologic Disease (7/E)
If phenytoin is started, attempts to stop this medication are best done prior to the child’s advancing to full oral feeds because this medication is not reliably absorbed orally. Discontinuing phenobarbital is considered when the neurologic examination is normal or, if the neurologic examination does not normalize, when the EEG is normal. Phenobarbital is discontinued as a slow taper over 6 weeks. The continued need for anticonvulsant medication should be evaluated prior to discharge and at each follow-up visit as an outpatient, in an attempt to treat for the shortest duration possible. Considerable advances continue to be made in understanding the mechanisms of neonatal encephalopathy. Preventing the conditions that underlie neonatal encephalopathy is ultimately the best treatment strategy. Several approaches, such as selective cerebral hypothermia, are now actively being evaluated to treat neonatal encephalopathy resulting from hypoxic-ischemic brain injury. The results of these forthcoming studies may substantially alter the management of affected infants. Until such strategies are proved effective and implemented, child neurologists will continue to follow survivors of neonatal encephalopathy. At follow-up, these infants and children require specific attention to language and cognitive function, motor function, feeding skills, and epilepsy. Acknowledgment The author thanks Drs. Donna Ferriero, Shannon Hamrick, and William Weiss for critical review of this chapter. SUGGESTED READING Badawi N, Kurinczuk JJ, Keogh JM, et al: Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study, BMJ 317:1549-1553, 1998. Badawi N, Kurinczuk JJ, Keogh JM, et al: Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study, BMJ 317:1554-1558, 1998. Cowan F, Rutherford M, Groenendaal F, et al: Origin and timing of brain lesions in term infants with neonatal encephalopathy, Lancet 361:736-742, 2003. Finer NN, Robertson CM, Richards RT, et al: Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome, J Pediatr 98:112-117, 1981. Ment LR, Bada HS, Barnes P, et al: Neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 58:1726-1738, 2002. Miller S, Newton N, Ferriero D, et al: MRS predictors of 30-month outcome following perinatal depression: role of socio-economic factors, Pediatr Res 52:71-77, 2002. Miller SP, Latal B, Clark H, et al: Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy, Am J Obstet Gynecol 190:93-99, 2004. Nelson KB, Ellenberg JH: The asymptomatic newborn and risk of cerebral palsy, Am J Dis Child 141:1333-1335, 1987. Vannucci RC, Perlman JM: Interventions for perinatal hypoxicischemic encephalopathy, Pediatrics 100:1004-1014, 1997. Volpe J: Neurology of the newborn, ed 4, Philadelphia, 2001, WB Saunders.
Developmental Disorders
initiated only after adequate ventilation and perfusion have been established and the blood glucose concentration has been measured. The following guidelines are presented for the treatment of neonatal encephalopathy with seizures:
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5
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Chiari Malformations and Syringomyelia
Chiari Malformations and Syringomyelia Roger W. Kula, M.D.
Chiari malformations were traditionally known to include a complex group of disorders characterized by herniation of the cerebellum through the foramen magnum into the spinal canal. Chiari malformation type I (CMIs) was first described by the pathologist Hans von Chiari in the late 1800s and constituted the simplest and most prevalent example of this continuum of hindbrain malformations. The easily recognized Chiari II malformation was associated with spinal myelomeningocele and hydrocephalus. The much rarer Chiari III/IV malformations were associated with cervical spina bifida and encephalocele or severe cerebellar hypoplasia. These more severe congenital malformations were apparent at birth and associated with complex abnormalities of the brain and spinal cord. CMI, which forms the focus of this chapter, is now properly considered to be a malformation of the mesoderm in which a hypoplastic posterior fossa results in neural compression within the posterior fossa. Herniated cerebellar tonsillar tissue, furthermore, blocks the circulation of cerebrospinal fluid between the posterior fossa and spinal canal and results in a 20% to 70% incidence of syrinx cavity formation within the spinal cord. Likewise, CMI defined as tonsillar herniation of at least 3 to 5 mm below the foramen magnum, accounts for the predominant overall etiology of syringomyelia (SM) (70%).
Epidemiology Having so set the stage, it is appropriate to shift focus from the early pathologic characterization of these disorders to their increasingly frequent clinical presentations. Until the advent of more easily obtainable magnetic resonance (MR) scanning and more sophisticated sagittal imaging, CMI was regarded as a rare condition. Current estimates range from 200,000 to 2 million Americans affected with this condition. New genetic studies support a hereditary tendency with a transmissibility rate approaching 12%. Women are affected three times more often than men. Not surprisingly, MR imaging technology has led to the recognition of syrinx cavities that previously might have escaped even postmortem identification. A recent estimate suggests the prevalence of SM in the U.S. population to be between 140,000 to 210,000 individuals, or about 1 in 1300 to 1900 Americans, considering all causes (Table 1). Since increasingly well-defined strategies now exist to investigate, diagnose, and medically and surgically manage these patients, it is of ever greater importance to understand their clinical presentations and redefine the place of these lesions in the neurologic differential
TABLE 1 Major Causes of Syringomyelia Chiari I malformation Spine/spinal cord trauma Meningitis and other infections including intraspinal abscess Subarachnoid hemorrhage Tumors of spinal column or cord Diastomatomyelia Developmentally persistent central canal
diagnosis. Older characterizations based on pathologic case reviews can be seen to fall short of current clinical understanding.
Clinical Presentations CHIARI MALFORMATION I Patients with CMI may experience no symptoms. When symptoms are present, they usually do not appear until adolescence or early adulthood. Most patients complain of severe pressure-like occipital headache and neck pain. Other common symptoms are listed in Table 2. Because of this complex symptomatology, patients with CMI are frequently misdiagnosed. At least one fourth of patients manifest symptoms following relatively minor head injury or neck injury, again frequently complicating the understanding of their underlying disorder and raising issues of malingering or secondary litigious gain. Symptoms can occasionally be seen in young children who are more likely to present with oropharyngeal dysfunction and scoliosis. A number of children younger than 3 years of age have undergone fundoplication and/or gastrostomy because of vomiting and reflux before a neurologic diagnosis was entertained. The typical posterior fossa or “Chiari headache” requires clearer definition. Patients describe a suboccipital pain in the head that is pressure like and more often continuous but variable rather than episodic. It is more likely to be exaggerated by bearing down with bowel movements or with laughter, crying, or orgasm than cough or sneeze, the fact of which many patients are reluctant to volunteer. The pain radiates most prominently to the retro-orbital regions and the vertex. It is explosive in character rather than throbbing or pounding. Although visual sparkles and scotomas may occur, these punctuate the peaks of headache rather than occurring as a prodrome, and the headache is almost never hemicranial. Many patients languish in headache clinics as medication-resistant or narcoticdependent chronic daily headache patients. Many, because of a longstanding history, chronic depression, and multiple symptomatic complaints in the absence of abnormal neurologic findings, have never been properly imaged. The frequent presence of neck pain without radicular features, except for evanescent hand numbness and tingling, and other generalized musculoskeletal complaints with negative rheumatologic evaluations have led to their frequent labeling as chronic fatigue or Johnson: Current Therapy in Neurologic Disease (7/E)
Chiari Malformations and Syringomyelia
93 Developmental Disorders
TABLE 2 Chiari Malformation Type I (CMI) Symptoms
From Milhorat TM, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings in 364 symptomatic patients, Neurosurgery, 44:1005-1017, 1999.
fibromyalgia patients. Many patients may be simultaneously affected by migraine headache because of its prevalence and both may be exacerbated premenstrually, but the Chiari headache responds little or not at all to common migraine treatments with antidepressants, beta blockers, and triptans. Commonly used non-narcotic medications (e.g., Fiorinal, Esgic, Midrin, and nonsteroidal anti-inflammatory drugs) may give some relief, and topiramate (Topamax) with its cerebrospinal fluid (CSF) pressure-lowering carbonic anhydrase activity may offer some falsely reassuring benefit. The patient’s neurologic examination is rarely objectively abnormal. The most typical finding is a vestibular-like dysequilibrium and difficulty in tandem standing and walking. Nystagmus is difficult to appreciate even with Fresnel lens examination. Objective findings frequently elude sophisticated vestibular testing, which only occasionally reveals nystagmus of possible central or peripheral etiology but which routinely fails treatment with vestibular rehabilitation. Classic downbeat nystagmus is rarely seen even with tonsillar descent as striking as 20 mm. SYRINGOMYELIA SM occurs when a tubular cavity or syrinx develops within the spinal cord resulting from an obstruction of spinal fluid circulatory pathways. In CMI, most (80%) of these occur within the cervical cord. The thoracic cord can, however, be affected in isolation, and more rarely a lumbosacral syrinx may appear associated with spinal cord tethering secondary to a thickened and restrictive filum terminale. Approximately 70% of SM cases result from CMI, with an additional small percentage associated with a hypoplastic posterior fossa as suggested by recent studies. The remaining occurrences are listed in Table 1. The syrinx cavities can give rise to painful sensory disturbances and both lower motor neuron and upper motor neuron paralytic signs. Painful neuropathic dysesthesias are most likely to occur at or adjacent to the caudal extent of the syrinx cavity. Johnson: Current Therapy in Neurologic Disease (7/E)
Symptoms are more related to the pace of evolution of the syrinx than to its absolute size. Otherwise healthy patients with slitlike syrinx cavities may present with severe localized spinal and radicular pain. Other patients with syrinx cavities displacing as much as 90% of the spinal cord mass may be virtually asymptomatic. The classic “dissociated sensory loss” (preserved touch sensation in the face of absent pain sensation) considered indicative of SM is rarely identifiable. The importance of identifying Chiari headache and associated CMI or its other causes (Table 3) and SM lies in the availability of sound medical and surgical approaches to treatment and the invaluable provision to these patients of an understandable explanation for their misery. The secret to their identification lies in elevating them to a level of consideration through a clear appreciation of their often insidious and subtle manifestations.
Initial Diagnostic Evaluation In the initial evaluation of these patients, an extensive clinical history and physical examination are appropriate with an open mind toward multisymptomatic
TABLE 3 Secondary Causes of Tonsillar Descent and “Chiari Headache” Hydrocephalus, obstructive Pseudotumor syndrome Arachnoid cyst of posterior fossa Basilar invagination Craniosynostosis Achondroplasia Hypophosphatemic rickets Paget’s disease or other hyperostotic bone disease Chronic spinal cerebrospinal fluid leak Spinal cord tethering either congenital or secondary to trauma
5
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Chiari Malformations and Syringomyelia
presentations (see Table 2). Once either of these conditions rises to a suspicion in differential diagnosis, appropriate imaging studies are a paramount consideration (Table 4). The diagnosis of CMI has traditionally been left in the hands of neuroradiologists identifying a threshold level of tonsillar descent usually greater than 3 to 5 mm. Although sagittal imaging of the craniocervical junction has revolutionized the detection of CMI, tonsillar structure and its radiological representation with volume averaging techniques frequently underestimate the anatomic degree of tonsillar descent. Specific radiologic criteria for the identification of tonsillar ectopia and CMI are fuzzy. Recent analyses of posterior fossa dimensions and subtle abnormalities of CSF flow at the craniocervical junction may make it possible to more easily identify a hypoplastic posterior fossa (with only minimal or no tonsillar descent) sometimes referred to as Chiari zero. This may increase diagnostic sensitivity but complicate an already controversial diagnosis. The average position of the cerebellar tonsils in normal series is approximately 3 mm above the foramen magnum. The most constant feature of CMI is a volumetrically small posterior fossa, which predisposes patients to hindbrain overcrowding. The goal of the diagnostic work-up is to establish a correct diagnosis, separate possibly concurrent or associated clinical problems (Table 5), provide a course of management, and clearly lay out the risks, benefits, and expectations of possible operative intervention. Patients with CMI frequently experience chronic fatigue (72%) or fibromyalgia-like (12%) symptoms, although only a small percentage of patients with such symptoms ( 70
Score 100
Yes
90
No
I carry on ...with effort and some symptoms. most normal activity.
80
I can manage all of my needs.
...but normal activities are limited.
70
I can manage most of my needs.
...but I require occasional assistance excluding personal care.
I require considerable assistance I can manage only some of my personal including some personal care. needs.
50
I require frequent assistance for most personal care.
40
I am severely disabled.
I require full assistance for most personal care.
30
I am totally disabled or very ill.
I require full assistance for all personal care. Home bound in bed or chair.
20
I am critically ill.
I have fatal processes that are rapidly progressing. I am near death.
10
Yes
P r i m a r y s u r g i c a l c r i t e r i a
Pituitary function studies Continued conservative medical management (Chronic fatigue, musculoskeletal pain, and vertigo are not considered reliable indicators for surgical management)
Progression?
5
MKS score < 70
60
I am disabled.
Empty sella?
No
Yes CT myelography
Yes Syrinx propagation?
Yes
Posterior fossa decompression
No
Failed? Progressive neurological deficit?
Yes Continuing Chiari headache?
No
Intractable Chiari headache?
Yes Yes
Repeat complete imaging
No
Tethering? CSF flow obstruction?
Yes Expansile spinal duroplasty Failed?
Continuing syrinx progression?
Yes Posterior fossa revision
Good surgical result?
No
Syringoperitoneal shunt
Yes No
High CSF pressure >200mm and headache relief with fluid removal Yes
Lumbar puncture: CSF pressure studies
VP shunt
FIGURE 1. Management algorithm for Chiari malformation type I (CMI) and syringomyelia. C-, T-, LS=, Cervical, thoracic, lumbosacral; CSF, cerebrospinal fluid; 3D, three-dimensional; MKS, Modified Karnofsky Scale; VP, ventriculoperitoneal. Johnson: Current Therapy in Neurologic Disease (7/E)
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Neurofibromatosis
SUGGESTED READING Cohen AR, Gaskill S J, topic editors: Chiari I malformation, Neurosurg Focus 11(1), 2001. http://www.aans.org/education/ journal/neurosurgical/july01/11-1-nsf-toc.asp Greenlee JDW, Donovan KA, Hasan DM, Menezes AH: Chiari I malformation in the very young child: the spectrum of presentations and experience in 31 children under the age 6 years, Pediatrics 110:1212-1219, 2002. Milhorat TH, Bolognese PA: Tailored operative technique for Chiari type I malformation using intraoperative color Doppler ultrasonography, Neurosurgery 53:899-906, 2003. Milhorat TH, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients, Neurosurgery 44:1005-1017, 1999. Milhorat TH, topic editor: Syringomyelia, Neurosurg Focus 8(3), 2000. http://www.aans.org/education/journal/neurosurgical/mar00/ 8-3-NSF-toc.asp Mueller DM, Oro JJ: Prospective analysis of presenting symptoms among 265 patients with radiographic evidence of Chiari malformation type I with or without syringomyelia, J Am Acad Nurse Pract 16:134-138, 2004. Tamaki N, Batzdorf U, Nagashima T, editors: Syringomyelia: current concepts in pathogenesis and management, Tokyo, 2001, Springer-Verlag.
PATIENT RESOURCES American Syringomyelia Alliance Project, Inc. P.O. Box 1586 Longview, TX 75606-1586 Phone: 903-236-7079 Toll-free phone: 800-ASAP-282 Fax: 903-757-7456 E-mail:
[email protected] http://www.asap.org/ World Arnold-Chiari Malformation Association Contact: Bernard H. Meyer 31 Newtown Woods Road Newtown Square, PA 19073 Phone: 610-353-4737 E-mail:
[email protected] http://www.wacma.com/ Chiari and Syringomyelia Patient Education Foundation Contact: Chiari and Syringomyelia News 346 Valerie Drive Cranberry Township, PA 16066 E-mail:
[email protected] http://www.chiari-syringo-news.com
Neurofibromatosis Laurence Walsh, M.D., and Bhuwan P. Garg, M.D.
Neurofibromatosis (NF) is not a single disease. The term subsumes at least two distinct disorders that share some common features. The two distinct types of NF most commonly recognized are NF-1 and NF-2. NF-1 is a single gene disorder with protean manifestations. The nervous system, blood vessels, bones, and skin all may be involved in NF-1. NF-2 likewise is a single gene disorder, with variable but more circumscribed clinical features. There are other types of NF: segmental NF usually is
the clinical result of mosaicism for NF-1 gene mutations. Other types are either allelic to NF-1 or are of unclear significance. We discuss NF-1 and NF-2 in this chapter.
Neurofibromatosis Type 1 (von Recklinghausen’s Disease) NF-1 is the most common form of NF and accounts for nearly 90% of NF cases. The incidence of NF-1 is 1 per 3500 individuals. It is inherited as an autosomal dominant disorder, but 50% of cases represent new mutations. Penetrance is nearly 100%, but expression varies widely. Mutational analysis of the gene encoding neurofibromin on 17q11.2 is available commercially. Although this test enjoys high sensitivity (95%), it is expensive, and diagnosis still rests on demonstration of clinical criteria. Two of seven age-dependent clinical criteria are required to make a clinical diagnosis (Table 1). In familial cases, clinical diagnostic criteria are present in 70% of 12-month-old children with NF-1 and 100% of affected 8-year-old children. In the sporadic cases, 97% of the patients display at least two diagnostic criteria by age 8 years; 100% do so by age 20 years. Other clinical manifestations, not part of the diagnostic criteria, are listed in Table 2. DIAGNOSIS Criteria as listed in Table 1 should be used as a guide for diagnostic purposes. Young infants do not always meet the criteria, especially when the disease is sporadic. However, the characteristic features develop over time, and careful and close follow-up is necessary, especially in children who have multiple café au lait spots (CALSs) but do not meet other criteria for the diagnosis for NF-1. They should be followed until the diagnosis can be confirmed or excluded. The usual order of appearance of the clinical features is CALSs, axillary freckles, Lisch nodules, and neurofibromas. Thorough physical, ophthalmologic, audiologic, and radiologic examinations and a team approach are essential. Subsequent investigations are determined by clinical necessity. Diagnostic criteria for NF-1 provide the clinician with a highly specific tool for clinical diagnosis. In individuals with only one criterion (usually skin lesions, parenchymal tumors, or bony changes), a differential diagnosis may be generated (Table 3). These diagnoses usually are easy to differentiate from NF-1. MANAGEMENT About 45% of individuals affected with NF-1 suffer a significant medical or neurodevelopmental complication of the disorder. Management consists of screening for treatable complications, subsequent interventions that may reduce morbidity and mortality, and patient and family education and genetic counseling. We discuss management of specific features and complications of NF-1 in the following sections. Johnson: Current Therapy in Neurologic Disease (7/E)
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Neurofibromatosis
SUGGESTED READING Cohen AR, Gaskill S J, topic editors: Chiari I malformation, Neurosurg Focus 11(1), 2001. http://www.aans.org/education/ journal/neurosurgical/july01/11-1-nsf-toc.asp Greenlee JDW, Donovan KA, Hasan DM, Menezes AH: Chiari I malformation in the very young child: the spectrum of presentations and experience in 31 children under the age 6 years, Pediatrics 110:1212-1219, 2002. Milhorat TH, Bolognese PA: Tailored operative technique for Chiari type I malformation using intraoperative color Doppler ultrasonography, Neurosurgery 53:899-906, 2003. Milhorat TH, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients, Neurosurgery 44:1005-1017, 1999. Milhorat TH, topic editor: Syringomyelia, Neurosurg Focus 8(3), 2000. http://www.aans.org/education/journal/neurosurgical/mar00/ 8-3-NSF-toc.asp Mueller DM, Oro JJ: Prospective analysis of presenting symptoms among 265 patients with radiographic evidence of Chiari malformation type I with or without syringomyelia, J Am Acad Nurse Pract 16:134-138, 2004. Tamaki N, Batzdorf U, Nagashima T, editors: Syringomyelia: current concepts in pathogenesis and management, Tokyo, 2001, Springer-Verlag.
PATIENT RESOURCES American Syringomyelia Alliance Project, Inc. P.O. Box 1586 Longview, TX 75606-1586 Phone: 903-236-7079 Toll-free phone: 800-ASAP-282 Fax: 903-757-7456 E-mail:
[email protected] http://www.asap.org/ World Arnold-Chiari Malformation Association Contact: Bernard H. Meyer 31 Newtown Woods Road Newtown Square, PA 19073 Phone: 610-353-4737 E-mail:
[email protected] http://www.wacma.com/ Chiari and Syringomyelia Patient Education Foundation Contact: Chiari and Syringomyelia News 346 Valerie Drive Cranberry Township, PA 16066 E-mail:
[email protected] http://www.chiari-syringo-news.com
Neurofibromatosis Laurence Walsh, M.D., and Bhuwan P. Garg, M.D.
Neurofibromatosis (NF) is not a single disease. The term subsumes at least two distinct disorders that share some common features. The two distinct types of NF most commonly recognized are NF-1 and NF-2. NF-1 is a single gene disorder with protean manifestations. The nervous system, blood vessels, bones, and skin all may be involved in NF-1. NF-2 likewise is a single gene disorder, with variable but more circumscribed clinical features. There are other types of NF: segmental NF usually is
the clinical result of mosaicism for NF-1 gene mutations. Other types are either allelic to NF-1 or are of unclear significance. We discuss NF-1 and NF-2 in this chapter.
Neurofibromatosis Type 1 (von Recklinghausen’s Disease) NF-1 is the most common form of NF and accounts for nearly 90% of NF cases. The incidence of NF-1 is 1 per 3500 individuals. It is inherited as an autosomal dominant disorder, but 50% of cases represent new mutations. Penetrance is nearly 100%, but expression varies widely. Mutational analysis of the gene encoding neurofibromin on 17q11.2 is available commercially. Although this test enjoys high sensitivity (95%), it is expensive, and diagnosis still rests on demonstration of clinical criteria. Two of seven age-dependent clinical criteria are required to make a clinical diagnosis (Table 1). In familial cases, clinical diagnostic criteria are present in 70% of 12-month-old children with NF-1 and 100% of affected 8-year-old children. In the sporadic cases, 97% of the patients display at least two diagnostic criteria by age 8 years; 100% do so by age 20 years. Other clinical manifestations, not part of the diagnostic criteria, are listed in Table 2. DIAGNOSIS Criteria as listed in Table 1 should be used as a guide for diagnostic purposes. Young infants do not always meet the criteria, especially when the disease is sporadic. However, the characteristic features develop over time, and careful and close follow-up is necessary, especially in children who have multiple café au lait spots (CALSs) but do not meet other criteria for the diagnosis for NF-1. They should be followed until the diagnosis can be confirmed or excluded. The usual order of appearance of the clinical features is CALSs, axillary freckles, Lisch nodules, and neurofibromas. Thorough physical, ophthalmologic, audiologic, and radiologic examinations and a team approach are essential. Subsequent investigations are determined by clinical necessity. Diagnostic criteria for NF-1 provide the clinician with a highly specific tool for clinical diagnosis. In individuals with only one criterion (usually skin lesions, parenchymal tumors, or bony changes), a differential diagnosis may be generated (Table 3). These diagnoses usually are easy to differentiate from NF-1. MANAGEMENT About 45% of individuals affected with NF-1 suffer a significant medical or neurodevelopmental complication of the disorder. Management consists of screening for treatable complications, subsequent interventions that may reduce morbidity and mortality, and patient and family education and genetic counseling. We discuss management of specific features and complications of NF-1 in the following sections. Johnson: Current Therapy in Neurologic Disease (7/E)
Neurofibromatosis
99
Usual Age of Occurrence
Prevalence (%) by 18 Years of Age
≥ 6 café au lait macules > 0.5 mm in diameter in prepubertal patients and > 15 mm in postpubertal patients
Birth
>99 (99 by 12 mo)
≥2 neurofibromas of any type (intracutaneous or subcutaneous) or ≥1 plexiform neurofibroma
8-12 yr
84 (48 by age 10 yr)
Congenital
>44 (25-30 apparent in infancy, 44 by age 5 yr)
Freckling in the axillary or inguinal regions (≥3 freckles) Optic pathway glioma ≥2 iris hamartomas (Lisch nodules) Distinctive osseous lesion, e.g., sphenoid wing hypoplasia or thinning of long bone cortex with or without pseudoarthrosis ≥1 first-degree relative with NF-1 according to the above criteria
3-5 yr 3-4 yr 5-12 yr Birth
>90 (by age 7 yr) ≤15 >70 (by age 10 yr) 7-14
—
50
Clinical Criteria*
Developmental Disorders
TABLE 1 Diagnostic Criteria for Neurofibromatosis (NF)-1
*A diagnosis of NF-1 requires ≥ 2 of these criteria.
Skin Lesions Skin lesions are the most common manifestations of NF-1. The earliest and most common cutaneous lesions are CALSs. Of infants with multiple (≥6) CALSs, more than 80% will develop NF-1. Cosmetic concerns may occur with multiple or very large CALSs, but they do not require medical intervention otherwise. Vitamin D analogs and laser therapy have been tried with initial success, but results await confirmation. CALSs often fade by middle age, if not earlier. Isolated CALSs (usually ≤3) occur in 10% to 20% of the population. They are slightly more common and are slightly more likely to be multiple in individuals of Mediterranean, African, or South Asian ancestry. Some families (with and without NF-1 gene mutations) transmit multiple CALSs as an isolated autosomal dominant trait. Multiple CALSs are also reported in children with tuberous sclerosis complex, Russell-Silver syndrome, and ataxia-telangiectasia, although there is argument concerning their specific association with those disorders. Intertriginous freckling is the second most common manifestation of NF-1. Axillary freckling is twice as common as inguinal freckling. This freckling has no medical significance other than as a criterion for diagnosis. More irregular or diffuse hyperpigmentation occurs
TABLE 2 Other Significant Features of Neurofibromatosis Type 1 Learning disabilities Macrocephaly Aqueductal stenosis Epilepsy Scoliosis Hypertension Ungual neurofibromas Interstitial pulmonary disease Johnson: Current Therapy in Neurologic Disease (7/E)
as well; large hyperpigmented areas, sometimes with hemangiomatous changes, may overlie an often palpable plexiform neuroma. Neurofibromas occur in 84% of people with NF-1. They are discrete and are either cutaneous or subcutaneous in location. Cutaneous neurofibromas may be violaceous or tan, and they feel soft or fleshy to palpation. Subcutaneous neurofibromas are not visibly pigmented, are firmer, and are more readily associated with peripheral nerve trunks. Either may be up to 3 to 4 cm in diameter. They usually appear in late school age or adolescence but may be present in toddlers. Although puberty may be associated with the appearance of multiple new neurofibromas, they occur throughout life. They may cause local itching and cosmetic problems and may be susceptible to repeated incidental trauma (e.g., from shaving). Angiomas and xanthomas are less commonly seen. Xanthogranulomas, rare in children with NF-1, may be associated with an increased risk of lymphoproliferative disorders; however, there currently is no specific recommendation regarding additional screening.
TABLE 3 Differential Diagnosis for Neurofibromatosis Type 1 Neurofibromatosis type 2 LEOPARD syndrome Multiple intradermal nevi Multiple lipomatosis Proteus syndrome Noonan’s syndrome Multiple café au lait spots McCune-Albright syndrome Multiple endocrine neoplasia type 2B Bannayan-Riley-Ruvalcaba syndrome LEOPARD, Lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness.
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Pruritus is common in NF-1. The itching may be severe, but the patient may not volunteer its presence. It occurs in association with neurofibromas but also diffusely, unattached to a specific cutaneous or subcutaneous lesion. Antihistamines have been tried with mixed results. Plexiform Neuromas Plexiform neurofibromas (plexiform neuromas) are larger than neurofibromas and may cause more serious problems. They occur equally on the trunk or head and neck (40% to 45% each) and less commonly on the limbs. They are congenital but may not be apparent until they enlarge with age. Plexiform neuromas start in nerve sheaths anywhere between the spinal roots and distal nerves in the extremities and appear as either nodular or diffuse lesions. Thirty percent of people with NF-1 have plexiform neuromas; malignant change to a malignant peripheral nerve sheath tumor (MPNST) occurs in 5% of cases. Deep nodular or diffuse plexiform neuromas are most likely to degenerate to MPNSTs. Even without transformation to an MPNST, plexiform neuromas may grow to compress nerves and other vital structures. Periorbital plexiform neurofibromas not only may have cosmetic consequences but may also cause ptosis, exophthalmos, and vision loss. Intraoral tumors may cause airway obstruction. Lesions in the neck may compress nearby arteries or veins with sometimes life-threatening consequences. Cephalic or paraspinous plexiform neurofibromas may extend intracranially or intraspinally. Intra-abdominal tumors also may encase important structures such as the renal artery or aorta, causing secondary hypertension or more serious complications. Plexiform neuromas that are visible on physical examination are measured during each annual or semiannual visit. Although not routinely included as part of a screening protocol, magnetic resonance (MR) imaging reveals the extent of larger tumors and allows follow-up of noncutaneous plexiform neuromas. Indications for therapeutic intervention include indications of possible malignant degeneration (rapid growth in a previously stable tumor or pain, especially associated with new growth), and impending compromise in patient function or important structures. Therapy is limited. Radiation therapy has no role in the treatment of plexiform neuromas. Chemotherapy has shown little efficacy to date. Complete surgical excision is optimal but often difficult to achieve. Incomplete resection risks recurrence but may be necessary if the tumor is especially large or if complete resection threatens vital structures. Therapy of MPNST consists of resection and chemotherapy in consultation with oncologists. Forty percent recur within 2 years. Five-year survival with MPNST is 35%; median survival is 36 months. Ophthalmic Lesions Lisch nodules in the iris are the most common eye signs in NF-1, appearing as brown nodules. These are melanocytic hamartomas. The presence of two nodules is required to meet the diagnostic criterion. They are
age dependent, and the incidence increases with age; only about 6% of children younger than 6 years of age have them, but more than 70% patients have them by teenage years. Pulsating exophthalmos due to sphenoid wing hypoplasia is seen in some children. Buphthalmos and congenital glaucoma have also been reported. These may be associated with an underlying plexiform neuroma. Optic nerve glioma is discussed in the following section. Neurologic Complications Macrocephaly (head size greater than 2 SD above mean) occurs in nearly half of the NF-1 patients. It usually is due to megalencephaly. Signs of increased intracranial pressure require exclusion of other causes such as obstructive hydrocephalus, posterior fossa tumors, aqueductal stenosis, tectal plate gliomas, and hypothalamic tumors. In some children a cause for ventriculomegaly is not found. Epilepsy occurs in 5% to 7% of affected individuals with NF-1. Seizures occur more frequently in children with NF-1 and severe neurodevelopmental disabilities than in children with NF-1 and normal development. Appropriate anticonvulsants are used for seizure control. Attention deficit with or without hyperactivity is seen often in children with NF-1, and learning disabilities (LDs) occur in about 50% (30% to 62%) of individuals with NF-1. The IQ score of patients with NF-1 averages 10 points lower than that of their siblings. Verbal scores exceed performance scores. Common, specific NF-1–associated LDs include poor visuospatial skills and specific reading and language disabilities. Mental retardation occurs less commonly in NF-1 patients and may be mutation specific. Management of children with NF-1 should include specific inquiry into learning or school difficulties. Psychoeducational testing should be sought aggressively if there is any hint of cognitive delay or school difficulty. MR imaging of the brain currently is not part of recommended screening protocols for NF-1 in otherwise asymptomatic children. However, our threshold for obtaining an MR scan in a child with NF-1 is extremely low. Indications include absolute macrocephaly (>2 SD above the mean), headaches (new or worsening), decreasing vision or unexplained nystagmus in a young child, funduscopic changes suggestive of an optic nerve glioma, developmental delay or LDs, decline in school performance, cephalic plexiform neuroma that may have intracranial extension, and abnormal neurologic examination that is not explained otherwise. Precocious puberty is an absolute indication for MR scan of the brain to include detailed study of the hypothalamus and sella. Headaches occur in one half of patients with NF-1; 10% are caused by an intracranial structural lesion. Intracranial tumors require management as discussed in the following section. Optic Pathway Glioma Optic pathway gliomas have been reported in 15% of children with NF-1. The tumor may involve the Johnson: Current Therapy in Neurologic Disease (7/E)
Neurofibromatosis
Johnson: Current Therapy in Neurologic Disease (7/E)
Vasculopathy Vasculopathy is an under-recognized aspect of NF-1. Renal artery stenosis is the best known, but the vasculopathy of NF-1 really is a generalized disorder. Carotid artery stenosis with moyamoya disease has been reported. Coarctation of aorta has been reported by several investigators. Other, less common associations include pheochromocytoma. Hypertension is a common complication of NF-1, occurring in at least 40% of adults and up to 20% of children with NF-1. It requires thorough evaluation and treatment. Renal artery stenosis and compression of the artery from a tumor should be excluded using abdominal MR or computed tomography (CT) scan. Hypertension caused by such structural lesions may be relatively refractory to medical management and may require surgery. Pheochromocytoma, usually after the age of 15 years, is a rare cause of hypertension in NF-1. It occurs in 0.1% to 1.5% of reported NF-1 patients and presents with initial episodic hypertension and other vasomotor phenomena. Appropriate consultation is advisable for evaluation of suspected pheochromocytoma. Data for vasculopathy-related morbidity in NF-1 are sketchy. People affected with NF-1 who die prior to age 30 years have an odds ratio of 2 to 3 of having vascular disease compared with non-NF individuals who die before 30 years of age. It has been suggested that the vasculopathy is a result of alteration of the function of neurofibromin (the NF-1 gene product) in the vascular endothelium and smooth muscle cells. Skeletal Lesions Multiple bony abnormalities have been reported in NF-1. Dysplasia of the greater wing of the sphenoid bone may cause pulsating exophthalmos and marked facial disfigurement. Dural ectasias may produce enlargement of various bony (cranial nerve) foramina and need to be distinguished from enlargement due to neurofibroma involving the nerve. Cranial CT with thin slices or MR scan is useful in evaluation. Scoliosis occurs in 12% of children with NF-1. Scoliosis in NF-1 is bimodal in onset and severity. Its presence is an indication for plain films and MR imaging of the complete spine. Scoliosis due to vertebral dysplasia begins in preschool- and school-age children; this tends to be progressive and severe. Teenage-onset scoliosis in NF-1 usually is less severe. Either age group may have scoliosis due to paraspinal or intraspinal tumors with symptoms specifically referable to the tumor site. Scalloping of the vertebral body is a common radiologic finding. Dural ectasia also occurs in the spine. Bowing of the tibia and fibula and secondary pseudoarthrosis of the tibia are other bony abnormalities in NF-1. The latter may result in significant disability and may necessitate amputation of the affected leg. Short stature is common and occurs in 25% to 43% of patients with NF-1. NF-1 patients on average are reported to fall short of their siblings’ height and their own predicted mid-parental height.
Developmental Disorders
optic nerve, optic chiasm, and/or the optic tracts. Sometimes the tumor spreads posteriorly along the optic radiations. Optic gliomas may present with decreased visual acuity, visual field defects, ptosis, proptosis, and signs and symptoms of increased intracranial pressure, or they may be asymptomatic and found on MR scans or ophthalmologic examinations. Diencephalic syndrome and precocious puberty in patients with NF-1 require exclusion of optic chiasm or hypothalamic gliomas. Most symptomatic gliomas present by 6 years of age and often do so by 2 years of age, but only about 30% to 50% of patients with optic gliomas have symptoms. Optic gliomas may remain static and behave as hamartomas, or they may grow actively. Periodic MR scans following initial detection are helpful in determining whether the tumor is progressive or static. One suggested protocol is MR scans (including optic nerve views) and ophthalmologic examinations every 3 months for 1 year, followed by MR imaging and ophthalmologic examinations every 6 months for 2 years and yearly scans and every-6-month ophthalmologic examinations thereafter. Some protocols relax surveillance even further after 36 months, but this decision rests on the age of the child and the behavior of the tumor on previous surveillance studies. Progression of optic gliomas after 10 years of age is rare. Static tumors should be watched and need no treatment. Actively growing tumors may be treated with chemotherapy, or surgery when possible. Radiation therapy may result in serious complications in NF-1 patients. These complications, including moyamoya disease, stroke, and secondary malignant glioma formation, make radiation therapy an unappealing last choice. About 25% of patients with optic gliomas require treatment for them, whereas the tumors may spontaneously regress in some patients. Routine screening for optic gliomas in a healthy asymptomatic child with NF-1 consists of yearly eye examinations by an ophthalmologist. This said, such examinations carry only about 50% to 60% sensitivity. Astrocytomas of the cerebellum, cerebrum, and brainstem are other common intracranial tumors in NF-1. Symptoms depend on location. Brainstem gliomas in patients with NF-1 may be indolent, with very slow growth and better outcome than brainstem gliomas in children without NF-1. Most (80%) occur in the medulla; 15% to 20% require intervention beyond shunt for hydrocephalus. Meningiomas and primitive neural-ectodermal tumors occur as well. Presence of symptomatic optic nerve glioma increases the likelihood of these other central nervous system tumors by a factor of nine. Intraspinal tumors may be single or multiple. Cervical neuromas may occur in 25% of children with NF-1. They may be extradural or intradural. Intramedullary spinal tumors are rare in NF-1. Intraspinal tumors may extend through the intervertebral foramen and assume a dumbbell shape. In some patients these intraspinal tumors may be in continuity with a subcutaneous plexiform neurofibroma. A 2% to 7% risk of sarcomatous change in these tumors has been reported. Appropriate treatment is necessary in symptomatic patients (e.g., with intractable pain or focal neurologic deficits).
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Additional MR Imaging Findings In addition to the abnormalities due to tumors, there are many other unusual findings in the cranial MR scans of patients with NF-1. Hyperintense foci occur on T2-weighted images in 43% to 77%. These usually are found incidentally, and most commonly occur in the globus pallidus, followed by the cerebellum, brainstem, thalamus, and periventricular white matter. Histologic verification is lacking, though they were described in the past as hamartomas. They more likely represent transient abnormalities of myelin structure. They are age dependent and usually vanish by age 12 years. Their clinical significance is unknown. Their presence is associated with LDs and may predict other NF-1related morbidities. Genetic Considerations All families affected by NF-1 require genetic counseling. The disorder is autosomal dominant. One half of cases are sporadic and suggest a new (noninherited) mutation. This may have occurred before or after conception. A mutation before conception raises the possibility of germline mosaicism in a parent. Although a presumed new mutation might suggest sibling recurrence risk of less than 1%, the possibility of a preexisting mutation limited to a parental germ cell line slightly raises the sibling recurrence risk in de novo cases. The clinically affected individual then has a 50% risk of passing the mutation to his or her offspring, with essentially 100% penetrance. In families with a clinically affected parent, offspring recurrence is 50%. There is some evidence that there is less intrafamilial than interfamilial variability in manifestations, but many exceptions exist. Thus, although the presence of only CALSs, freckling, and Lisch nodules in a given family may be reassuring, vigilance for more serious sequelae still is required. There are several specific variant clinical subtypes (Noonan-NF syndrome, Watson syndrome, a microdeletion syndrome, familial CALSs, and spinal NF with MPNST). Medical genetic consultation may be advisable in some instances, and even in cases requiring only genetic counseling, genetic counselors often are far more effective than physicians in conveying this information to affected families.
Neurofibromatosis Type 2 NF-2 is less common than NF-1. The major hallmark of NF-2 is the development of bilateral acoustic neuromas. Occasionally there are also other brain and spinal cord tumors. The clinical mnemonic for NF-2 is “MISME” (multiple inherited schwannomas, meningiomas, ependymomas). NF-2 is transmitted as an autosomal dominant trait. As with NF-1, 50% of cases are sporadic and represent new mutations. Diagnostic criteria are presented in Table 4. Most patients have few or no CALSs; Lisch nodules are generally not seen. Peripheral neurofibromas are not present. Patients have a high frequency of presenile
TABLE 4 Diagnostic Criteria for Neurofibromatosis (NF)-2 Bilateral vestibular schwannomas Unilateral vestibular schwannoma and first-degree relative with NF-2 First-degree relative with NF-2 and any two of the following: Glioma Meningioma Neurofibroma Schwannoma Juvenile posterior subcapsular contract Unilateral vestibular schwannoma with any two of the following*: Meningioma Schwannoma Gliomas Neurofibroma Juvenile posterior subcapsular lenticular opacities Multiple meningiomas and one of the following*: Unilateral vestibular schwannoma Any two of schwannoma, glioma, neurofibroma, cataract *The presence of any one of these criteria is sufficient for the diagnosis of NF-2 except as noted with the asterisk. Any one of criteria with the asterisk is sufficient for probable or presumptive diagnosis.
posterior subcapsular and nuclear cataracts. These predate the symptoms of bilateral acoustic neuromas and sometimes require surgery. Acoustic neuromas or schwannomas are the hallmark of NF-2 and usually appear in late adolescence or early adulthood. They are often bilateral. Hearing loss is the first symptom. Facial weakness is a late complication. Schwannomas of other cranial nerves may also occur and are often multiple. Meningiomas are other intracranial tumors in NF-2. Optic gliomas do not occur. Spinal schwannomas may be multiple and present management difficulties. There may be two types of NF-2: one with early onset, rapid course, and multiple other tumors in addition to bilateral vestibular schwannomas, and the second with late onset, more benign course, and usually only bilateral vestibular schwannomas. As mentioned earlier, age of presentation is late teens to mid twenties. Prognosis is worse overall than in NF-1, with historical survival usually into middle age. This likely has improved with improvement in therapy for the various tumors. The NF-2 gene has been mapped to chromosome 22. NF-2 gene product is schwannomin. This protein shows a close relationship to the family of ERM (ezrin-radixinmoesin) proteins, which serve as linkers of cytoskeleton to membrane proteins. This may be a novel class of tumor suppressor genes. Audiologic evaluation is essential. BAER is often helpful. CT scan and especially MR imaging with gadolinium enhancement are helpful in visualizing even small vestibular schwannomas or acoustic neuromas. Management is symptomatic, with surgery and radiation therapy as appropriate. Johnson: Current Therapy in Neurologic Disease (7/E)
Tuberous Sclerosis Complex
DeBella K, Szudek J, Friedman JM: Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children, Pediatrics 105:608-614, 2000. Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, editors: Neurofibromatosis: phenotype, natural history, and pathogenesis, ed 3, Baltimore, 1999, Johns Hopkins University Press. http://www.genetests.org/ (search term: neurofibromatosis) North KN, Riccardi V, Samango-Sprouse C, et al: Cognitive function and academic performance in neurofibromatosis 1: Consensus statement from the NF-1 Cognitive Disorders Task Force, Neurology 48:1121-1127, 1997. Nunes F, MacCollin M: Neurofibromatosis 2 in the pediatric population, J Child Neurol 18:718-724, 2003. Ruggieri M, Husom SM: The clinical and diagnostic implications of mosaicism in the neurofibromatosis, Neurology 56:1433-1443, 2001.
PATIENT RESOURCES National Neurofibromatosis Foundation 95 Pine Street, 16th Floor New York, NY 10005 Phone: 212-344-NNFF Toll-free phone: 800-323-7938 Fax: 212-747-0004 E-mail:
[email protected] or
[email protected] http://www.nf.org/ Neurofibromatosis, Inc. 8855 Annapolis Road, Suite 110 Lanham, MD 20706-2924 Phone: 301-577-8984 Toll-free phone: 800-942-6825 Fax: 301-577-0016 E-mail:
[email protected] http://www.nfinc.org/
Tuberous Sclerosis Complex John B. Bodensteiner, M.D., and Vinodh Narayanan, M.D.
Tuberous sclerosis complex (TSC) is a disorder that affects many tissues in the body including brain, heart, lungs, kidneys, skin, eyes, and bone. The disease complex is a disorder of cellular differentiation and proliferation resulting in hamartomata and true neoplasms, most prominently in the brain, kidney, and heart. The disease complex results from deletion/mutation abnormalities in either of two genes that work in concert in cell growth control pathways and produce indistinguishable disease manifestations although on average, the patients with TSC2 have a somewhat greater severity of manifest disease than those with TSC1. TSC1 is found on 9q34 (hamartin) and TSC2 on 16p13 (tuberin). Abnormal migration of cerebral neurons plays a central role in the neurologic manifestations of the disease. The prevalence of TSC is estimated at 1 in 6000 to 9000 individuals. Because of the striking variability of the clinical manifestations and severity of the disease, Johnson: Current Therapy in Neurologic Disease (7/E)
the diagnosis remains difficult in individuals with subtle disease manifestations. The clinical diagnostic criteria established for TSC are highly reliable, and patients who meet the clinical diagnostic criteria for definite TSC do not require genetic testing for diagnostic purposes. It is likely that gene testing might be more useful in less obvious cases depending on the clinical situation and the age of the patient in question.
Developmental Disorders
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Clinical Aspects The clinical features of TSC may involve neurologic, psychiatric, behavioral, and cognitive features including epilepsy (especially infantile spasms), mental retardation, pervasive developmental disorder and autism, renal disease and tumors, cardiac tumors, ocular lesions, and pulmonary disease. The characteristic brain lesions are unique enough to be considered part of the diagnostic criteria and include cortical tubers, subependymal glial nodules (SGNs), and subependymal giant cell astrocytomas (SEGAs). Almost any other organ system can be involved with the disease complex in some patients, though any individual usually has only a relatively limited number of organs with significant involvement. We address the most commonly encountered clinical manifestations of TSC. DERMATOLOGIC The dermatologic manifestations of TSC, which are characteristic enough to be considered major features in the diagnostic criteria, include hypomelanotic macules (ash leaf spots), ungual or periungual fibroma, facial angiofibroma (sebaceous adenomas), forehead plaques, and the shagreen patch. The confetti skin lesion is less specific and is considered only a minor feature. The hypomelanotic macules are found on the skin in more than 90% of patients with TSC. The lesions are usually present on the trunk, abdomen, back, or extremities at birth and are more easily seen on a pigmented background or with the use of an ultraviolet light in fair-skinned individuals. Because hypomelanotic macules are often present as single lesions in the normal population, the diagnostic criteria require more than three lesions. The confetti lesions may develop later, after the newborn period, and are usually on the extremities. Facial angiofibromata are fibrovascular lesions that are present in about 75% of patients. They are not present at birth and begin to develop after 2 to 4 years of age. Frequently they are mistaken for acne even though they are noted well before the usual age at which acne is seen. Beginning as small red papules, the lesions increase in number and perhaps size also as the patient ages. Puberty seems to produce the most rapid changes in the number and distribution of the lesions. The angiofibromata are generally distributed over the malar region of the face and may spread over the nasolabial folds on to the chin (frequently sparing the angle of the mouth). Although they are considered specific for TSC, the fact that they are not reliably present limits their use as a
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DeBella K, Szudek J, Friedman JM: Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children, Pediatrics 105:608-614, 2000. Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, editors: Neurofibromatosis: phenotype, natural history, and pathogenesis, ed 3, Baltimore, 1999, Johns Hopkins University Press. http://www.genetests.org/ (search term: neurofibromatosis) North KN, Riccardi V, Samango-Sprouse C, et al: Cognitive function and academic performance in neurofibromatosis 1: Consensus statement from the NF-1 Cognitive Disorders Task Force, Neurology 48:1121-1127, 1997. Nunes F, MacCollin M: Neurofibromatosis 2 in the pediatric population, J Child Neurol 18:718-724, 2003. Ruggieri M, Husom SM: The clinical and diagnostic implications of mosaicism in the neurofibromatosis, Neurology 56:1433-1443, 2001.
PATIENT RESOURCES National Neurofibromatosis Foundation 95 Pine Street, 16th Floor New York, NY 10005 Phone: 212-344-NNFF Toll-free phone: 800-323-7938 Fax: 212-747-0004 E-mail:
[email protected] or
[email protected] http://www.nf.org/ Neurofibromatosis, Inc. 8855 Annapolis Road, Suite 110 Lanham, MD 20706-2924 Phone: 301-577-8984 Toll-free phone: 800-942-6825 Fax: 301-577-0016 E-mail:
[email protected] http://www.nfinc.org/
Tuberous Sclerosis Complex John B. Bodensteiner, M.D., and Vinodh Narayanan, M.D.
Tuberous sclerosis complex (TSC) is a disorder that affects many tissues in the body including brain, heart, lungs, kidneys, skin, eyes, and bone. The disease complex is a disorder of cellular differentiation and proliferation resulting in hamartomata and true neoplasms, most prominently in the brain, kidney, and heart. The disease complex results from deletion/mutation abnormalities in either of two genes that work in concert in cell growth control pathways and produce indistinguishable disease manifestations although on average, the patients with TSC2 have a somewhat greater severity of manifest disease than those with TSC1. TSC1 is found on 9q34 (hamartin) and TSC2 on 16p13 (tuberin). Abnormal migration of cerebral neurons plays a central role in the neurologic manifestations of the disease. The prevalence of TSC is estimated at 1 in 6000 to 9000 individuals. Because of the striking variability of the clinical manifestations and severity of the disease, Johnson: Current Therapy in Neurologic Disease (7/E)
the diagnosis remains difficult in individuals with subtle disease manifestations. The clinical diagnostic criteria established for TSC are highly reliable, and patients who meet the clinical diagnostic criteria for definite TSC do not require genetic testing for diagnostic purposes. It is likely that gene testing might be more useful in less obvious cases depending on the clinical situation and the age of the patient in question.
Developmental Disorders
SUGGESTED READING
103
Clinical Aspects The clinical features of TSC may involve neurologic, psychiatric, behavioral, and cognitive features including epilepsy (especially infantile spasms), mental retardation, pervasive developmental disorder and autism, renal disease and tumors, cardiac tumors, ocular lesions, and pulmonary disease. The characteristic brain lesions are unique enough to be considered part of the diagnostic criteria and include cortical tubers, subependymal glial nodules (SGNs), and subependymal giant cell astrocytomas (SEGAs). Almost any other organ system can be involved with the disease complex in some patients, though any individual usually has only a relatively limited number of organs with significant involvement. We address the most commonly encountered clinical manifestations of TSC. DERMATOLOGIC The dermatologic manifestations of TSC, which are characteristic enough to be considered major features in the diagnostic criteria, include hypomelanotic macules (ash leaf spots), ungual or periungual fibroma, facial angiofibroma (sebaceous adenomas), forehead plaques, and the shagreen patch. The confetti skin lesion is less specific and is considered only a minor feature. The hypomelanotic macules are found on the skin in more than 90% of patients with TSC. The lesions are usually present on the trunk, abdomen, back, or extremities at birth and are more easily seen on a pigmented background or with the use of an ultraviolet light in fair-skinned individuals. Because hypomelanotic macules are often present as single lesions in the normal population, the diagnostic criteria require more than three lesions. The confetti lesions may develop later, after the newborn period, and are usually on the extremities. Facial angiofibromata are fibrovascular lesions that are present in about 75% of patients. They are not present at birth and begin to develop after 2 to 4 years of age. Frequently they are mistaken for acne even though they are noted well before the usual age at which acne is seen. Beginning as small red papules, the lesions increase in number and perhaps size also as the patient ages. Puberty seems to produce the most rapid changes in the number and distribution of the lesions. The angiofibromata are generally distributed over the malar region of the face and may spread over the nasolabial folds on to the chin (frequently sparing the angle of the mouth). Although they are considered specific for TSC, the fact that they are not reliably present limits their use as a
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diagnostic feature. Furthermore, though they are of no functional significance and have no malignant potential, attempted removal is commonly undertaken for cosmetic reasons. The shagreen patch can be found on the back or flank most commonly. It is an irregularly shaped, slightly raised patch of skin that has a texture resembling the surface of a football. This lesion is also found infrequently in younger patients and in only 20% to 30% of patients overall. Ungual fibromas are nodular or fleshy lesions arising at the nail bed. Not usually seen in preadolescent patients with TSC, they occur in only 15% to 20% of the patients with TSC, and though they are considered by many as specific for the disease, similar lesions can result from trauma to the nail beds. We have seen several patients who have undergone procedures to remove the lesions that have been mistaken for warts. RENAL Renal lesions occur in 75% to 80% of patients with TSC. There are two types of renal lesions: cysts (single or multiple) and tumors (angiomyolipomata). Cysts tend to appear early and may be solitary, in which case they may disappear, or the cysts may be so numerous or large as to be symptomatic. Most often the solitary cysts are only an incidental feature. The presence of multiple cysts and multiple angiomyolipomata is characteristic of TSC. Bilateral tumors with many angiomyolipomata per kidney are typical. The prevalence and size of the renal tumors increase with age, so they must be followed serially with ultrasonography. Lesions that reach more than 4 cm in diameter are more likely to become symptomatic than are the smaller ones (hemorrhage into the tumor causing pain, hematuria, or acute renal failure), and the lesions that attain that size usually are treated with embolization or surgical intervention. There is a small but definite risk (3) Shagreen patch (connective tissue nevus) Subependymal nodule Cortical tuber* Subependymal giant cell astrocytoma Multiple retinal nodular hamartomata Cardiac rhabdomyomata, single or multiple Lymphangiomyomatosis† Renal angiomyolipomata
Developmental Disorders
seizures are multifocal or generalized and a single epileptic focus cannot be identified. Most patients with seizures and TSC are retarded, but many patients with TSC and mental retardation do not have seizures. There is a rough correlation between the severity of cognitive impairment and the number and size of the cortical tubers. There is also a rough correlation between the number and size of the cortical lesions and the likelihood of behavioral disorders including autism, hyperkinesis, frank psychosis, and particularly aggressiveness, which is likely to worsen about puberty. The percentage of patients with TSC who will manifest severe behavior disturbances is not well established, but the onset of aggressive behavior near the time of puberty is characteristic of TSC in our experience. The intracranial tubers are well-localized hamartomata and do not enlarge over time. The SGNs have the potential to enlarge as the patient ages. Most SGNs are less than 2 cm in size; however, the most common location is at the level of the foramen of Monro, which can be obstructed, leading to unilateral or bilateral ventricular obstruction and hydrocephalus, which may produce acute of subacute changes in neurologic function of the affected patient. Some people believe the SEGAs represent enlarged SGNs, but there is some evidence that they are different lesions histologically. In either case, this subependymal lesion may have the potential to enlarge, and lesions larger than 1 cm are the ones most likely to do so. The frequency of this event is not well established but is sufficient to justify longitudinal evaluation of these patients. Once a SEGA begins to grow, it can be locally invasive. Because surgical removal is curative, the identification of an enlarging SEGA before the onset of symptoms has therapeutic implications.
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Minor Features Multiple, randomly distributed dental enamel pits Hamartomatous rectal polyps‡ Bone cysts§ Cerebral white matter “migration tracts”*,§ Gingival angiofibromata Nonrenal hamartomata‡ Retinal achromic patch “Confetti” skin lesions Multiple renal cysts‡ Definite TSC Either 2 major features or 1 major feature and 2 minor features Probable TSC One major feature plus 1 minor feature Suspect TSC Either 1 major feature or 2 or more minor features *When cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of TSC. †When both lymphangiomyomatosis and renal angiomyolipomas are present, other features of TSC should be present before a definite diagnosis is assigned. ‡Histologic confirmation is suggested but not required. §Radiographic confirmation is sufficient. Modified from Roach ES, Gomez MR, Northrup H: Tuberous Sclerosis Complex Consensus Conference: revised clinical diagnostic criteria, J Child Neurol 13:624-628, 1998.
Infantile spasms are so characteristic of TSC that they were part of the diagnostic criteria in the past. The evaluation of patients with infantile spasms always includes a careful evaluation of the integument of the patient and parents as well as family history. In this setting it is important to remember the ultraviolet light because at 4 to 6 months of age, when infantile spasms most frequently begin, the depigmented macules may not be readily apparent without the Wood’s light. EEG is necessary to make the diagnosis of infantile spasms but is not useful in the diagnosis otherwise. Neuroimaging is considered part of the evaluation of these seizures and generally MR imaging is considered the study of choice because a good-quality study will identify even the small uncalcified SGNs. Though vigabatrin is touted as the drug of choice for infantile spasms associated with TSC, the recently published practice parameter concluded that there was insufficient evidence to conclude
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valproate is started with the intent that it will be used as the maintenance drug when the steroid is stopped. We do an echocardiogram at the onset of therapy and follow blood pressures weekly, and if the patient develops hypertension we repeat the echo. If the repeat echo shows thickening of the myocardium, we begin the taper of the ACTH at that point. About two thirds of the patients develop hypertension and myocardial hypertrophy, which is transient and therapy related. The child who presents with seizures may already be suspected of having TSC. Stereotypic, focal seizures in a small infant should prompt the search for focal cortical dysplasias, including the cortical tubers of TSC. The evaluation includes EEG, MR imaging, and a search for other characteristic features. The choice of AED is made on the same basis as with any other seizure patient, that is, the seizure type and the EEG findings. Diagnosis in this context frequently has a major impact on prognosis and also frequently necessitates genetic counseling. Once the diagnosis is suspected, cardiac and renal ultrasound examinations are appropriate. Features that suggest the need for further or more intensive follow-up include SGN or SEGA larger than 1 cm in diameter or located precisely at the foramen of Monro on MR imaging. Renal ultrasound revealing an angiomyolipoma greater than 4 cm in size requires intervention, but smaller lesions require periodic evaluations to follow their growth. The discovery of TSC in a patient being evaluated for mental retardation or delayed acquisition of motor milestones is a relatively frequent event in practice. The principal components of the evaluation would include a careful history and physical examination, including a search of the integument and examination of the family members. MR imaging is the imaging study most likely to provide diagnostic information. On several occasions, we have made the diagnosis in a parent who was unaware of this condition. MR is the imaging study most likely to provide diagnostic information. Cardiac and renal ultrasound studies provide a baseline and help design the serial examination schedule. The patient referred from the renal or dermatology clinic for the possible diagnosis of TSC should be
TABLE 2 Important Aspects of the Evaluation of the Patient with TSC Presenting Signs and Symptoms Infantile spasms Seizures in childhood Mental retardation Seizures in a renal patient Skin abnormalities: white patches, acne-like lesions, shagreen patch, wartlike lesions under nails Important History Features Family history: epilepsy, mental retardation, skin lesions, consanguinity Autistic features Cardiac tumor in infancy Renal cysts or tumors Skin lesions Seizures Important Examination Features Integument Funduscopic Nail beds Malar rash Gingival angiofibromata Diagnostic Tests EEG if appropriate for seizures MR imaging or, if necessary, CT Renal ultrasound examination Cardiac ultrasound examination, if indicated Wood’s lamp (ultraviolet) examination of the integument Ophthalmologic examination TSC, Tuberous sclerosis complex; EEG, electroencephalogram.
that vigabatrin is effective in these seizures. We use adrenocorticotropic hormone (ACTH), 150 units/m2, as a once-daily injection as the primary therapy for infantile spasms. A 4-week course of everyday therapy is completed if possible. Then the patient is switched to every other day, and a taper is begun that lasts over 6 to 8 weeks. When ACTH is changed to every other day,
TABLE 3 Suggested Serial Examinations for Various Abnormalities in Patients with TSC Lesion Location
Abnormal Finding
Size
MRI Identification SGN or SEGA
Lesion < 1 cm in diameter Lesion > 1 cm in diameter
Ultrasonographic Identification Renal cysts or renal angiomyolipoma
Recommendation
Lesion at foramen of Monro Lesion elsewhere on ependymal surface Lesion at foramen of Monro Lesion elsewhere on ependymal surface
MRI q 1-2 yr if asymptomatic MRI q 3-5 yr MRI q yr MRI q 1-2 yr if asymptomatic
Lesion < 4 cm in diameter
Repeat renal ultrasound q yr
Lesion > 4 cm in diameter
Treatment advised
TSC, Tuberous sclerosis complex; SGN, subependymal glial nodule; SEGA, subependymal giant cell astrocytoma.
Johnson: Current Therapy in Neurologic Disease (7/E)
Tuberous Sclerosis Complex
Genetics, Genetic Testing, and Genetic Counseling About two thirds of the cases of TSC are sporadic, and the remaining cases are familial. The inheritance pattern is autosomal dominant. In most patients, the diagnosis can be made by clinical examination and radiologic studies. Genetic testing is not a part of the routine diagnostic evaluation. More than 300 distinct mutations in the TSC1 and TSC2 genes have been identified, and these are scattered over all the exons of the two genes. This makes the job of mutation detection difficult. Research studies looking for mutations in either TSC1 or TSC2 among sporadic patients with TSC report an identification rate of between 60% and 80%. The question of looking for a mutation in one of the two TSC genes comes up in certain special circumstances, and most of these deal with genetic counseling. One of these comes about because of the phenomenon of germinal mosaicism. This might be suspected when there are two or more affected children in a family, without any evidence of the disorder in either parent or other family members. Knowing the genetic mutation in the children allows us to define the carrier status of the parents, as well as to differentiate between germinal mosaicism in a parent and different spontaneous mutations in the children. A second scenario in which genetic testing may be useful is when the diagnosis is made in the child of a young unaffected couple. Again, the problem in providing accurate genetic risk information is because of the phenomenon of germinal mosaicism in a parent. Identification of the mutation in the affected child will permit prenatal testing in future pregnancies. A third setting in which genetic testing is done is when clinical and radiologic testing is not conclusive, and early diagnosis is important (e.g., when the mother is pregnant). In this situation, identification of a genetic mutation (as distinct from a polymorphism) is helpful, Johnson: Current Therapy in Neurologic Disease (7/E)
TABLE 4 Genetic Testing in Tuberous Sclerosis Complex Indications Diagnostic confirmation in a suspected case Prenatal testing in an unaffected mother with a single affected child Testing for germinal mosaicism in unaffected parents with more than one affected child Testing in familial cases for genetic counseling
Developmental Disorders
approached just like the patient with seizures or mental retardation with signs of TSC. Frequently, though they may have been identified as possibly having TSC, the patients referred from other medical clinics have not had the disease, its genetics, and implications explained to them or the family. The long-term management of patients with TSC includes treatment of active neurologic problems (seizures, behavior problems, mental retardation), as well as surveillance testing to prevent complications from known hamartomata. Surveillance testing usually consists of brain MR imaging, renal ultrasonography, and ophthalmologic examination. Serial brain imaging is aimed at identifying enlarging SGNs (which might actually be astrocytomas) and SEGAs, as well as detecting ventricular obstruction at the foramen of Monro. Serial renal ultrosonography is aimed at identifying renal cysts that are at risk for rupture or renal angiomyolipamas that are larger than 4 cm and are at risk for hemorrhage and other complications (see Table 3).
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Current Methods Amplification of exons and screening by DHPLC Direct sequencing of selected exons Future Methods Direct sequencing of TSC1 and TSC2 genes by microarray hybridization Resources: http://www.genetests.org/ DHPLC, Denaturing high-performance liquid chromatography.
but failure to define a gene mutation should not be interpreted as ruling out the diagnosis. This is because of the limitations of the methods used to screen for mutations, and the fact the known mutations in TSC1 and TSC2 are scattered over the entire extent of the genes. SUGGESTED READING Kandt RS: Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases, Neurol Clin North Am 20:941-964, 2002. Mackay MT, Weiss SK, Adams-Webber T, et al: Medical treatment of infantile spasms, Neurology 62:1668-1681, 2004. Roach ES, DiMario FJ, Kandt RS, Northrup H: Tuberous Sclerosis Consensus Conference: recommendations for diagnostic testing, J Child Neurol 14:401-407, 1999. Roach ES, Gomez MR, Northrup H: Tuberous Sclerosis Complex Consensus Conference: revised clinical diagnostic criteria, J Child Neurol 13:624-628, 1998. Shevell M, Ashwal S, Donley D, et al: Evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology; Committee of the Child Neurology Society, Neurology 60:367-380, 2003.
PATIENT RESOURCE Tuberous Sclerosis Alliance 801 Roeder Road, Suite 750 Silver Spring, MD 20910 Phone: 301-562-9890 Toll-free phone: 800-225-6872 http://www.tsalliance.org
[email protected]/
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Sturge-Weber Syndrome
Sturge-Weber Syndrome Anne Comi, M.D.
Sturge-Weber syndrome (SWS) is the third most common neurocutaneous disorder and occurs sporadically. There is typicallya facial port-wine stain in the ophthalmic distribution of the trigeminal nerve, glaucoma and vascular eye abnormalities, and a parieto-occipital leptomeningeal angioma ipsilateral to the cutaneous and ocular anomalies. The usual presentation is in infancy; however, presentation with first seizure and subsequent diagnosis is known to occur in adulthood. Somatic mutation has been proposed as a possible etiology; however, the putative gene is unknown. Patients with SWS often develop neurologic problems including seizures, migraines, strokelike episodes, learning difficulties or mental retardation, visual field cuts, and hemiparesis. These problems frequently persist into adulthood and can be further complicated by psychological problems and difficulty establishing independence from the family of origin. Multiple specialists, including a neurologist, ophthalmologist, dermatologist, medical rehabilitation specialist, occupational and physical therapists, speech and language pathologist, psychiatrist, and behavioral psychologist, are therefore often involved in the care of individuals with SWS (Figure 1).
Presentations The diagnosis of SWS can frequently be suspected when an individual is noted to have a facial port-wine stain. The diagnosis of SWS means that the cutaneous port-wine stain is associated with either brain or eye involvement. The risk of an associated underlying leptomeningeal angioma and/or glaucoma is about 8% with a port-wine stain anywhere on the face. Thus, most patients with a facial port-wine stain do not have SWS. This risk increases to about 25% when the skin angioma is in the cranial nerve V1 ophthalmic distribution on the face. A careful examination of the upper eyelid may reveal cutaneous involvement of just a few millimeters in some cases. The risk of intracranial involvement increases to 33% with bilateral facial port-wine stains. In approximately 85% of individuals with SWS, the involvement is unilateral with the brain and eye involvement on the same side as the port-wine stain. However, a unilateral port-wine stain can be paired with bilateral leptomeningeal angioma involvement or vice versa. The most frequent presentation for the neurologic manifestations in SWS is focal and complex partial seizures in an infant with a facial port-wine stain. Onset of seizures is usually in the first 2 years of life but occasionally can start later in childhood or even adulthood. Other presentations for SWS include a visual field cut presenting as an infant that neglects a hemivisual space or the early onset of handedness in a child with a facial port-wine stain. An adult can present with a facial
port-wine stain and new onset of complex partial seizures and a strokelike episode with hemiparesis following the event. In each case, a thorough assessment of involvement is needed so that the patient and family can be appropriately counseled and treatment initiated.
Diagnosis and Evaluation Any child with a facial port-wine stain in the cranial nerve V1 distribution, or an adult presenting with this and neurologic symptoms, should have a head computed tomography (CT) scan to image the calcification and magnetic resonance (MR) imaging of the brain with and without contrast to detect the angioma. The typical CT findings are cortical calcifications often in a gyral pattern and atrophy, although these findings may not be present in neonates or infants. The brain MR scan demonstrates increased T2-weighted signal in the white matter and focal meningeal enhancement. When possible, we also ask for postcontrast fluid-attenuated inversion recovery (FLAIR) imaging because this appears to have greater sensitivity for visualizing the angioma. Imaging with technetium-99m hexamethylpropyleneamine oxime single-photon emission CT (SPECT) or perfusion MR imaging is useful for assessing the extent and localization of the perfusion defects and metabolic imaging with fluorodeoxyglucose positron emission tomography (FDG-PET) or MR spectroscopy may also be helpful in characterizing the extent of brain disease in SWS. If MR imaging is negative in infancy, one may need to repeat it by the first birthday or with the onset of neurologic symptoms. Close neurologic and developmental follow-up is essential for children with SWS to diagnose and treat developmental delays, seizures, headaches, hemiparesis, learning difficulties, and behavioral issues as they arise. Most children with SWS require occupational and physical therapy for their hemiparesis and visual field cut. Developmental and neuropsychological assessments can be quite helpful for addressing attentional issues and learning difficulties. Attention deficit disorder occurs in about 20% and mental retardation in about 50% of children and adults with SWS. Screening for glaucoma should be done at birth, under anesthesia if necessary, and then at least every 3 to 4 months in the first year, every 6 months in the second year, and yearly thereafter. The peak time for diagnosis of glaucoma is in infancy, but a second smaller peak occurs in young adulthood. Ophthalmologic evaluations can determine the extent of abnormal vessel involvement with the eye. Patients with port-wine stains involving both the upper and the lower eyelids are at the greatest risk for glaucoma. Glaucoma in the young child can present with eye enlargement (buphthalmos) or with corneal clouding and vision loss at any time, and these signs and symptoms need urgent evaluation. Patients with a port-wine stain are also referred for dermatologic assessment. In infancy the port-wine stain is often pink and flat. The port-wine stain generally grows commensurate with growth and often darkens or Johnson: Current Therapy in Neurologic Disease (7/E)
Sturge-Weber Syndrome
Patient with facial port-wine stain including the V1 trigeminal nerve distribution
Dermatologic and ophthalmologic evaluations
Obtain MRI of the brain with and without contrast Normal
Abnormal
Consider reimaging and metabolic imaging with perfusion MRI, SPECT or FDG-PET
Provide Diastat, anticipatory guidance for seizures, daily multivitamin, screen for iron deficiency anemia, anticipatory guidance for illness and avoidance of dehydration and close neurodevelopmental follow-up
Developmental Disorders
FIGURE 1. Evaluating a patient with facial cutaneous capillovascular malformation (port-wine stain). SPECT, Single-photon emission computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography; AED, antiepileptic drug; EEG, electroencephalogram.
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Have seizures occurred? No Close neurologic follow-up
Yes Aggressive seizure management: First line AED: Carbamazepine Second line AED: Valproic acid or topiramate Maintain high-normal blood levels of AED Diastat for seizure >5 minutes If unsuccessful, consider video EEG Monitoring and PET imaging for surgery
Have focal weakness or stroke-like episodes? No Close neurologic follow-up
may become raised with time. It is recommended that port-wine stains be treated in infancy, before hypertrophy and blebbing develop and make treatment more difficult. Later in childhood, plastic surgery may be judiciously considered to deal with the tissue hypertrophy that can occur in the region of the port-wine stain. Presenting the diagnosis of SWS to patients and parents is complex and requires the coordinated input of multiple specialists to address the different organ systems involved in this disorder. It is essential that time is spent answering questions so that seizures, strokelike episodes, and other complications are recognized and appropriately managed to minimize brain injury.
Therapy In all patients with SWS and intracranial involvement, I advise the empirical use of a daily multivitamin. Patients with SWS should be screened for iron deficiency anemia, which is relatively common in young children and some adults and, if present, could exacerbate ischemic brain injury and should be treated. Johnson: Current Therapy in Neurologic Disease (7/E)
Yes Occupational/physical therapy Low dose aspirin 3–5 mg/kg/day if stroke-like episodes present
SEIZURES Infants with SWS typically develop complex partial seizures in the first 3 years of life, most in the first year. It is essential that family members receive counseling regarding what seizures look like and how to obtain help rapidly for a first seizure. Seizures are managed acutely with benzodiazepines, phosphenytoin, and, if necessary, phenobarbital. A prolonged hemiparesis, lasting days, weeks, or months is common after a seizure episode, and a permanent hemiparesis frequently develops over time. Although controversial, there is evidence that seizures, particularly if they are frequent or prolonged, may result in increased brain injury resulting from the impairments in blood flow. Therefore, chronic anticonvulsants should be initiated after the first seizure, whether febrile or afebrile, in a patient with SWS and brain involvement. Vigorous efforts should be made to gain control of seizures. I recommend medication levels (when applicable) at least in the high-therapeutic range and regular adjustments of dose for weight gain to best maintain seizure control. Generally the first-choice anticonvulsant is carbamazepine, or phenobarbital transitioning to carbamazepine, depending on the age of the child, because
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most seizures in SWS are complex partial. Oxcarbazine (Trileptal) may also be used. Second-line choices include topiramate and valproic acid. Rectal or oral diazepam is given to the family for use with seizures lasting longer than 5 minutes or with clusters of seizures. Seizures in SWS, as in other settings, commonly occur during illness. I advise family members and patients to treat fevers and maintain good hydration during illness, even if intravenous fluids are needed. I advise continuing the anticonvulsant for a few years, until the fifth birthday if possible, because older children appear to be less susceptible to permanent neurologic decline that may be exacerbated by seizures in the younger children. If seizures are not controlled with anticonvulsants, are occurring frequently so as to interfere with development, or deterioration in neurologic status is occurring, then children should be considered for surgical resections. Surgery may include focal resections or hemispherectomies. Most candidates for surgery have significant developmental delay and hemiparesis. Timing of surgery should be carefully weighed for risks and benefits; however, in the appropriate situation surgery can result in cessation of seizures and resumption in development. There is no evidence that surgical resection of the affected cortex is the proper course of action in the absence of intractable epilepsy.
precede the onset of seizures or strokelike episodes. When frequent, valproic acid may provide prophylaxis for both seizures and recurrent headaches. Alternatively, a combination of an anticonvulsant, such as carbamazepine, and a calcium channel blocker or beta blocker may be required. COGNITIVE AND PSYCHOLOGICAL ISSUES Learning disabilities and mental retardation frequently develop in SWS and need to be evaluated and addressed educationally. Attention deficit disorder is common in SWS and should be addressed with a combination of behavioral and pharmacologic approaches. When behavioral approaches are insufficient, then treatment with either a stimulant or atomoxetine should be initiated and response closely monitored. Depression and anxiety are also common in SWS. Older children and adolescents can demonstrate a decline in function or new behavioral issues, and psychological factors should be evaluated when this occurs. Treatment with a selective serotonin reuptake inhibitor or tricyclic may be helpful. However, the safety and efficacy of these approaches have not been studied specifically in SWS.
STROKELIKE EPISODES
Treatment of Ophthalmologic and Dermatologic Complications
Strokelike episodes can occur in SWS and present as episodes of transient visual field cuts or weakness that can occur independent of seizures or may precede or follow seizures. It is not entirely clear what these episodes represent; however, thrombosis, hypoxia-seizure, complicated migraine, and/or seizure activity all may have some role in these episodes. Minor head trauma can trigger these events as well. I recommend prophylactic use of aspirin when strokelike episodes have occurred. Experience with its use in the prevention of pediatric stroke, and anecdotal evidence in SWS, suggest that low-dose aspirin at 3 to 5 mg/kg/day is safe and effective; however no randomized, placebo-controlled trial has been done. Children on aspirin therapy should receive varicella immunization and the yearly influenza vaccine because of the association between these illnesses, aspirin use, and Reye’s syndrome in children. The international experience with low-dose aspirin use for stroke prophylaxis in children, however, suggests that this therapy is safe. Preventing severe illness with these vaccinations is probably a good idea anyway because episodes of deterioration in SWS often occur in the setting of illness. Occupational and physical therapies are prescribed when weakness is persistent to maximize function and prevent contractures.
Treatment of the port-wine stain requires a series of laser treatments. Pulsed-dye laser can improve the appearance of the vascular malformation in about 10 treatments. Without treatment, the port-wine stains often develop blebbing and hypertrophy of underlying soft tissue and bone that can lead to significant psychological and functional issues depending on the location and extent of involvement. It is unknown if infancy is the best time for treatment of SWS, given the other systems involved; however, the current practice in SWS is to treat the port-wine stain early. Laser treatments are painful and can occasionally result in scarring, and older children should therefore be included in discussions for timing for treatment. Glaucoma may occur at any age, although two peaks exist in infancy and in early adulthood. The goal of treatment is to reduce intraocular pressure to protect vision. Medical and surgical approaches are used and concentrate on either reducing the production of aqueous fluid or promoting its drainage. Medications include beta-agonist eye drops, adrenergic eye drops, and carbonic anhydrase inhibitors. Trabeculectomy and goniotomy are common surgical options. SUGGESTED READING
HEADACHES Headaches and migraines are also common in SWS. Acutely, antimigraine medications such as ibuprofen are used; however, the safety of triptans has not been studied in SWS. In older children and adults, it seems that seizures can provoke headaches, and headaches can
Bodensteiner JB, Roach ES, editors: Sturge-Weber syndrome, Mt. Freedom, NJ, 1999, Sturge-Weber Foundation. Chapieski L, Friedman A, Lachar D: Psychological functioning in children and adolescents with Sturge-Weber syndrome, J Child Neurol 15:660-665, 2000. Comi AM: Pathophysiology of Sturge-Weber syndrome, J Child Neurol 18:509-516, 2000. Johnson: Current Therapy in Neurologic Disease (7/E)
Autism
PATIENT RESOURCES Sturge-Weber Foundation P.O. Box 418 Mt. Freedom, NJ 07970 Phone: 800-627-5482 Fax: 973-895-4846 http://www.sturge-weber.com/ The Kennedy Krieger Institute and Johns Hopkins Medicine Sturge-Weber Syndrome Center 707 N Broadway Baltimore, MD 21205 Phone: 443-923-9128 Fax: 443-923-9160 http://www.sturge-weberkennedy krieger.org
Autism Andrew W. Zimmerman, M.D.
Autism is a heterogeneous group of lifelong neurobehavioral syndromes, now referred to as autism spectrum disorders (ASDs), that result from abnormal early neural development with appearance of initial symptoms by the age of 3 years. Known etiologies are detectable in up to 10% of patients, although the causes in most are still unknown. Patients typically present with delayed or disordered language development, abnormal social relatedness, and repetitive, odd behaviors. Autistic symptoms and cognitive deficits vary widely among patients in their age at onset, severity, and clinical course. Regression in previously acquired language and social skills occurs in approximately 30%, usually between 18 and 21 months. “Classic,” or Kanner-type, autism is grouped with other ASDs (or pervasive developmental disorders [PDDs] in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), including Asperger’s syndrome and PDD/NOS (“not otherwise specified”). Idiopathic autism is genetic; concordance for the broad autism spectrum in monozygotic twins is 90% and in dizygotic twins, 10%. The recurrence risk for a family with one child with autism is up to 9%. The disorders typically affect boys more than girls (4:1) and occur in all cultural and racial groups. The estimated prevalence of ASDs is 1:250 to 500 and appears to be increasing. However, this may result in part from broader definition and improved recognition in recent years. In any case, autism is now the most common neurodevelopmental disorder. Johnson: Current Therapy in Neurologic Disease (7/E)
Neuropathologic findings in autism postmortem brain tissue include altered neuronal populations in the limbic system, decreased Purkinje cells, altered cortical minicolumns, increased white matter, and neuroglial activation. Most of the findings are consistent with abnormal developmental programs of prenatal onset. These altered programs could result in observations of altered neuropeptides at birth, accelerated brain growth during infancy, and increased platelet serotonin. In addition to genetic influences, epigenetic and environmental factors may affect selectively vulnerable neural networks through multiple mechanisms. Several neurobiologic processes have been implicated in the pathogenesis of autism, including abnormal neurotransmitters, experience-dependent synaptic plasticity, glutamate excitotoxicity, and neuroimmune mechanisms.
Developmental Disorders
Kossoff EH, Buck C, Freeman JM: Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide, Neurology 59: 1735-1738, 2002. Maria BL, Neufeld JA, Rosainz LC, et al: Central nervous system structure and function in Sturge-Weber syndrome: evidence of neurologic and radiologic progression, J Child Neurol 13:606-618, 1998. Rothfleisch JE, Kosann MK, Levine VJ, Ashinoff R: Laser treatment of congenital and acquired vascular lesions, Dermatol Clin 20:1-18, 2002.
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Diagnosis and Evaluation Early detection of autism is important because early intensive intervention improves outcome for most children. An effective screening tool for autism is the Modified Checklist for Autism in Toddlers (M-CHAT) (available at http://www.firstsigns.org/). Clinical indicators for a more structured evaluation include (1) failure to point at objects to get another’s attention (normally present at 12 months of age); (2) impaired receptive and expressive language (e.g., failure to use single words by 18 months, 2-word phrases by 2 years, answer “what,” “where,” and “who” questions by 3 years); and (3) the use of sustained high-pitched sounds (“eeeee”) or echolalia. An exception is Asperger’s syndrome, in which semantics are usually spared. Early signs of abnormal social relatedness may include difficulty engaging in “peek-aboo” games, making and maintaining eye contact, and showing reciprocal emotion. The child may be affectionate on his or her own terms or relate to older children and adults rather than peers. Children and adults with ASDs lack “theory of mind”: they are unable to perceive the thoughts and feeling states of others. Repetitive and stereotypic behaviors may include waving the hands in the lateral visual fields, flapping the hands, and ordering objects. Persons with autism exhibit an insistence on “sameness” without apparent meaning. Certain autistic behaviors, such as covering the ears, scratching the skin, and repeating visual patterns, may result from abnormal neurophysiologic processing of sensory inputs. A preliminary impression of ASD in preschool children, based on observation and screening tests (e.g., M-CHAT or Childhood Autism Rating Scale [CARS]), should be followed by a coordinated team evaluation (physician, speech and language pathologist, and psychologist). The diagnosis is confirmed and further defined using the Autism Diagnostic Observation Schedule (ADOS) or Autism Diagnostic Interview-Revised (ADI-R), both of which are administered by specially trained testers. Evaluations should also include assessments of cognitive functions and adaptive skills. All children should have audiologic, speech and language therapy (SLT), and occupational therapy (OT) evaluations. It is important to rule out hearing loss using age-appropriate
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Autism
PATIENT RESOURCES Sturge-Weber Foundation P.O. Box 418 Mt. Freedom, NJ 07970 Phone: 800-627-5482 Fax: 973-895-4846 http://www.sturge-weber.com/ The Kennedy Krieger Institute and Johns Hopkins Medicine Sturge-Weber Syndrome Center 707 N Broadway Baltimore, MD 21205 Phone: 443-923-9128 Fax: 443-923-9160 http://www.sturge-weberkennedy krieger.org
Autism Andrew W. Zimmerman, M.D.
Autism is a heterogeneous group of lifelong neurobehavioral syndromes, now referred to as autism spectrum disorders (ASDs), that result from abnormal early neural development with appearance of initial symptoms by the age of 3 years. Known etiologies are detectable in up to 10% of patients, although the causes in most are still unknown. Patients typically present with delayed or disordered language development, abnormal social relatedness, and repetitive, odd behaviors. Autistic symptoms and cognitive deficits vary widely among patients in their age at onset, severity, and clinical course. Regression in previously acquired language and social skills occurs in approximately 30%, usually between 18 and 21 months. “Classic,” or Kanner-type, autism is grouped with other ASDs (or pervasive developmental disorders [PDDs] in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), including Asperger’s syndrome and PDD/NOS (“not otherwise specified”). Idiopathic autism is genetic; concordance for the broad autism spectrum in monozygotic twins is 90% and in dizygotic twins, 10%. The recurrence risk for a family with one child with autism is up to 9%. The disorders typically affect boys more than girls (4:1) and occur in all cultural and racial groups. The estimated prevalence of ASDs is 1:250 to 500 and appears to be increasing. However, this may result in part from broader definition and improved recognition in recent years. In any case, autism is now the most common neurodevelopmental disorder. Johnson: Current Therapy in Neurologic Disease (7/E)
Neuropathologic findings in autism postmortem brain tissue include altered neuronal populations in the limbic system, decreased Purkinje cells, altered cortical minicolumns, increased white matter, and neuroglial activation. Most of the findings are consistent with abnormal developmental programs of prenatal onset. These altered programs could result in observations of altered neuropeptides at birth, accelerated brain growth during infancy, and increased platelet serotonin. In addition to genetic influences, epigenetic and environmental factors may affect selectively vulnerable neural networks through multiple mechanisms. Several neurobiologic processes have been implicated in the pathogenesis of autism, including abnormal neurotransmitters, experience-dependent synaptic plasticity, glutamate excitotoxicity, and neuroimmune mechanisms.
Developmental Disorders
Kossoff EH, Buck C, Freeman JM: Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide, Neurology 59: 1735-1738, 2002. Maria BL, Neufeld JA, Rosainz LC, et al: Central nervous system structure and function in Sturge-Weber syndrome: evidence of neurologic and radiologic progression, J Child Neurol 13:606-618, 1998. Rothfleisch JE, Kosann MK, Levine VJ, Ashinoff R: Laser treatment of congenital and acquired vascular lesions, Dermatol Clin 20:1-18, 2002.
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Diagnosis and Evaluation Early detection of autism is important because early intensive intervention improves outcome for most children. An effective screening tool for autism is the Modified Checklist for Autism in Toddlers (M-CHAT) (available at http://www.firstsigns.org/). Clinical indicators for a more structured evaluation include (1) failure to point at objects to get another’s attention (normally present at 12 months of age); (2) impaired receptive and expressive language (e.g., failure to use single words by 18 months, 2-word phrases by 2 years, answer “what,” “where,” and “who” questions by 3 years); and (3) the use of sustained high-pitched sounds (“eeeee”) or echolalia. An exception is Asperger’s syndrome, in which semantics are usually spared. Early signs of abnormal social relatedness may include difficulty engaging in “peek-aboo” games, making and maintaining eye contact, and showing reciprocal emotion. The child may be affectionate on his or her own terms or relate to older children and adults rather than peers. Children and adults with ASDs lack “theory of mind”: they are unable to perceive the thoughts and feeling states of others. Repetitive and stereotypic behaviors may include waving the hands in the lateral visual fields, flapping the hands, and ordering objects. Persons with autism exhibit an insistence on “sameness” without apparent meaning. Certain autistic behaviors, such as covering the ears, scratching the skin, and repeating visual patterns, may result from abnormal neurophysiologic processing of sensory inputs. A preliminary impression of ASD in preschool children, based on observation and screening tests (e.g., M-CHAT or Childhood Autism Rating Scale [CARS]), should be followed by a coordinated team evaluation (physician, speech and language pathologist, and psychologist). The diagnosis is confirmed and further defined using the Autism Diagnostic Observation Schedule (ADOS) or Autism Diagnostic Interview-Revised (ADI-R), both of which are administered by specially trained testers. Evaluations should also include assessments of cognitive functions and adaptive skills. All children should have audiologic, speech and language therapy (SLT), and occupational therapy (OT) evaluations. It is important to rule out hearing loss using age-appropriate
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Autism
audiometric techniques or, if necessary, brainstem auditory evoked responses. Structured behavioral therapies (e.g., applied behavioral analysis) should be considered for young children, with assisted programming based on psychological and educational testing in school-age children. Additional help with play or social skills groups may be needed. The differential diagnosis of ASD includes more than 100 conditions that show autistic behaviors. Many of these include “double syndromes,” in which the phenotype of autism is associated with another disorder of known cause, such as Rett, Down, and fragile X syndromes, and tuberous sclerosis. Rett syndrome results from defects in the methyl-CpG-binding protein 2 (MeCP2) gene and affects mainly females, who regress after the first year of life and often develop seizures and typical hand-wringing movements. Fragile X syndrome, due to expansion of trinucleotide repeats within the FMR1 gene, is a major cause of mental retardation and may present with “autism” in boys, as well as learning disabilities in girls. Autism, by itself, in most cases does not have an identifiable cause. Identification of a specific etiology can have important implications for prognosis and treatment, such as for seizures and mitochondrial dysfunction. Neurologic evaluations for ASDs should include histories of the prenatal and perinatal periods, early development, infections, gastrointestinal (GI) and immune functions, and seizures. The family history may reveal conditions concurrent with autism or elements of ASDs (e.g., difficulties with social or pragmatic language skills). The neurologic examination, often a challenge to perform, should include direct observation of the child’s communication and play behaviors; evaluation of receptive, expressive, and social aspects of language; measurements of growth; notation of dysmorphic features; and Wood’s lamp examination.
Laboratory Testing Recommendations for laboratory testing in children with autism range from no studies to a comprehensive evaluation. In my opinion basic laboratory studies in children with ASDs should include complete blood count, serum chemistries (including aspartate aminotransferase [AST]/amino alanine transferase [ALT] and creatine kinase), red blood cell lead levels, and thyroid function. Marginal or low hemoglobin levels occur frequently, especially in children with restricted food preferences. Genetic testing should include a karyotype with subtelomere screening by fluorescence in situ hybridization (FISH), and fragile X by DNA (in girls as well as boys). If there has been regression of language and other skills, further testing of mitochondrial function is indicated, including fasting lactic acid, serum carnitine, plasma amino and urinary organic acids; the ratios of plasma alanine-to-lysine should normally be less than 3:1 and serum AST/ALT less than 2:1. An overnight or extended electroencephalographic (EEG) study including deep natural sleep is also suggested, to evaluate for
seizure activity (atypical Landau-Kleffner syndrome). Other tests may be indicated for specific syndromes, such as 7-dehydrocholesterol for Smith-Lemli-Opitz syndrome, FISH for velocardiofacial and Angelman’s syndrome, transferrin electrophoresis for congenital disorders of glycosylation, 24-hour urinary uric acid for “purine autism,” and serum ammonia levels. Cranial computed tomography (CT), single-photon emission CT, and magnetic resonance (MR) scans are generally not performed routinely and should be reserved for those with special indications based on the history and neurologic examination. Other imaging methods, such as positron emission tomography, functional MR imaging, and MR spectroscopy, are strictly research tools.
Treatment Established therapies for autism include individualized special school programs and speech/language and behavioral therapies in a setting that is coordinated, structured, and predictable and contains visual supports and high degrees of reinforcement. Beginning therapies early takes advantage of potential synaptic plasticity. Although most children improve, an individual child’s trajectory for improvement varies over time. Outcomes for independent functioning correlate with attainment of functional language and adaptive skills by school age. Periodic, regular assessments should include cognitive, social skills and educational testing, in additional to SLT, OT, and occasionally physical therapy. Drug therapies for ASDs (Figure 1) are symptomatic and are chosen to improve short-term function and behavior such as calming, improving attention, or reducing aggression to enable the child to remain in the classroom. There is no evidence to suggest pharmacotherapy affects long-term outcomes. In individual cases, therapy targeted to the treatment of concurrent medical disorders, such as mitochondrial dysfunction, allergy, or hypothyroidism, can be beneficial. Children with GI symptoms (recurrent loose stools or constipation in 24%) may benefit from GI evaluation and elimination diets (e.g., gluten- and casein free). Sleep is disordered in 60% of ASD patients (more in young children), and abnormal rapid eye movement arousals can be observed on sleep studies. Treatment with melatonin, up to 3 mg/day, or clonidine, 0.025 to 0.1 mg, at bedtime may help to initiate —but not maintain—sleep, whereas trazodone, 25 to 75 mg, may benefit both. The following steps are suggestions for drug treatment and may be selected in any order, depending on the patient’s symptoms. The goal is to improve function with as few agents as possible, allowing adequate time between trials to assess their efficacy. Step 1. Selective serotonin reuptake inhibitors (SSRIs)— SSRIs improve function in most children with ASDs. Multiple clinical and experimental studies over 30 years have shown that altered serotonin (increased in platelets; decreased synthesis in the central nervous system [CNS]) is a critical component of ASDs in many patients and suggest that treatment may Johnson: Current Therapy in Neurologic Disease (7/E)
Autism
Anxiolytic: buspirone 2.5–5 mg t.i.d.
(or)
Developmental Disorders
FIGURE 1. Suggested drug treatment plan over 1 year for 4- to 8-year-old children with autistic spectrum disorders. Successive treatment trials for clinical symptoms should start with smallest doses and increase slowly to assess responses and to avoid overstimulation, due to sensitivity to serotonergic agents (buspirone, selective serotonin reuptake inhibitors [SSRIs]). Regimens should be limited to one or two drugs if possible.
113
(Treat anxiety, mood, attention, repetitive behaviors)
1st SSRI: e.g., citalopram 0.5 mg q.a.m.; increase weekly by 0.5 mg, up to 4–5 mg; avoid overstimulation
2nd
(Sleep, calming)
3rd
4th
Alpha-2 adrenergic agonists: e.g., clonidine 0.05–0.1 mg q.h.s.; up to 0.1 mg t.i.d.
(Focus, attention)
(usually not together)
Stimulants: e.g., methylphenidate 2.5–10 mg q.a.m. and afternoon
(Seizure activity, mood)
Antiepileptics/mood stabilizers: e.g., divalproex sprinkles, 10–15 mg/kg; up to 30 mg/kg; monitor labs
(Mood, aggressive behaviors)
5th
3
6
Atypical antipsychotics: e.g., risperidone 0.25 mg q.h.s., up to 1 mg b.i.d. 9
12
Months
improve outcomes. Unfortunately, currently available clinical assays of circulating serotonin are not useful to guide treatment. SSRIs decrease anxiety and repetitive behaviors and improve attention and mood. Experience shows that most children with ASDs have increased sensitivity to SSRIs and respond to small doses; a few children show decreased sensitivity and require high doses. I prefer to begin therapy with very small doses of citalopram (using liquid preparations of 0.5 to 1 mg daily, usually in the morning) and to increase weekly by a similar amount, being cautious to avoid overstimulation as the dose is increased. This may occur when the dose exceeds the individual’s “therapeutic window,” usually in doses from 1 to 5 mg in young children. Individual responses to different SSRIs vary, so repeated trials of different medications may be needed, each over 2 to 3 months. Full therapeutic benefits may not become apparent for 6 to 8 weeks and may be superseded by side effects if the dose is increased too rapidly. Treatment should continue for 6 to 12 months and then be tapered slowly over 6 to 8 weeks. Most young children maintain their gains after the SSRI is discontinued, although loss of function may dictate restoration of drug therapy. Step 2. Sleep, calming, and attention—Alpha2-adrenergic agonists (e.g., clonidine, guanfacine) are useful agents; clonidine helps induce sleep and can be used during the day for calming and to improve focus and attention but may also induce drowsiness. Guanfacine produces less sedation and calming but may be more effective for focus and attention. Step 3. Stimulants for attention—Although symptoms of attention deficit hyperactivity disorder (ADHD) occur frequently, children with ASDs are less likely than typical children with ADHD to respond favorably to stimulant medications. Children with ASDs overfocus and have selective attention. Brief medication Johnson: Current Therapy in Neurologic Disease (7/E)
trials with stimulants (e.g., methylphenidate) are indicated but may lead to irritability and increased hyperactivity. Imipramine and atomoxetine are often good alternatives. Step 4. Anticonvulsants—EEGs following language regression or seizures may reinforce a decision to treat with anticonvulsant medications, such as divalproex or carbamazepine. Although guidelines for the evaluation, treatment, and prognosis of children with abnormal EEGs (but without clinical seizures) have not been determined, experience suggests that approximately one half of these patients will improve in their behavior and language when treated with anticonvulsants. Such improvements, however, likely result from the effect of these medications as mood stabilizers and suggest that epileptiform activity on EEGs reflects, rather than causes, underlying CNS dysfunction. Approximately 30% of persons with autism develop generalized tonic-clonic epilepsy, usually during adolescence. Step 5. Atypical antipsychotics—These medications are helpful for aggression and adverse behaviors in ASDs. Despite their demonstrated efficacy in short-term trals, risperidone and related drugs deserve cautious follow-up for side effects that include extrapyramidal movements, weight gain, and hyperprolactinemia. Olanzapine and other atypical antipsychotics may induce diabetic changes requiring glucose monitoring.
Summary Current therapies for ASDs may take advantage of inherent CNS plasticity and lead to improved outcomes. Basic and clinical research in autism is evolving rapidly and should provide approaches based on new knowledge of the underlying pathogenesis of ASDs.
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Acknowledgment
EVALUATION
The author thanks Dr. Susan Connors for her review and helpful suggestions.
The evaluation of an individual with suspected ADHD includes the following:
SUGGESTED READING Bauman, ML, Kemper TL, editors: The neurobiology of autism, ed 2, Baltimore, 2005, Johns Hopkins University Press. Palermo MT, Curatolo P: Pharmacologic treatment of autism, J Child Neurol 19:155-164, 2004. Tuchman R: Autism, Neurol Clin North Am 21:915-932, 2003. Zimmerman AW: Autism spectrum disorders. In Singer HS, Kossoff EH, Hartman AL, Crawford TO, editors: Treatment of pediatric neurologic disorders, New York, 2005, Marcel Dekker, pages 489-494.
PATIENT RESOURCES Autism Society of America http://www.autism-society.org/ Cure Autism Now Foundation http://www.cureautismnow.org/ National Alliance for Autism Research http://www.naar.org/ Kennedy Krieger Institute http://www.kennedykrieger.org/
Attention Deficit Hyperactivity Disorder and Learning Disabilities Max Wiznitzer, M.D.
Attention Deficit Hyperactivity Disorder Attention deficit hyperactivity disorder (ADHD) is a common reason for consultation with primary care providers and pediatric specialists. The prevalence for this biologically based disorder is 5% to 10% in children and 2% to 4% in adults. The core symptoms of ADHD are short attention span for mental age, impulsivity (acting without thinking of consequences), easy distractibility (inability to maintain focus on a needed task), and motor overactivity (which may range from fidgetiness to continuous movement). These core features have been organized into two major groupings (inattentiveness and hyperactivity-impulsivity) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and are listed in Table 1. Features can vary by age at presentation—disruptive behavior in the preschool years; academic struggles in the school-age years; and disorganization, impulsive risk taking, social difficulties, and educational and employment challenges in adolescence and adulthood.
1. Identification of ADHD features that continue to impair function and fulfill diagnostic criteria. This should include information from multiple sources (individual, family member, educators, job colleagues, and friends) and from preexisting documents (report cards, school assessments, psychological testing). Rating scales can be helpful as part of the assessment of individuals with ADHD, with results interpreted in conjunction with other information. Common tools include Conners Parent and Teacher Rating Scales, ADHD Rating Scale, and Vanderbilt Assessment Scale (available as part of an ADHD Toolkit at http:// www.nichq.org/). Adult scales include Adult ADHD Self-Report Scale Wender Utah Rating Scale, Conners Adult ADHD Rating Scales, and Brown Adult ADD Scale. 2. Confirmation that the individual manifested features of ADHD during childhood, especially during or prior to the early school-age years. 3. Review of prenatal, birth, and developmental history for factors that can cause ADHD and for timing and severity of presentation. These include in utero ethanol exposure, prematurity, encephalitis and meningitis, and traumatic brain injury. Individuals with neurodevelopmental disabilities can have an increased risk for ADHD. 4. Delineation of possible alternative diagnoses (psychiatric and medical) and comorbid conditions (Figure 1). Neuropsychological testing (either through a schoolbased multifactorial evaluation or an independent evaluator) should be done when there is a question about the diagnosis or the presence of other learning problems. 5. Family history of psychiatric and neurologic conditions, including ADHD, bipolar disorder, and Tourette syndrome. ADHD may be the first feature of Tourette syndrome or chronic tic disorder, which usually presents during the school-age years in 10% to 12% of this population. Children with bipolar disorder may initially have features of ADHD with excessive mood lability prior to the overt presentation of bipolar features. 6. Physical examination for possible underlying medical condition that may mimic ADHD or impact on treatment (sleep disturbance, hypertension, endocrinopathy, medication side effect from anticonvulsant or beta adrenergic drugs) or neurologic abnormalities (dyspraxia, cerebral palsy, movement disorder).
TREATMENT The management of ADHD requires an approach that combines behavioral and educational techniques with judicious use of medication. This conclusion is supported by the findings in the Multimodal Treatment Study of Children with ADHD, which showed that the core features of ADHD were best managed with Johnson: Current Therapy in Neurologic Disease (7/E)
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Acknowledgment
EVALUATION
The author thanks Dr. Susan Connors for her review and helpful suggestions.
The evaluation of an individual with suspected ADHD includes the following:
SUGGESTED READING Bauman, ML, Kemper TL, editors: The neurobiology of autism, ed 2, Baltimore, 2005, Johns Hopkins University Press. Palermo MT, Curatolo P: Pharmacologic treatment of autism, J Child Neurol 19:155-164, 2004. Tuchman R: Autism, Neurol Clin North Am 21:915-932, 2003. Zimmerman AW: Autism spectrum disorders. In Singer HS, Kossoff EH, Hartman AL, Crawford TO, editors: Treatment of pediatric neurologic disorders, New York, 2005, Marcel Dekker, pages 489-494.
PATIENT RESOURCES Autism Society of America http://www.autism-society.org/ Cure Autism Now Foundation http://www.cureautismnow.org/ National Alliance for Autism Research http://www.naar.org/ Kennedy Krieger Institute http://www.kennedykrieger.org/
Attention Deficit Hyperactivity Disorder and Learning Disabilities Max Wiznitzer, M.D.
Attention Deficit Hyperactivity Disorder Attention deficit hyperactivity disorder (ADHD) is a common reason for consultation with primary care providers and pediatric specialists. The prevalence for this biologically based disorder is 5% to 10% in children and 2% to 4% in adults. The core symptoms of ADHD are short attention span for mental age, impulsivity (acting without thinking of consequences), easy distractibility (inability to maintain focus on a needed task), and motor overactivity (which may range from fidgetiness to continuous movement). These core features have been organized into two major groupings (inattentiveness and hyperactivity-impulsivity) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and are listed in Table 1. Features can vary by age at presentation—disruptive behavior in the preschool years; academic struggles in the school-age years; and disorganization, impulsive risk taking, social difficulties, and educational and employment challenges in adolescence and adulthood.
1. Identification of ADHD features that continue to impair function and fulfill diagnostic criteria. This should include information from multiple sources (individual, family member, educators, job colleagues, and friends) and from preexisting documents (report cards, school assessments, psychological testing). Rating scales can be helpful as part of the assessment of individuals with ADHD, with results interpreted in conjunction with other information. Common tools include Conners Parent and Teacher Rating Scales, ADHD Rating Scale, and Vanderbilt Assessment Scale (available as part of an ADHD Toolkit at http:// www.nichq.org/). Adult scales include Adult ADHD Self-Report Scale Wender Utah Rating Scale, Conners Adult ADHD Rating Scales, and Brown Adult ADD Scale. 2. Confirmation that the individual manifested features of ADHD during childhood, especially during or prior to the early school-age years. 3. Review of prenatal, birth, and developmental history for factors that can cause ADHD and for timing and severity of presentation. These include in utero ethanol exposure, prematurity, encephalitis and meningitis, and traumatic brain injury. Individuals with neurodevelopmental disabilities can have an increased risk for ADHD. 4. Delineation of possible alternative diagnoses (psychiatric and medical) and comorbid conditions (Figure 1). Neuropsychological testing (either through a schoolbased multifactorial evaluation or an independent evaluator) should be done when there is a question about the diagnosis or the presence of other learning problems. 5. Family history of psychiatric and neurologic conditions, including ADHD, bipolar disorder, and Tourette syndrome. ADHD may be the first feature of Tourette syndrome or chronic tic disorder, which usually presents during the school-age years in 10% to 12% of this population. Children with bipolar disorder may initially have features of ADHD with excessive mood lability prior to the overt presentation of bipolar features. 6. Physical examination for possible underlying medical condition that may mimic ADHD or impact on treatment (sleep disturbance, hypertension, endocrinopathy, medication side effect from anticonvulsant or beta adrenergic drugs) or neurologic abnormalities (dyspraxia, cerebral palsy, movement disorder).
TREATMENT The management of ADHD requires an approach that combines behavioral and educational techniques with judicious use of medication. This conclusion is supported by the findings in the Multimodal Treatment Study of Children with ADHD, which showed that the core features of ADHD were best managed with Johnson: Current Therapy in Neurologic Disease (7/E)
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A. Either (1) or (2): (1) six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Inattention (a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities (b) often has difficulty sustaining attention in tasks or play activities (c) often does not seem to listen when spoken to directly (d) often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) (e) often has difficulty organizing tasks and activities (f) often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework) (g) often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools) (h) is often easily distracted by extraneous stimuli (i) is often forgetful in daily activities (2) six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Hyperactivity (a) often fidgets with hands or feet or squirms in seat (b) often leaves seat in classroom or in other situations in which remaining seated is expected (c) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) (d) often has difficulty playing or engaging in leisure activities quietly (e) is often “on the go” or often acts as if “driven by a motor” (f) often talks excessively Impulsivity (g) often blurts out answers before questions have been completed (h) often has difficulty awaiting turn (i) often interrupts or intrudes on others (e.g., butts into conversations or games) B. Symptoms that caused impairment were present before 7 years C. Impairment from the symptoms is present in two or more settings (e.g., at school, work, and home) D. Clinically significant impairment in social, academic, or occupational functioning E. The symptoms do not occur exclusively during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by another mental disorder (e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder) Attention-Deficit/Hyperactivity Disorder, Combined Type: if both Criteria A1 and A2 are met for the past 6 months Attention Deficit/Hyperactivity Disorder, Predominantly Inattentive Type: if Criterion A1 is met but Criterion A2 is not met for the past 6 months Attention Deficit/Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type: if Criterion A2 is met but Criterion A1 is not met for the past 6 months From American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC, 1994, American Psychiatric Association.
appropriate dosing of medication, whereas the consequences of ADHD (school performance, peer and family relations, self-esteem) best improved with combined pharmacologic and behavioral/educational intervention. For individuals with mild to moderate ADHD (especially the inattentive type), nonpharmacologic intervention may be sufficient. For those with moderate to severe symptomatology, medication is necessary to improve attention and reduce impulsivity before they can learn new learning and behavioral habits. Recommendations for nonpharmacologic intervention include: Behavioral interventions with psychosocial interventions that focus on family, school, and child; teach parenting skills; and provide support in multiple environments. Involvement with a parent support Johnson: Current Therapy in Neurologic Disease (7/E)
group can be useful. Intervention should focus on the encouragement of wanted behaviors using verbal or tangible reward techniques rather than the sole use of extinction of unwanted behaviors. Frequent changes in rewards and positive approach methods may be needed in this population. Social skills training is frequently necessary because of the social immaturity present in many children with ADHD (especially the combined type). Behavioral intervention should also focus on aggressive intervention for any comorbid condition such as oppositional-defiant disorder, anxiety, or depression. This management is usually done by a psychologist or counselor/therapist with consultation with a psychiatrist for significant psychiatric comorbidities. Academic intervention requires an organized environment, a well-trained educational staff that understands
Developmental Disorders
TABLE 1 Diagnostic Criteria for Attention Deficit Hyperactivity Disorder
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Referral for suspected inattention, hyperactivity and/or impulsivity presenting as: disruptive behavior, academic difficulties, social issues, work difficulties History from: family, other caregivers; school/camp personnel and reports; employers and work evaluations Physical and neurological examination Confirmation with parent and teacher rating scales
Diagnosis of ADHD
Neuropsychological assessment
No
Yes
Cognitive deficiency Learning disability/style Peripheral sensory deficit Epilepsy Sleep disorder Medication effect Oppositional-defiant disorder Conduct disorder Anxiety disorder Mood disorder Autism spectrum disorder Environmental/social stressors “Difficult” child Medical illness
Behavioral
Medication (see Table 2)
Comorbidity monitoring
Parent training (positive reinforcement) Social skills training
Stimulant (methylphenidate or amphetamine) as first choice. Try the other if first not effective or has side effects. Extended release preparation is preferred.
Oppositional-defiant disorder Dyspraxia Learning/language disability Temperament dysregulation Anxiety disorder Mood disorder Conduct disorder Substance use disorder Tic disorder
Educational Family education School accommodations
Atomoxetine as a first line choice: Need early AM or late PM effect History of substance abuse Stimulant nonresponder/side effects
Preschool years
School age years
Adult years
Mixed amphetamine salt D-Methylphenidate Clonidine
8 hour effect (methylphenidate) Only needed for school Need 16 hour effect (bid dose) 12 hour effect (stimulant, atomoxetine) Homework, behavior problems Desire once daily dosing Lower abuse potential
Long-acting stimulant Atomoxetine
FIGURE 1. Referral for suspected inattention, hyperactivity, and/or impulsivity presenting as disruptive behavior, academic difficulties, social issues, and work difficulties. ADHD, Attention deficit hyperactivity disorder.
Incomplete response, consider: Stimulant + Atomoxetine Stimulant + Clonidine or Guanfacine Nortriptyline
the need for structure and routine, and a defined educational approach to children with a short attention span. This can include more time for lessons and tests, smaller work units, and a decrease in external distractions. Use of a schedule, daily teacher feedback, and a positive reward mechanism can be successful. Medications can successfully improve attention span and, consequently, decrease distractibility and overactivity in more than 80% to 90% of children with ADHD. The primary medications and recommended initial starting doses are listed in Table 2. Medication use is indicated when ADHD causes a risk of physical injury, impaired family and social relationships or academic failure, and nonpharmacologic intervention has an
inadequate effect. General usage rules include to start at a low dose and increase slowly (usually every 4 to 7 days) and to titrate to maximal efficacy without undue side effects. Whether medication is needed on a daily basis or only for in-school use needs to be determined on an individual basis. Children with comorbid behavioral problems and difficulties with peer interactions should take medication on a daily basis. Medication choice is influenced by age and ability to swallow pills. Stimulants (methylphenidate and amphetamine) are first-line treatment and appear to be equally effective. If the child does not show a good response to one, another should be tried since responses can be idiosyncratic. When possible, long-acting preparations should Johnson: Current Therapy in Neurologic Disease (7/E)
TABLE 2 Medications Used in the Treatment of Attention Deficit Hyperactivity Disorders Daily Dose
Stimulants Methylphenidate
0.3-2 mg/kg
IR ER
Frequency
Dosing*
Methylphenidate—Start with 0.3 mg/kg/dose for immediate release and 0.5-1 mg/kg/day for extended-release preparation. Increase dose every 4-7 days as tolerated by 0.15-0.3 mg/kg up to 2 mg/kg/day. Although maximum recommended dose is 60 mg/day, adolescents and adults may require higher daily doses. Monitor blood pressure, height, and weight. Side effects include insomnia, appetite suppression, headache, and nausea bid-qid q AM
Metadate CD Ritalin LA Concerta Amphetamine
Duration
Developmental Disorders
Generic Class
3-4 hr 8 hr 8 hr 12 hr
0.15-1.5 mg/kg
IR ER
Amphetamine—Start with 0.15 mg/kg/dose for immediate release and 0.2-0.3 mg/kg/day for extended release preparation. Increase dose every 4-7 days as tolerated by 0.15-0.3 mg/kg up to 1.5 mg/kg/day. While maximum recommended dose is 40 mg/day, adolescents and adults may require higher daily doses. Monitor blood pressure, height and weight. Side effects include insomnia, appetite suppression, headache and nausea q q
AM-bid AM
Dexedrine Spansule Adderall XR
4-6 hr
5
6-8 hr 12 hr
Antidepressants Atomoxetine
1-2 mg/kg
qd or bid
Imipramine
2-5 mg/kg
bid
Nortriptyline
1-3 mg/kg
bid-tid
Bupropion
2-6 mg/kg
qd-tid
Venlafaxine Others
1-3 mg/kg
bid-tid
Clonidine
3-10 μg/kg
bid-qid
2-4 hr
Guanfacine
30-100 μg/kg
bid-tid
4-8 hr
Atomoxetine—Start with 0.5-0.7 mg/kg/day as a qd or bid dose. Increase after 4-7 days to 1-1.4 mg/ kg/day as qd or bid dose. It may take 4-6 weeks to observe the full effect. Although the maximum recommended dose is 100 mg/day, adolescents and adults may require higher doses. Slow metabolizers through CYP2D6 require lower doses. Side effects include tiredness, decreased appetite, GI upset and nausea, urinary retention, and liver dysfunction Nortriptyline—Start 0.5-1 mg/kg day qhs or bid and increase weekly by 0.5-1 mg/day increments to 1-3 mg/kg/day bid or tid. Electrocardiogram at baseline and with dose changes (especially at final dose) to monitor QTc. Side effects include fatigue, dizziness, constipation, tachycardia, and irritability
Clonidine—Start with 0.1 mg tablets at a dose of 1/41/ 2 tablet qhs and increase by 1/4-1/2-tablet increments q wk to a tid or qid regimen with maximum dose of ∼10 μg/kg/day. If effective, consider use of transdermal patch. Monitor blood pressure. Side effects include lethargy and irritability Guanfacine—Start with 1-mg tablets at a dose of 0.25-0.5 mg qhs and increase weekly by 0.25-0.5 mg increments to a bid or tid regimen with maximum of about 100 μg/kg/day. Monitor blood pressure. Side effects include lethargy and irritability
*Goal is maximal efficacy without undue side effects. IR, Immediate release; ER, extended release; GI, gastrointestinal; QTc, QT correction.
Johnson: Current Therapy in Neurologic Disease (7/E)
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be used since they minimize the number of daily doses and provide more even effect throughout the day. Although atomoxetine may not be as effective as the stimulants, it should be considered as a first-line therapy in individuals who need early-morning or late-evening treatment, have a history of substance use, have failed or do not tolerate stimulants, or require combined therapy with stimulants. Stimulant side effects include transient headache and upset stomach that can be ameliorated with medication administration after a meal, a sleep disturbance that may need additional treatment, and a worsening in mood that disappears with discontinuation. As the medication effect diminishes, “rebound” hyperactive behavior lasting 35 to 40 minutes may occur and probably represents a return to baseline ADHD. This effect can be lessened by changing from a shorter- to longer-acting stimulant medication. Tics may occur during use of stimulant medication, although research does not suggest that de novo causation or exacerbation of tics occurs. Most children with tics have little change in tic frequency or severity over time. If tics occur within 2 weeks of stimulant initiation, a decrease in dose or change to another medication should be considered. Children with well-controlled epilepsy do not have a seizure exacerbation when placed on methylphenidate. Children on stimulants should have periodic measurement of height and weight because of potential appetite suppression and reports of possible slowing of growth, especially in children at the higher height percentile who are on daily therapy. Whether this effect is transient and will disappear during the pubertal growth spurt or whether it will produce a small but permanent blunting of growth has not been determined. Blood pressure and pulse should be checked. Effective treatment of ADHD with stimulants reduces the risk of substance use to the age-matched peer level and does not contribute to illicit drug use in this population. Diversion and use by non-ADHD individuals can occur but is not a prominent problem. Atomoxetine, a selective norepinephrine reuptake inhibitor, has become available and is useful in the management of ADHD. Its side effects include tiredness, gastrointestinal complaints, and decreased appetite. In adults, modest blood pressure and heart rate elevation, urinary retention, and sexual dysfunction can occur. Liver dysfunction with elevated aspartate aminotransferase, alanine aminotransferase, and bilirubin has been rarely reported. Since it is metabolized through CYP2D6, dosing reduction may be warranted in slow metabolizers and those on medications that inhibit CYP2D6 (such as paroxetine, fluoxetine, or quinidine). It should be considered as first-line therapy in the nonstimulant category, especially for those who do not tolerate or want a stimulant or whose history precludes use of a stimulant. Clonidine and guanfacine are alpha-adrenergic agonists that have shown some efficacy in the treatment of children with ADHD. Most frequently, they are used in conjunction with stimulant medications and for stabilization of mood and decrease in aggression and overarousal. Abrupt discontinuation is not recommended.
Learning Disabilities Learning disabilities are a severe discrepancy between achievement and intellectual ability in one or more areas that include reading, mathematics, written language, oral expression, or listening comprehension. The prevalence is 10% to 15%, with dyslexia (reading disability) being most common. The physician is frequently the first professional who is asked to address family concerns about the child’s developmental progress. The assessment includes the following: 1. History that investigates potential risk factors such as family history of learning disability, prematurity, past central nervous system insult (toxin, infection, trauma), epilepsy, or congenital syndrome and examines developmental milestones (language delay/disorder, difficulties learning letters), present academic progress (isolated difficulty in one or more academic areas with otherwise normal development), and available school records and teacher reports 2. Medical examination that identifies a syndrome that can be associated with learning disabilities (e.g., neurofibromatosis, Turner’s syndrome, velocardiofacial syndrome) and motor difficulties (dyspraxia) that can aggravate learning problems; office-based screening should include hearing and vision (if not yet done) and samples of reading, writing, and math skills 3. Screening for comorbid disorders such as ADHD, anxiety disorder, depression, and social skills impairment 4. No specific medical testing (e.g., electroencephalogram or other electrophysiologic tests, magnetic resonance imaging, positron emission tomography or singlephoton emission computed tomography scan) without clinical indications 5. Referral for psychoeducational testing through the school system or neuropsychological evaluation for diagnosis of a learning disability; other assessments for motor or language problems should be obtained as necessary, with the physician maintaining a position within the multidisciplinary team After identification of and intervention for the learning disability, the physician’s input may be requested. Educating the child and family about the diagnosis and available resources, planning a referral for counseling, prescribing medication for comorbid conditions, and addressing questions about alternative/complementary therapies may be needed. The remaining part of the management team helps with advocacy issues and monitoring of the child’s clinical course. SUGGESTED READING American Academy of Child and Adolescent Psychiatry: Practice parameters of the use of stimulant medications in the treatment of children, adolescents and adults with attention-deficit/hyperactivity disorder, J Am Acad Child Adolesc Psychiatry 41(2 Suppl):26S-49S, 2002. American Academy of Pediatrics: Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder, Pediatrics 105:1158-1170, 2000.
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Attention Deficit Hyperactivity Disorder and Learning Disabilities
International Dyslexia Society Chester Building, Suite 382 8600 LaSalle Road Baltimore, MD 21286 Phone: 800-ABC-D123 http://www.interdys.org/ Learning Disabilities Association of America 4156 Library Road Pittsburgh, PA 15234 Phone: 412-341-1515 http://www.ldanatl.org/
Children and Adults with Attention Deficit Hyperactivity Disorder (CHADD) 8181 Professional Place, Suite 150 Landover, MD 20785 Phone: 800-233-4050 http://www.chadd.org/ American Academy of Pediatrics: ADHD: A Complete and Authoritative Guide, Elk Grove Village, IL, 2003, AAP. National Institute for Child Health Quality (NICHQ) ADHD Practitioners’ Toolkit (http://www.nichq.org/resources/toolkit/) contains assessment and management documents for ADHD, including the Vanderbilt Assessment Scale.
Developmental Disorders
PATIENT RESOURCES
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SECTION 6 ●
Viral Infections Herpesvirus Infections Micheline McCarthy, M.D., Ph.D.
Human herpesviruses (HHVs) constitute a diverse group of ubiquitous viral pathogens capable of both acute and persistent infection in the host. These complex DNAcontaining viruses typically infect humans early in life and establish latent infection at the cellular level. Latent infection is clinically dormant, but reactivation of viral replication can lead to recurrent clinical illness. Primary (initial) or reactivated infection by these viruses can also cause severe neurologic illness. Neurologic complications are especially prominent in aging or immunocompromised patients, and these pose an increasing diagnostic and treatment challenge to the neurologist.
Antiherpesvirus Therapy Among human viral infections of the nervous system, herpesvirus infections are probably the most amenable to antiviral therapy. This is largely due to the growing drug family of purine nucleoside analogs that are activated by virus-specific kinases and then interfere with herpes viral DNA replication. The prototype drug, acyclovir (acycloguanosine), was identified about 30 years ago, followed by penciclovir and ganciclovir a decade or more later. Now available are oral prodrugs of acyclovir (valacyclovir, the L-valyl ester of acyclovir), penciclovir (famciclovir, the diacetate ester of 6-deoxy-penciclovir), and ganciclovir (valganciclovir, the L-valyl ester of ganciclovir). The oral prodrug provides greater bioavailability and higher plasma levels of the active antiviral drug. Acyclovir is most active against herpes simplex viruses (HSVs), then varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus (HHV-6), in decreasing order of antiviral potency. Valacyclovir, with its greater bioavailability, allows a simpler dosing regimen than oral acyclovir. It is likely to eventually replace oral acyclovir, but currently generic oral acyclovir is much less expensive. The antiviral spectrum of penciclovir is similar to that of acyclovir, Johnson: Current Therapy in Neurologic Disease (7/E)
although inhibition of viral DNA polymerase is less efficient. Penciclovir achieves a much longer intracellular half-life than acyclovir, allowing for two- or three-timesa-day dosing. Ganciclovir has relatively greater potency against CMV and HHV-6, good activity against HSV, and less activity against VZV and EBV. Intravenous (IV) ganciclovir has been the first-line therapy for CMV infection in immunocompromised patients. But oral ganciclovir has poor bioavailability, making it ineffective for long-term prophylactic suppressive regimens. Valganciclovir provides an oral bioavailability for ganciclovir of 60% and is replacing IV ganciclovir as the first choice for anti-CMV maintenance. Two additional, clinically effective drugs, foscarnet and cidofovir, directly inhibit herpesvirus DNA polymerases. Both have broad-spectrum antiherpesvirus activity but require IV administration. Herpesvirus resistance to acyclovir or ganciclovir can arise through mutations in viral thymidine kinase or DNA polymerase enzymes. Drug-resistant mutants occur rarely among herpesvirus isolates from immunocompetent patients; however, among immunocompromised patients, including those treated with prophylactic courses of antiviral drugs, drug-resistant mutants are more likely to be clinically significant and occur more than ten times more frequently. Foscarnet and cidofovir are used to treat herpesvirus infections that are resistant to first-line antiviral therapy. The antiherpesvirus drugs all have varying degrees of nephrotoxic potential. Ganciclovir is also myelosuppressive. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are rare but life-threatening complications reported with high-dose (8 gm/day) valacyclovir therapy in severely immunocompromised patients. The antiherpesvirus drugs must be administered with careful attention to detailed, current prescribing information. Dosages must be adjusted for renal function. Patients should be well hydrated, and IV infusions should be administered slowly with an infusion pump. There are no standards for the use of prophylactic valacyclovir or famciclovir in children.
Herpes Simplex Viruses Two human HSVs—HSV-1 and HSV-2—have similar molecular structures but tend to cause different neurologic illnesses. HSV-1 is most frequently associated with 121
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recurrent orolabial mucocutaneous lesions (“cold sores”), whereas HSV-2 is associated with recurrent genital mucocutaneous lesions. These viruses establish latency in the sensory ganglia subserving these anatomic locations. Either primary or reactivated HSV infection can cause neurologic illness. HERPES SIMPLEX ENCEPHALITIS (HSE) HSV-1 is the most common cause of fatal sporadic viral encephalitis in adults and children. Beyond the neonatal period, most cases of fatal encephalitis are due to HSV-1 and are more commonly reactivated rather than primary infection. The classic clinical presentation is necrotic, hemorrhagic, frontal-temporal lobe encephalitis, but the distribution of lesions can be diffuse and may involve the brainstem. HSV-2 accounts for less than 10% of frontal-temporal encephalitis in immunocompetent patients. Milder or atypical cases of HSE can also occur, particularly in immunocompromised patients. Diagnostic evaluation and treatment should be instituted speedily since delayed onset of therapy, along with coma and older age, are poor prognostic indicators. Mortality among untreated patients exceeds 70%. Polymerase chain reaction (PCR) testing for HSV DNA in the cerebrospinal fluid (CSF) is the diagnostic test of choice for herpes simplex encephalitis (HSE). Treatment should be with IV acyclovir for 14 to 21 days (Table 1). Follow-up PCR determination of HSV DNA in the CSF may be useful to monitor the adequacy of therapy. Patients treated with IV acyclovir for 14 days should have a negative CSF PCR test for HSV DNA. If not, treat an additional 14 days. Acyclovir-resistant HSE occurs almost exclusively in immunocompromised patients, particularly those with recurrent HSV infections requiring repeated courses of antiviral therapy. Treatment of acyclovir-resistant HSE is with foscarnet for 14 to 21 days (see Table 1). If HSE is resistant to both acyclovir and foscarnet, treat with cidofovir (see Table 1). When treating any HSV infection that appears resistant to acyclovir, isolate virus from CSF, if possible, or from a peripheral source (e.g., mucocutaneous lesion), and test the isolates for antiviral drug susceptibility. Even with clinical improvement after treatment of HSE, relapse or progressive neurologic impairment may occur. This may be due to reactivation of latent virus in the brain. The efficacy of long-term oral antiviral therapy to suppress viral reactivation, increase survival, and/or decrease sequelae after HSE has not been demonstrated. However, this issue is being addressed in randomized, placebo-controlled, double-blind trials of oral valacyclovir given for 3 months after IV acyclovir. These trials are being conducted by the Collaborative Antiviral Study Group (CASG), a multi-institutional collaborative network funded by the National Institute of Allergy and Infectious Diseases. NEONATAL ENCEPHALITIS Neonatal HSE is due to HSV-2 in approximately two thirds of cases and to HSV-1 in the remainder. The virus
is acquired from the female genital tract in the intrapartum interval. Neonatal HSE can be a devastating disease, associated with serious neurologic sequelae even with aggressive antiviral treatment. Neonates with HSE should receive IV acyclovir for 21 days (see Table 1). The CASG is conducting trials of oral acyclovir given for 6 months after IV acyclovir to prevent relapse in neonatal HSE. BELL’S PALSY Idiopathic peripheral seventh cranial nerve palsy, or Bell’s palsy, is the most common cause of unilateral facial paralysis. VZV infection is known to cause Bell’s palsy as part of the Ramsay Hunt syndrome. More recently, studies using PCR have linked HSV-1 with Bell’s palsy through detection of viral DNA sequences in endoneural fluids or auricular muscle. Since HSV-1 typically establishes latency in peripheral sensory ganglia, not motor neurons, the role of HSV-1 in the pathogenesis of Bell’s palsy remains controversial. Appropriate diagnostic evaluation is essential. Addition of oral acyclovir to standard prednisone treatment for Bell’s palsy has been demonstrated to produce a moderate clinical improvement in volitional facial muscle action. Combination therapy should be started within 3 days of symptom onset and should continue for 10 days (see Table 1). To date no conclusive benefit has been demonstrated with antiviral therapy alone. HSV MENINGITIS AND MYELITIS HSV infection can cause aseptic meningitis, including benign recurrent lymphocytic meningitis. These clinical presentations are usually due to HSV-2 infection in immunocompetent patients. HSV-2 is likely the major viral agent responsible for recurrent meningitis, including many or most cases of Mollaret’s meningitis. Aseptic HSV-2 meningitis occurs concomitant with or after primary HSV-2 genital infection but may also occur in the absence of recent genital lesions. Rarely necrotizing meningitis has been reported in association with immunosuppression (e.g., corticosteroid treatment). The treatment of single or recurrent episodes of HSV meningitis has not been defined by clinical trials. In practice, patients presenting with acute aseptic meningitis are often treated empirically with IV acyclovir until CSF test results are available. Confirmed HSV meningitis may be treated with IV acyclovir for 5 to 7 days, followed by oral valacyclovir to complete a total 14-day course of therapy (see Table 1). With recurrent lymphocytic meningitis due to HSV-2, there is limited evidence for the efficacy of oral antiviral therapy for recurrent episodes or for continuous prophylaxis (see Table 1). Myelitis or radiculomyelitis can result from HSV infection of immunocompetent patients, with most reported cases resulting from HSV-2. In immunocompromised patients, HSV-2 central nervous system (CNS) infection may result in ascending necrotizing myelitis or myelopathy. These clinical presentations should be treated with IV acyclovir for 14 days or longer with more extensive illness (see Table 1). Johnson: Current Therapy in Neurologic Disease (7/E)
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Viral Infection
Clinical Presentation
Herpes simplex: Immunocompetent
Encephalitis Adult and adolescent (≥12 yr) Pediatric (3 months to 12 years) Neonatal (birth to 3 months) Postencephalitis (clinical trials) HSV Neonatal Bell’s palsy
Meningitis Single episode
Recurrent episode Continuous prophylaxis
Herpes simplex: Immunocompromised
Myelitis, radiculomyelitis Chronic suppression
Acyclovir resistant Acyclovir and foscarnet resistant
Varicella zoster: Immunocompetent
Zoster (shingles); herpes zoster ophthalmicus; varicella in adults, adolescents
Drug*,†
Dosage*
Acyclovir
10-15 mg/kg IV q 8 hr for 14-21 days 500 mg/m2 or 20 mg/kg IV q 8 hr for 14-21 days 20 mg/kg IV q 8 hr for 21 days
Acyclovir Acyclovir
Valacyclovir Acyclovir Prednisone plus
PO, 3-mo course PO, 6-mo course 1 mg/kg PO qd divided bid for 3-5 days, then tapered over total 10-day course
Acyclovir
400 mg PO 5 times/ day for 10 days
Comments These antiviral drugs are nephrotoxic; adjust dose for renal function, infuse over 1 hr Consider serial CSF PCR for HSV DNA to monitor adequacy of therapy Acyclovir-resistant HSE is rare in immunocompetent patients but is more likely to occur in patients with prior recurrent or chronic anti-HSV therapy Postencephalitis regimens are in clinical trials to evaluate efficacy Do appropriate diagnostic evaluation Role of HSV in Bell’s palsy etiology is controversial; more data needed to support antiviral therapy Drug therapy should be started within 3 days of symptom onset
HSV-2 is major cause of meningitis 5-10 mg/kg IV No controlled trials have established q 8 hr for 5-7 days treatment of single or recurrent then episodes of HSV meningitis Valacyclovir 1000 mg PO bid for 7-9 days to complete a 14-day course Valacyclovir 1000 mg PO tid for 10 days Valacyclovir 1000 mg PO qd Only anecdotal evidence for efficacy or of antiviral prophylaxis Acyclovir 400 mg PO bid Acyclovir 10-15 mg/kg IV q Use a longer course for more serious 8 hr for 14 days illness Valacyclovir 500 mg PO bid TTP and HUS have been reported in or severely immunocompromised patients treated with high doses Famciclovir 500 mg PO bid of valacyclovir (8 mg/day) for or extended periods Acyclovir 400-800 mg PO No standards available for bid or tid valacyclovir or famciclovir in children Foscarnet 40 mg/kg IV q 8 hr Isolate virus for antiviral susceptibility for 14-21 days testing Cidofovir 5 mg/kg IV once/wk Isolate virus for antiviral susceptibility twice, then 5 mg/ testing kg IV q 2 wk; coadminister cidofovir with probenecid (2 gm PO 3 hr prior to cidofovir; 1 gm 2 hr after cidofovir; 1 gm 8 hr after cidofovir) Valacyclovir 1000 mg PO tid for Valacyclovir preferable (higher or 5-7 days bioavailability of active drug) Start antiviral therapy within 3 days of rash Acyclovir then
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Viral Infections
TABLE 1 Human Herpesvirus Infections: Antiviral Therapy for Neurologic Illness
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TABLE 1 Human Herpesvirus Infections: Antiviral Therapy for Neurologic Illness—cont’d Viral Infection
Clinical Presentation
Herpes zoster in patients > 50 yr of age; Ramsay Hunt syndrome (zoster oticus)
Drug*,†
Dosage*
Comments
Acyclovir or
800 mg PO 5 times/ day for 7-10 days
Hospitalized zoster patients should be isolated to prevent transmission of VZV to other patients
Famciclovir Valacyclovir or
500 mg PO tid for 7 days 1000 mg PO tid for 7 days
Acyclovir therapy plus prednisone
800 mg PO 5 times/ day for 7-10 days; prednisone, 1 mg/ kg/day, tapered over 10 days
CNS complications of zoster Aseptic meningitis with rash Myelitis or myelopathy VZV vasculopathy Stroke (contralateral to zoster)
Varicella zoster: Immunocompromised
Cytomegalovirus: Immunocompromised
Diagnostics should include CSF for antiviral antibody and viral DNA (PCR) testing Valacyclovir Acyclovir Acyclovir plus prednisone
1000 mg PO tid for 7 days 10-15 mg/kg IV q 8 hr for 7-10 days 10-15 mg/kg IV q 8 hr for 7-10 days; prednisone, 60-80 mg for 3-5 days 1000 mg IV qd divided qid or bid for 5 days, then oral steroid taper 10-15 mg/kg IV q 8 hr for 7-10 days
Encephalomyelitis (immunemediated demyelination) Zoster sine herpete (dermatomal pain without rash)
Methylprednisolone
Varicella with cerebellar ataxia (postvaricella cerebellitis) Varicella (primary infection) Shingles >1 dermatome Disseminated herpes zoster Acyclovir-resistant zoster Progressive encephalitis, ventriculitis, meningoencephalitis
Acyclovir
20 mg/kg (800 mg max) PO qid for 5 days
Acyclovir
10 mg/kg IV q 8 hr for 7 days 10 mg/kg IV q 8 hr for 7-14 days 15 mg/kg IV q 8 hr for ≥ 7 days 40 mg/kg IV q 8 hr for 14-21 days 10 mg/kg IV q 8 hr for 10 days or longer in severely immunocompromised patients
Retinitis (systemic therapy)
Induction therapy Ganciclovir or Valganciclovir or Cidofovir
Acyclovir
Acyclovir Acyclovir Foscarnet Acyclovir
5 mg/kg IV q 12 hr for 14-21 days 900 mg PO bid for 21 days 5 mg/kg IV once per wk twice (give 1 L normal saline IV
Stroke usually delayed complication of herpes zoster ophthalmicus Postinfectious neurologic complication of VZV infection Confirm rising titers of VZV-specific antibody and VZV DNA in the CSF Efficacy of antiviral therapy reported but not established Usual course is self-limited without sequelae Antiviral therapy not proven to alter course
Isolate virus for antiviral susceptibility testing
These antiviral drugs are nephrotoxic. Use with caution in combination with immunosuppressive drug regimens Dosages must be adjusted for renal function CMV retinitis should be diagnosed and monitored by ophthalmologic specialists
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Clinical Presentation
Drug*,†
Dosage* before cidofovir); give with probenecid (2 gm PO 3 hr prior to cidofovir, 1 gm 2 hr after cidofovir, 1 gm 8 hr after cidofovir)
Maintenance therapy Valganciclovir or Ganciclovir or Cidofovir Ganciclovir resistant
Monotherapy resistant Nervous system complications Lumbosacral polyradiculitis, myelitis
60 mg/kg IV q 8 hr or 90 mg/kg IV q 12 hr for 14-21 days Maintenance 90-120 mg/kg IV qd Ganciclovir 5 mg/kg IV qd plus Foscarnet 90-125 mg/kg IV qd
Induction therapy Ganciclovir
Induction therapy Ganciclovir plus (?) Foscarnet Maintenance therapy Ganciclovir plus (?) Foscarnet
Human herpesvirus 6 (HHV-6, B variant)
Encephalitis: focal features and/or demyelination
5 mg/kg IV qd or 6 mg/kg IV qd 5 days per wk 5 mg/kg IV q 2 wk; give with probenecid
Systemic therapy as adjunct to intraocular antiviral therapy can prevent CMV disease in contralateral eye and other organs Immune recovery inflammatory vitreitis may occur with inactive CMV retinitis in HIV-infected patients recovering CD4+ cell counts on HAART; this may require steroid treatment Consider discontinuing maintenance therapy with CD4+ count >100 cells/mm3 after 6 mo HAART and retinitis is inactive
Foscarnet Induction
Maintenance therapy Valganciclovir or Ganciclovir Encephalitis, ventriculoencephalitis
900 mg PO qd
Comments
5 mg/kg IV q 12 hr for 14-21 days
6
Polyradiculitis most likely to be seen in AIDS patients Consider combination ganciclovir and foscarnet if patient develops symptoms despite prior anti-CMV therapy
900 mg PO qd 5 mg/kg IV qd or 6 mg/kg IV qd 5 days/wk 5 mg/kg IV q 12 hr for 14-21 days 60 mg/kg IV q 8 hr for 14-21 days 5 mg/kg IV qd or 6 mg/kg IV qd 5 days/wk 90-120 mg/kg IV qd
Foscarnet
Induction
60 mg/kg IV q 8 hr for 14 days Maintenance 90 mg/kg IV qd for or 1-4 wk
Serial CSF PCR for CMV DNA may be useful to monitor response to anti-CMV therapy Long-term maintenance therapy may be necessary in patients who remain profoundly immunosuppressed Consider combined therapy in HIV-infected patients with low CD4+ counts (2.5 mg/dL); (2) severe or persistent infusion-related events despite pretreatment with medications; (3) disease progression after more than 500 mg total dose of amphotericin B; and (4) necessary concomitant administration of nephrotoxic drugs such as cyclosporine or tacrolimus. Although sufficient human studies have not been completed to be certain of benefit, we believe that for CNS fungal infections, liposomal amphotericin B is excellent as the initial amphotericin treatment. At present all lipid formulations are considerably more expensive. Thus, for non-CNS fungal infections and some CNS fungal infections, conventional amphotericin B is often started and converted to a lipid formulation if the above indications develop. FLUCYTOSINE 5-Flurocytosine, a fungicidal nucleoside analog, is converted within cells to 5-fluorouracil, which inhibits DNA synthesis. Flucytosine is well absorbed from the gastrointestinal tract, minimally binds to serum proteins, and is excreted unchanged in urine. CSF concentrations approach 85% of serum levels. The drug is particularly active against Candida sp., C. neoformans, and some molds. Unfortunately, the drug cannot be used as a single agent because of the rapid development of drug resistance. Flucytosine is usually combined with amphotericin B and is administered for only 2 weeks during the induction phase of treatment. Adverse effects of flucytosine include rash, nausea and vomiting, diarrhea, hepatic dysfunction, and bone marrow suppression. To minimize the risk of toxicity, twice-weekly hemograms and liver function studies should be obtained and serum flucytosine levels can be obtained. Therapeutic levels measured in serum 2 hours after a dose range between 30 and 80 mg/mL. Serum levels greater than 100 mg/mL are considered toxic. If renal failure is present, flucytosine dosage reduction is essential and blood levels should be monitored.
Nonviral Infectious Disease
infusion-related events and cumulative dose-related renal toxicity. Infusion-related events include chills, fever, headache, nausea, and vomiting. These acute adverse events usually diminish with repeated amphotericin B administration. If an adverse event persists or is severe, pretreatment with diphenhydramine, acetaminophen, prochlorperazine, narcotics, and/or corticosteroids is helpful. Hypokalemia and normochromic anemia can also develop with treatment, so serum electrolytes and complete blood counts should be monitored frequently. Amphotericin B is usually begun at a daily dose of 0.25 mg/kg/day prepared as a 0.1 mg/mL infusion and slowly administered via a central venous catheter for 3 to 6 hours eliminating the need for pretreatment with heparin to prevent phlebitis commonly seen when the drug is administered in peripheral veins. The daily dosage is slowly increased to 0.5 to 1 mg/kg/day or higher for Aspergillus and Zygomycetes infections. Amphotericin B is frequently nephrotoxic, with accumulating dosage limiting the total amount that can be administered. Patients should be well hydrated before drug administration and followed with frequent serum creatinine and urinalyses in which red blood cell or white blood cell casts can be seen. Potentially nephrotoxic agents such as aminoglycoside antibiotics, cisplatin, cyclosporine, tacrolimus, and radiocontrast agents should be avoided if possible. If these drugs are necessary, use of the liposomal amphotericin B should be considered since it is the least nephrotoxic. Rare life-threatening idiosyncratic reactions of anaphylaxis, seizures, ventricular fibrillation, and cardiac arrest have been reported and require the drug to be discontinued. An intrathecal formulation of amphotericin B is available and has been used to achieve higher CSF levels of the drug than are possible by IV infusion. This is necessary since IV amphotericin B does not cure some fungal meningitides such as coccidioidal meningitis. At first, amphotericin B (0.2 to 0.5 mg/day) can be administered into the lumbar subarachnoid space from a lumbar puncture. The amphotericin B is usually mixed with 2 mL of a hyperbaric (hypertonic) solution of 10% dextrose in water, which has a greater specific gravity than CSF. After slow administration, the patient is placed in the Trendelenburg position for 45 minutes to allow the injected bolus to flow via gravity to the basal cisterns (see Stevens and Shatsky article in Suggested Reading list for more details of intrathecal administration). Complications of lumbar antifungal therapy following lumbar puncture or lumbar reservoir include severe headaches, nausea, vomiting, back pain, cranial nerve palsies, paresthesias, radiculopathy, and myelopathy from drug toxicity, and spinal arachnoiditis is triggered by the drug. Over time, the spinal arachnoiditis may prevent the drug from reaching cerebral subarachnoid spaces. At this point amphotericin B must be administered into the cisternal subarachnoid space via cisternal puncture or catheter reservoir system. Infusionrelated inflammation augments the existing cerebral subarachnoiditis, hastening the development of communicating hydrocephalus and creating isolated pockets of infected meninges that cannot be reached by the cisternally injected amphotericin B.
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AZOLES Azoles act by inhibiting fungal cytochrome P-450 (CYP) and sterol C-14-α-demethylation leading to a loss of fungal membrane sterols. At present, four azoles (fluconazole, ketoconazole, itraconazole, and voriconazole) are available for systemic fungal infections. Azoles are effective against many common fungal pathogens, including C. neoformans, H. capsulatum, C. immitis, Candida sp., B. dermatitidis, Paracoccidioides brasiliensis, and Sporothrix schenckii. Voriconazole and itraconazole are also active against Aspergillus sp., but no azoles are effective against Zygomycetes sp. The CSF penetration is best for fluconazole (>75% of serum levels) and voriconazole (>50% of serum levels). Itraconazole and ketoconazole achieve CSF levels less than 10% of serum and are seldom used as primary drugs for CNS infections. Fluconazole can be administered orally and IV. The oral form has good bioavailability, long half-life, low protein binding, and wide tissue distribution, including brain and CSF. The drug has few adverse effects that include rash, nausea, abdominal pain, reversible alopecia, elevated liver enzymes, and, rarely, Stevens-Johnson syndrome. Fluconazole should be used with caution in pregnant or nursing mothers since congenital defects have been reported and breast milk contains similar azole concentrations to those in serum. One potential problem with azole drugs is their interactions with coadministered drugs (Table 4). One type of interaction leads to decreased azole plasma concentrations by either decreasing azole absorption or increasing its metabolism. The second type of interaction leads to increased plasma concentrations of other coadministered drugs by altering hepatic metabolism via the cytochrome P-450 system. This could lead to toxicity of the coadministered drug. The emergence of fluconazole-resistant fungi appears rare but has been reported to occur with Candida sp. Voriconazole is well absorbed after oral administration, is moderately protein bound, enters the CSF reasonably well (50% to 60% of serum levels), and is extensively metabolized by the liver, with only 1% excreted in urine. An IV form of the drug is also available. The drug is usually begun with a loading dose of twice the daily dose. Voriconazole has many adverse effects and drug interactions similar to those of fluconazole (see Table 4), and visual disturbances occur in 20% to 45%. The transient visual effects generally occur 30 minutes after dosing and last for 15 to 30 minutes and include altered visual perception, color vision change, blurred vision, and photophobia. Voriconazole, but not fluconazole, has better efficacy than amphotericin B for systemic infections, including the brain, with Aspergillus sp. and is becoming the drug of choice for CNS Aspergillus, Fusarium, and Scedosporium infections. However, its efficacy compared with that of fluconazole for other CNS fungal infections is unclear. All azoles are fungistatic, leading to suppression, but not necessarily cure, of the fungal infection. As such, relapses are common when the azole is discontinued.
TABLE 4 Drug Interactions with Oral Fluconazole and Voriconazole Drug
Potential Sequelae
Increased plasma concentration of coadministered drug leading to potential toxicity of coadministered drug and altered fluconazole or voriconazole blood levels Sirolimus Bone marrow toxicity, diarrhea Ribufutin Uveitis, eye pain, visual loss Ergot alkaloids Nausea, vasospastic ischemia Cyclosporine Nephrotoxicity Tacrolimus Nephrotoxicity Phenytoin and Nystagmus, ataxia, sedation fosphenytoin Carbamazepine Ataxia, nystagmus, headache, vomiting Sulfonylureas Hypoglycemia Warfarin Increased INR and bleeding diathesis Benzodiazepines Sedation Tricyclic antidepressants Sedation, cardiac arrhythmias Statins Rhabdomyolysis Calcium channel blockers Dizziness, peripheral edema HIV protease inhibitors Variable toxicity, especially ritonavir HIV non-nucleoside Variable toxicity, especially reverse transcriptase efavirenz inhibitors Coadministration of the following drugs can result in cardiac toxicity with QT prolongation and, rarely, torsade de pointes Terfenadine Astemizole Cisapride Pimozide Quinidine Sulfamethoxazole Tricyclic antidepressants Chloroquine and mefloquine Antiarrhythmic agents (classes IA and III) Foscarnet Antipsychotics Pentamidine Probucol Vasopressin Venlafaxine Increased metabolism of fluconazole and voriconazole leading to lower azole blood levels Rifampin and rifabutin Carbamazepine Phenobarbital Phenytoin Cimetidine Herbal preparations may cause hepatitis and jaundice if coadministered Chaparral (Larrea tridentata) Valerian (Valeriana officinalis) Skullcap (Scutellaria baicalensis) Pennyroyal (Mentha pulegium) Kava (Piper methysticum) Germander (Teucrium chamaedrys) Coltsfoot (Tussilago farfara) Petasites (Petasites japonicus) Bold drugs are not recommended for coadministration with fluconazole and/or voriconazole per the manufacturer. HIV, Human immunodeficiency virus; INR, international normalized ratio.
Johnson: Current Therapy in Neurologic Disease (7/E)
Fungal Infections
CRYPTOCOCCAL MENINGITIS C. neoformans is the most common fungus to invade the CNS and infects healthy (20% of total cases with incidence of 1/100,000 population) and immunocompromised (80% of cases with incidence of 20 to 50/1000 in human immunodeficiency virus [HIV] patients not receiving effective HIV therapy) persons alike. C. neoformans is a ubiquitous fungus found worldwide in association with bird excrement and decaying plant material. C. neoformans differs from most fungal pathogens in that it is neurotrophic and has a predilection to disseminate from the localized lung infection via blood to the CNS. Thus, patients with cryptococcal meningitis may lack fungus present in other organs. Most patients develop subacute meningitis, but a few may also have cryptococcomas in the basal ganglia or cortex. When considered, the diagnosis is straightforward because organisms usually are isolated from CSF within a few days and the CSF cryptococcal antigen test is highly sensitive and specific. Recent studies demonstrate a faster time to CSF sterilization with amphotericin B and flucytosine (60% to 90% CSF sterilization at 2 weeks) than with fluconazole (see Table 3). If a repeat lumbar puncture at 2 weeks shows the CSF is still positive for growth of C. neoformans, a longer period of induction should be considered. Relapse after primary treatment is a concern if the patient is immunosuppressed or has AIDS. Relapse rates as high as 50% have been reported. Accordingly, these patients should be continued on lifelong maintenance therapy. However, for HIV patients on modern antiretroviral therapy with normal CD4+ counts and nondetectable serum HIV viral titers, lifelong maintenance therapy may not always be needed. More than 50% of patients with cryptococcal meningitis, especially patients with AIDS, have demonstrated increased intracranial pressure with a lumbar CSF opening pressure of greater than 250 mm CSF. Elevated CSF pressure is associated with papilledema, hearing loss, visual acuity problems, marked confusion, and severe headaches and has a poorer prognosis. Although the pathogenesis is unclear, inflammatory cell debris and capsule material from C. neoformans likely interfere with CSF absorption into the superior sagittal vein resulting in a communicating hydrocephalus and secondary cryptococcomas. Large-volume removal of lumbar CSF to reduce CSF pressure by 50%, done daily until the opening pressure returns to normal for several consecutive days, improves outcome. If the opening pressure is extremely high (>400 mm CSF), a temporary ventricular drain should be considered. If there is obstructive hydrocephalus or the ventricular drain is unsuccessful, a ventriculoperitoneal shunt may be necessary. Corticosteroids, mannitol, and acetazolamide have demonstrated little benefit for reduction of elevated CSF pressures. COCCIDIOIDAL MENINGITIS C. immitis infections occur in the California San Joaquin valley, Arizona, New Mexico, southwestern Texas, and Johnson: Current Therapy in Neurologic Disease (7/E)
northern Mexico. The risk of dissemination from the initial lung infection is about 0.5%. Nearly one third of the time dissemination affects the CNS and occurs within several months of the primary infection. Occasional patients also develop C. immitis granulomas in brain. Coccidioidal meningitis may be the only extrapulmonary infection, but other organs commonly involved are skin, joints, and bones. CSF complement fixation test for C. immitis antibody is an excellent test to diagnose coccidioidal meningitis and may be helpful in following treatment response. Successful antifungal treatment is difficult, and patients are at risk for development of communicating or obstructive hydrocephalus during therapy. Successful treatments have employed lifelong fluconazole and intrathecal amphotericin B (see Table 3). Because liposomal amphotericin B achieves higher brain levels and effects more cures in experimental animals than amphotericin B, its use should be considered for the induction phase of treatment. There are insufficient data to recommend exact duration and total dose of therapy.
Nonviral Infectious Disease
Specific CNS Infections
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HISTOPLASMA MENINGITIS H. capsulatum infections are associated with the moist, temperate Mississippi and Ohio river valleys but have been reported in South America, Europe, and Asia. The risk of dissemination from the initial lung infection is rare but is highest in those who are immunosuppressed, very young, or elderly. When dissemination occurs, the CNS is infected in 5% to 20% of the cases, producing a meningitis and/or brain abscesses. The mortality rate from a CNS infection is high (20% to 40%) even when treated with amphotericin B, and up to 50% of patients relapse when treatment is discontinued. As a consequence, liposomal amphotericin B should be considered since higher CNS amphotericin B concentrations can be achieved (see Table 3). Prolonged maintenance therapy with an azole should also be considered.
CANDIDA MENINGITIS Candida sp. is now the most common etiologic agent of fungal infections but uncommonly causes CNS infections. Candida sp. may cause meningitis, brain microabscesses, and cerebral infarction following thrombosis or hemorrhage from angioinvasion. Healthy individuals rarely develop CNS Candida infections. The diagnosis may be difficult because isolation from blood does not establish a CNS infection and isolation from CSF is uncommon. A recent enzyme immune assay (EIA) or latex agglutination Candida antigen test looking for mannan, a Candida antigen, may prove helpful if positive in CSF. Definite diagnosis may require meningeal or cerebral abscess biopsy. Current induction treatment is with amphotericin B often with flucytosine, except for Candida lusitaniae, which is amphotericin resistant (see Table 3). However, liposomal amphotericin B has successfully cured five of six cases of newborn Candida meningitis. Fluconazole and voriconazole are alternatives. However, if an azole is to be given in the setting of prior azole therapy or
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Fungal Infections
isolation of a non-albicans species, laboratory testing of the isolate for fluconazole or voriconazole resistance should be considered. The CSF often becomes sterilized before brain and meningeal tissues, so neuroimaging and CSF findings should be followed for resolution. If CSF shunts are present before the development of Candida meningitis, they should be removed because Candida biofilms may be present, leading to a relapse. The shunt ideally should be replaced after CSF sterilization. However, if the patient is on full antifungal therapy, new shunts seldom become infected. The duration of therapy has not been established, but maintenance therapy should continue a minimum of 4 weeks after resolution of all clinical signs and associated neuroimaging lesions. CNS ASPERGILLOSIS Aspergillus fumigatus, Aspergillus terreus, and Aspergillus flavus are the main species that cause human disease. CNS infections typically develop either by direct extension from infected paranasal sinuses or following head trauma or cranial surgery or by hematogenous spread from infected lung (occurs in 15% of patients with pulmonary aspergillosis and 50% of patients with disseminated aspergillosis). Hematogenous spread producing multiple cerebral abscesses typically develops in severely immunocompromised patients such as neutropenic patients who have an underlying hematologic malignancy, or patients receiving solid organ, bone marrow, or stem cell transplants. Extension from infected sinuses usually produces lesions in the frontal or temporal lobes, which are pathologically characterized by granulomas and cerebral infarctions following hyphal angioinvasion and vessel thrombosis. Diagnosis is often difficult since CSF is usually sterile. Cerebral or sinus biopsy with fungal culture and histologic examination of tissue for hyphae is diagnostic. The presence of galactomannan in CSF by EIA looks promising. Definitive therapy usually requires surgical resection of infected brain tissue plus antifungal therapy (see Table 3). A recent study finds that treatment of systemic infections including the brain with voriconazole is superior to amphotericin B. However, lipid formulations of amphotericin B were not studied.
Management of CNS Complications SEIZURES Focal or generalized seizures occur in up to 33% of patients with CNS fungal infections. Evaluation includes neuroimaging, looking for a fungal abscess, infarction, or hemorrhage, and serum sodium levels for hyponatremia. Anticonvulsive therapy is usually with phenytoin. However, if the patient is receiving fluconazole or voriconazole, reduction of phenytoin dosage and monitoring of phenytoin blood levels should be done because azoles interfere with phenytoin metabolism.
Likewise, phenobarbital and carbamazepine interact with azoles (see Table 4). The duration of anticonvulsant therapy depends on the cause of the seizures. NAUSEA AND VOMITING Repeated vomiting can lead to dehydration and electrolyte imbalance. Causes include meningeal inflammation, increased intracranial pressure, and treatment with amphotericin B. Phenergan often lessens the nausea. Other antinausea medications may interact with azoles (see Table 4). STUPOR AND COMA The development of stupor or coma is serious, and its cause should be sought. Neuroimaging may suggest hydrocephalus, bilateral thalamic damage, or brainstem damage from an abscess, hemorrhage, or infarction. Patients may require mechanical ventilation or surgical intervention with ventricular shunting or removal of the localized infection. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION SYNDROME AND CEREBRAL SALT WASTING (CSW) Chronic basilar meningitis may result in either syndrome of inappropriate antidiuretic hormone (SIADH) or cerebral salt wasting (CSW) leading to hyponatremia. The hyponatremia predisposes to seizures. Serum sodium levels and serum and urine osmolality can be followed. For symptomatic patients with SIADH, therapy is usually fluid restriction. Therapy for symptomatic CSW is replacement of sodium and extracellular volume deficits, avoiding rapid correction. INCREASED INTRACRANIAL PRESSURE Papilledema and depressed mental status may be due to obstructive or communicating hydrocephalus, expanding intracranial mass (abscess, infarction, or hemorrhage), or interference with CSF resorption in the superior sagittal sinus. Neuroimaging is helpful in establishing the diagnosis and should determine the best plan to lower CSF pressure. (See section on cryptococcal meningitis for methods to remove CSF to lower the pressure.) SUGGESTED READING Cortez KJ, Walsh TJ: Space-occupying fungal lesions. In Scheld WM, Whitley RJ, Marra CM, editors: Infections of the central nervous system, ed 3, Philadelphia, 2004, Lippincott Williams & Wilkins, 713-733. Galgiani JN, Ampel NM, Cantanzaro A, et al: Practice guidelines for treatment of coccidioidomycosis, Clin Infect Dis 30:658-661, 2000. Pappas PG, Rex JH, Sobel JD, et al: Guidelines for treatment of candidiasis, Clin Infect Dis 38:161-189, 2004. Perfect JR: Fungal meningitis. In Scheld WM, Whitley RJ, Marra CM, editors: Infections of the central nervous system, ed 3, Philadelphia, 2004, Lippincott Williams & Wilkins, 691-712. Saag MS, Graybill RJ, Larsen RA, et al: Practice guidelines for the management of cryptococcal disease, Clin Infect Dis 30:710-718, 2000. Johnson: Current Therapy in Neurologic Disease (7/E)
Brain Abscess and Parameningeal Infection
Brain Abscess and Parameningeal Infection Wendy L. Wright, M.D.
When a patient presents with fever and focal neurologic deficits, a central nervous system (CNS) abscess or parameningeal focus of infection must be suspected so treatment can begin without delay. Treatment of brain abscesses and parameningeal infections usually combines antibiotic therapy with surgical treatment. The urgency of treatment depends somewhat on the anatomic location because brainstem, cerebellum, and spinal cord foci are less well tolerated than infections affecting the cerebral hemispheres. The clinical status of the patient, the function of the patient’s immune system, and the nature of the infection are other factors that can influence treatment options (Figure 1).
Brain Abscess Brain abscesses most commonly arise from hematogenous spread, direct extension from local infections, neurosurgical procedures or penetrating head injury. The organisms responsible for brain abscesses are often streptococcal, staphylococcal, or anaerobic. Risk factors include acquired immunodeficiency syndrome, organ transplantation, intravenous (IV) drug use, chemotherapy, cardiac anomaly or prosthetic cardiac valves, and diabetes. Clinically, patients present with fever, headache (which may be unilateral), and signs and symptoms of increased intracranial pressure (nausea, vomiting, lethargy, papilledema); they may also have meningismus, focal neurologic deficits, and seizures. Diagnosis is most commonly made with contrast-enhanced computed tomographic (CT) scanning of the brain, which will show a space-occupying lesion with stages that correlate with histologic findings. The cerebritis stages (early cerebritis, days 1 to 3; late cerebritis, days 4 to 9) show a poorly demarcated, hypodense lesion with associated localized edema. Histologically, this correlates with acute inflammation but no tissue necrosis. The encapsulation stages (early encapsulation, days 10 to 13; late encapsulation, days 14 and up) show ring enhancement with surrounding edema on CT, and histologically this correlates Johnson: Current Therapy in Neurologic Disease (7/E)
with necrosis and liquefaction, and the lesion becomes surrounded by a fibrotic capsule. Magnetic resonance (MR) imaging with gadolinium enhancement is more sensitive for detecting satellite lesions and early cerebritis and can more adequately characterize the extent of capsule formation, central necrosis, and cerebral edema. Lumbar puncture is relatively contraindicated in brain abscesses that are causing mass effect, because of the herniation risk, but is sometimes done before brain abscess is suspected. The cerebrospinal fluid (CSF) may show a moderate pleocytosis. Glucose is usually normal, and protein may be normal or elevated. Cultures are usually negative. If the CSF is more consistent with bacterial meningitis (very elevated white blood cell count (WBC), positive cultures, or low glucose), rupture of the abscess into the ventricular system should be suspected. Serologic studies useful in the diagnosis may include complete blood count, which will usually show an elevated WBC, and blood cultures, which are usually negative (but if positive can provide useful information about the organism responsible for the abscess). Treatment of brain abscesses depends on the severity on presentation; the number, size, and location of lesions; and the organisms implicated. Medical treatment consisting of antibiotic therapy (Table 1) should be initiated in all patients once the diagnosis is suspected, without delay for pending diagnostic studies. Until specific culture and sensitivity data are available, empirical antibiotics are chosen based on common organisms and patient risk factors. Initial antibiotic therapy should include a third-generation cephalosporin, such as ceftriaxone or cefotaxime, plus vancomycin and metronidazole. If cultures show methicillin- sensitive Staphylococcus aureus, the vancomycin can be changed to nafcillin or oxacillin. If methicillin-resistant S. aureus is present, consider adding rifampin for synergy with vancomycin. Metronidazole should be continued until the presence of anaerobes is excluded. If the cultures are consistent with Streptococcus, penicillin G therapy is usually sufficient. Immunocompromised patients are at risk for CNS toxoplasmosis and Nocardia infection, which are treated with trimethoprim-sulfamethoxazole. Listeria should be suspected in patients on chronic steroid therapy and is best covered by ampicillin. Some fungal species known to cause brain abscesses include Aspergillus, Cryptococcus, Coccidioides, Candida albicans, and the group Mucorales which cause mucormycosis (Zygomycetes). These fungal infections are treated with amphotericin. Certain patient populations can be susceptible to parasitic infections due to travel or immigration, most commonly cysticercosis, which is treated with praziquantel. Antibiotics should be adjusted based on culture and sensitivity results and on the known pathogenic flora in the area of treatment. Total duration of therapy should be 6 to 8 weeks, 4 weeks of which should be IV. Medical treatment alone is not generally advocated, although it may be considered if a patient is too sick to undergo surgical therapy. This is rare; almost any patient can undergo stereotactic needle aspiration, unless an underlying coagulopathy or thrombocytopenia exists. Medical treatment alone may be considered if the lesions are multiple (especially if small); if the location
Nonviral Infectious Disease
Stevens DA, Kan VL, Judson MA, et al: Practice guidelines for diseases caused by Aspergillus, Clin Infect Dis 30:696-709, 2000. Stevens DA, Shatsky SA: Intrathecal amphotericin in the management of coccidioidal meningitis, Semin Resp Infect 16:263-269, 2001. Wheat J, Sarosi G, McKinsey D, et al: Practice guidelines for management of patients with histoplasmosis, Clin Infect Dis 30:688-695, 2000.
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Brain Abscess and Parameningeal Infection
Brain Abscess and Parameningeal Infection Wendy L. Wright, M.D.
When a patient presents with fever and focal neurologic deficits, a central nervous system (CNS) abscess or parameningeal focus of infection must be suspected so treatment can begin without delay. Treatment of brain abscesses and parameningeal infections usually combines antibiotic therapy with surgical treatment. The urgency of treatment depends somewhat on the anatomic location because brainstem, cerebellum, and spinal cord foci are less well tolerated than infections affecting the cerebral hemispheres. The clinical status of the patient, the function of the patient’s immune system, and the nature of the infection are other factors that can influence treatment options (Figure 1).
Brain Abscess Brain abscesses most commonly arise from hematogenous spread, direct extension from local infections, neurosurgical procedures or penetrating head injury. The organisms responsible for brain abscesses are often streptococcal, staphylococcal, or anaerobic. Risk factors include acquired immunodeficiency syndrome, organ transplantation, intravenous (IV) drug use, chemotherapy, cardiac anomaly or prosthetic cardiac valves, and diabetes. Clinically, patients present with fever, headache (which may be unilateral), and signs and symptoms of increased intracranial pressure (nausea, vomiting, lethargy, papilledema); they may also have meningismus, focal neurologic deficits, and seizures. Diagnosis is most commonly made with contrast-enhanced computed tomographic (CT) scanning of the brain, which will show a space-occupying lesion with stages that correlate with histologic findings. The cerebritis stages (early cerebritis, days 1 to 3; late cerebritis, days 4 to 9) show a poorly demarcated, hypodense lesion with associated localized edema. Histologically, this correlates with acute inflammation but no tissue necrosis. The encapsulation stages (early encapsulation, days 10 to 13; late encapsulation, days 14 and up) show ring enhancement with surrounding edema on CT, and histologically this correlates Johnson: Current Therapy in Neurologic Disease (7/E)
with necrosis and liquefaction, and the lesion becomes surrounded by a fibrotic capsule. Magnetic resonance (MR) imaging with gadolinium enhancement is more sensitive for detecting satellite lesions and early cerebritis and can more adequately characterize the extent of capsule formation, central necrosis, and cerebral edema. Lumbar puncture is relatively contraindicated in brain abscesses that are causing mass effect, because of the herniation risk, but is sometimes done before brain abscess is suspected. The cerebrospinal fluid (CSF) may show a moderate pleocytosis. Glucose is usually normal, and protein may be normal or elevated. Cultures are usually negative. If the CSF is more consistent with bacterial meningitis (very elevated white blood cell count (WBC), positive cultures, or low glucose), rupture of the abscess into the ventricular system should be suspected. Serologic studies useful in the diagnosis may include complete blood count, which will usually show an elevated WBC, and blood cultures, which are usually negative (but if positive can provide useful information about the organism responsible for the abscess). Treatment of brain abscesses depends on the severity on presentation; the number, size, and location of lesions; and the organisms implicated. Medical treatment consisting of antibiotic therapy (Table 1) should be initiated in all patients once the diagnosis is suspected, without delay for pending diagnostic studies. Until specific culture and sensitivity data are available, empirical antibiotics are chosen based on common organisms and patient risk factors. Initial antibiotic therapy should include a third-generation cephalosporin, such as ceftriaxone or cefotaxime, plus vancomycin and metronidazole. If cultures show methicillin- sensitive Staphylococcus aureus, the vancomycin can be changed to nafcillin or oxacillin. If methicillin-resistant S. aureus is present, consider adding rifampin for synergy with vancomycin. Metronidazole should be continued until the presence of anaerobes is excluded. If the cultures are consistent with Streptococcus, penicillin G therapy is usually sufficient. Immunocompromised patients are at risk for CNS toxoplasmosis and Nocardia infection, which are treated with trimethoprim-sulfamethoxazole. Listeria should be suspected in patients on chronic steroid therapy and is best covered by ampicillin. Some fungal species known to cause brain abscesses include Aspergillus, Cryptococcus, Coccidioides, Candida albicans, and the group Mucorales which cause mucormycosis (Zygomycetes). These fungal infections are treated with amphotericin. Certain patient populations can be susceptible to parasitic infections due to travel or immigration, most commonly cysticercosis, which is treated with praziquantel. Antibiotics should be adjusted based on culture and sensitivity results and on the known pathogenic flora in the area of treatment. Total duration of therapy should be 6 to 8 weeks, 4 weeks of which should be IV. Medical treatment alone is not generally advocated, although it may be considered if a patient is too sick to undergo surgical therapy. This is rare; almost any patient can undergo stereotactic needle aspiration, unless an underlying coagulopathy or thrombocytopenia exists. Medical treatment alone may be considered if the lesions are multiple (especially if small); if the location
Nonviral Infectious Disease
Stevens DA, Kan VL, Judson MA, et al: Practice guidelines for diseases caused by Aspergillus, Clin Infect Dis 30:696-709, 2000. Stevens DA, Shatsky SA: Intrathecal amphotericin in the management of coccidioidal meningitis, Semin Resp Infect 16:263-269, 2001. Wheat J, Sarosi G, McKinsey D, et al: Practice guidelines for management of patients with histoplasmosis, Clin Infect Dis 30:688-695, 2000.
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Aspiration –Can be done under local anesthesia if patient is unstable
Anticonvulsants if patient seizes; consider steroids if significant vasogenic edema is contributing to clinical deterioration
Negative or other lesion
Epidural abscess
Emergent surgical drainage (unless complete spinal cord dysfunction >3 days, prohibitive operative risk factors, or involvement of extensive length of spinal cord) and antibiotics
Emergent MRI of spine with and without gadolinium
Neurologic deficits localize to spinal cord
Work-up based on clinical and radiographic suspicion
FIGURE 1. Approach to the patient with possible brain abscess or parameningeal infection.
Adjust antibiotics based on culture and sensitivity data, and patient’s clinical response and information about patient’s immune status
Excision –Especially if abscess is encapsulated or debridement is indicated
Empiric antibiotics: third generation cephalosporin plus vancomycin plus metronidazole
Emergent surgical drainage and antibiotics
Antibiotic therapy, strongly consider surgery (unless multiple small lesions or high risk of bleeding complications), supportive care prn –Follow up with serial CTs and reassess surgical options and antibiotics based on clinical and radiographic response
Supportive care
Subdural empyema
CT of brain with and without IV contrast
Neurologic deficits localize to brain
Brain abscess
Surgery (especially if abscess is larger than 3 cm, close to a ventricle, in the cerebellum; or if definitive culture data are needed)
Negative or other lesion
Work-up based on clinical and radiographic suspicion
None
Focal neurologic deficits
Fever, mental status change, headache/back pain, seizure, or other factors that suggest central nervous system infection
170 Brain Abscess and Parameningeal Infection
Johnson: Current Therapy in Neurologic Disease (7/E)
Brain Abscess and Parameningeal Infection
Antibiotic
Dosage
Coverage
Vancomycin Cefotaxime Ceftriaxone Metronidazole Nafcillin Oxacillin Penicillin G
MRSA Broad spectrum Broad spectrum Anaerobes MSSA MSSA Streptococcus
Ampicillin Rifampin
1 gm IV q 12 hr 2 gm IV q 6-8 hr 2 gm IV q 12 hr 500 mg IV q 6 hr 2 gm IV q 4 hr 2 gm IV q 4 hr 3-4 million units IV q 4 hr 2 gm IV q 4 hr 600 mg IV/PO qd
Trimethoprimsulfamethoxazole Praziquantel Amphotericin
5-6 mg/kg IV q 6 hr 15 mg/kg PO tid 1 mg/kg/day IV
Listeria Synergy with vancomycin ˜ for MRSA Toxoplasmosis, Nocardia Cysticercosis Fungus
MRSA, Methicillin-resistant Staphylococcus aureus; MSSA, methicillinsensitive Staphylococcus aureus.
is surgically inaccessible or if the surgical approach would traverse eloquent tissue or the ventricular system; if there is concomitant meningitis or ependymitis; or if the patient has hydrocephalus requiring a shunt that could become infected during the operative procedure. Medical therapy alone is more likely to be successful if treatment is begun in the cerebritis stage before a capsule forms (generally within 10 days of symptom onset), if the lesions are small ( 5/μL
CSF protein
≤ 45 mg/dL
> 45 mg/dL
CSF FTA-ABS
Nonreactive
No neurosyphilis
Reactive
Treat for neurosyphilis
FIGURE 1. Algorithm for the laboratory diagnosis of neurosyphilis in an HIV-uninfected patient. TPPA, Treponema pallidum particle agglutination; FTA-ABS, fluorescent treponemal antibody absorption test; CSF, cerebrospinal fluid; VDRL, Venereal Disease Research Laboratory test; WBC, white blood cell count; HIV, human immunodeficiency virus.
antibiotic regimens have been proposed, based not on efficacy in clinical trials but on their ability to produce sufficient antibiotic concentrations in CSF to kill T. pallidum. The Adult AIDS Clinical Trials Group conducted a study that compared 10 days of neurosyphilis therapy with ceftriaxone, 2 gm IV once daily, and aqueous crystalline penicillin G, 4 million units IV every 4 hours, in 30 HIV-infected subjects. There were clinical differences between the two groups, and more of the ceftriaxone-treated subjects than the penicillin-treated subjects had early syphilis. Nonetheless, there was no difference in the proportion of subjects in each group with improved CSF measures after therapy. However, even after controlling for differences in the two groups at baseline, decline in serum RPR titers was significantly greater in the ceftriaxone-treated subjects. These data suggest that ceftriaxone may be an alternative to penicillin in HIV-infected individuals with neurosyphilis Johnson: Current Therapy in Neurologic Disease (7/E)
Neurosyphilis
TABLE 2 Treatment for Neurosyphilis*
Serum TPPA or FTA-ABS
Type of Neurosyphilis Nonreactive
Reactive
No neurosyphilis
CSF VDRL
Nonreactive
All forms
Reactive
CSF WBC
≤ 5/μL
6–20/μL
> 20/μL
CSF protein
≤ 45 mg/dL
> 45 mg/dL
CSF FTA-ABS
Nonreactive
No neurosyphilis
Reactive
Treat for neurosyphilis
FIGURE 2. Algorithm for the laboratory diagnosis of neurosyphilis in an HIV-infected patient. TPPA, Treponema pallidum particle agglutination; FTA-ABS, fluorescent treponemal antibody absorption test; CSF, cerebrospinal fluid; VDRL, Venereal Disease Research Laboratory test; WBC, white blood cell count; HIV, human immunodeficiency virus.
and concomitant early syphilis. There are no data on whether ceftriaxone would be effective for late parenchymal neurosyphilis. Thus, I recommend that ceftriaxone may be considered as an alternative treatment for early neurosyphilis in individuals who are allergic to penicillin. Patients who have late neurosyphilis and are allergic to penicillin should be desensitized and treated with one of the two recommended penicillin regimens (see Table 2).
Response to Therapy The best outcome after treatment of neurosyphilis in terms of resolution of symptoms or signs is seen in patients with CSF pleocytosis before treatment. Although treatment does not reverse parenchymal damage seen in patients with meningovascular neurosyphilis, general Johnson: Current Therapy in Neurologic Disease (7/E)
Penicillin-allergic patients with early neurosyphilis Penicillin-allergic patients with late neurosyphilis
Drug, Dosage Aqueous crystalline penicillin G, 3-4 million units IV q 4 hr or 24 million units IV as a continuous infusion, for 10-14 days or Procaine penicillin, 2.4 million units IM qd plus probenecid 500 mg PO qid, both for 10-14 days (probenecid contraindicated if severe sulfa allergy) Ceftriaxone, 2 gm IV qd for 10-14 days Penicillin desensitization then Aqueous crystalline penicillin G, 3-4 million units IV q 4 hr or 24 million units IV as a continuous infusion for 10-14 days or Procaine penicillin, 2.4 million units IM qd plus probenecid 500 mg PO qid, both for 10-14 days (probenecid contraindicated with severe sulfa allergy)
*Many experts recommend following high-dose IV or IM penicillin therapy for neurosyphilis with IM benzathine penicillin G 2.4 million units weekly for 3 wk.
paresis, or tabes dorsalis, it prevents further disease progression. Traditionally, the criteria for assessing response to treatment of neurosyphilis have relied on improvement, or lack of progression, of neurologic findings and resolution of serum and CSF abnormalities. The CDC guidelines recommend that CSF should be examined every 6 months after neurosyphilis treatment until the cell count is normal. Retreatment is advised if the cell count has not declined at 6 months or if the CSF is not entirely normal by 2 years after therapy. No recommendations are provided regarding rate of decline of CSF protein concentration or of decline in CSF VDRL or serum VDRL or RPR titers. We recently examined the time to normalization and likelihood of normalization of CSF WBC, CSF protein, CSF VDRL reactivity, and serum RPR reactivity in 59 individuals treated with one of the regimens in Table 2. We found that the median time for normalization of all measures except CSF protein was about 4 months and that by 12 to 14 months after treatment, virtually all subjects had normalized CSF WBC and CSF VDRL reactivity. In contrast, CSF protein concentration remained abnormal despite resolution of the other CSF abnormalities. These results suggest that
Nonviral Infectious Disease
HIV-INFECTED PATIENT WITH SUSPECTED NEUROSYPHILIS
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TABLE 3 Suggested Criteria for Retreatment of Neurosyphilis Increase in serum VDRL or RPR titer by two dilutions (fourfold increase) at any time after therapy (repeat the test to confirm) Increase in CSF WBCs 3 mo after therapy Increase in CSF VDRL titer by two dilutions (fourfold increase) 3 mo after therapy CSF WBC > 5/μL 6 mo after therapy in an HIV-uninfected patient CSF WBC > 5/μL and no change in CSF VDRL or serum VDRL or RPR titer 6 mo after therapy in an HIV-infected patient Persistence of any CSF abnormality 2 yr after therapy in an HIV-uninfected patient Persistent CSF VDRL reactivity 2 yr after therapy in an HIV-infected patient Worsening neurologic symptoms or signs Development of new neurologic symptoms or signs VDRL, Venereal Disease Research Laboratory; RPR, rapid plasma reagin; CSF, cerebrospinal fluid; WBC, white blood cell count; HIV, human immunodeficiency virus.
persistently abnormal CSF protein concentration may not necessarily be an indication of treatment failure. Of note, we found that among the HIV-infected subjects, those with peripheral blood CD4+ T cell counts less than 200/μL were approximately four times less likely to normalize CSF VDRL than those with CD4+ cell counts higher than 200/μL. These results suggest that HIV-infected individuals, particularly those with low peripheral blood CD4+ T cell counts, might require more intensive therapy for neurosyphilis than those who are HIV uninfected. Previous case reports of neurosyphilis treatment failure in HIV-infected individuals underscore the need to carefully follow HIV-infected patients after neurosyphilis treatment. With these findings in mind, I suggest that serum VDRL or RPR titers be determined every 3 months and CSF be examined at 3 and 6 months, and then every 6 months thereafter, following treatment for neurosyphilis in both HIV-uninfected and HIV-infected individuals. Earlier follow-up than is recommended by the CDC will decrease the likelihood of loss to follow-up and will allow for earlier identification of treatment failure. Serial CSF examinations should continue until CSF pleocytosis and CSF VDRL reactivity normalize— by this I mean that the CSF WBC should be less than or equal to 5/μL and the CSF VDRL should revert to nonreactive, or the titer should drop by two dilutions (fourfold decline, such as a drop from 1:64 to 1:16). Serial serum examinations can be terminated when the serum VDRL or RPR becomes nonreactive or the titer drops by two dilutions. Although it is easy to devise such criteria for “cure,” we do not know if failure to meet these criteria is equivalent to treatment failure. Despite these limitations, suggested criteria for retreatment are listed in Table 3.
SELECTED READING Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002, MMWR Morb Mortal Wkly Rep 51:18-30, 2002. Golden MR, Marra CM, Holmes KK: Update on syphilis: resurgence of an old problem, JAMA 290:1510-1514, 2003. Katz DA, Berger JR, Duncan RC: Neurosyphilis: a comparative study of the effects of infection with human immunodeficiency virus, Arch Neurol 50:243-249, 1993. Lukehart SA, Hook EW III, Baker-Zander SA, et al: Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and therapy, Ann Intern Med 109:855-862, 1988. Marra CM, Boutin P, McArthur JC, et al: A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals, Clin Infect Dis 30:540-544, 2000. Marra CM, Maxwell CL, Smith SL, et al: Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features, J Infect Dis 189:369-376, 2004. Marra CM, Maxwell CL, Tantalo L, et al: Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 38:1001-1006, 2004. Marra CM, Tantalo LC, Maxwell CL, et al: Alternative cerebrospinal fluid tests to diagnose neurosyphilis in HIV-infected individuals, Neurology 63:85-88, 2004. Merritt HH, Adams RD, Solomon HC: Neurosyphilis, New York, 1946, Oxford University Press.
Lyme Disease Andrew R. Pachner, M.D.
Lyme borreliosis (LB) is a multisystemic illness caused by the tick-transmitted spirochete Borrelia burgdorferi. The neurologic manifestations of LB, often called Lyme neuroborreliosis (LNB), can be difficult to diagnose and treat. Many excellent reviews of LB and LNB are available, and this chapter focuses on practical aspects of management for the neurologist. Although ideally the diagnosis would be straightforward and management would be primarily focused on issues of therapy, the major efforts of the neurologist, and the most perplexing problems, lie in diagnosis. If diagnosis is approached in a rational manner, therapy and management are generally straightforward. Thus, this chapter addresses the diagnosis in depth first and then discusses therapy.
Diagnosis The diagnosis of LNB can occasionally be made purely from the history and neurologic examination. Usually, the diagnosis is considered as possible or probable on the initial evaluation and then confirmed by laboratory testing. Johnson: Current Therapy in Neurologic Disease (7/E)
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Lyme Disease
TABLE 3 Suggested Criteria for Retreatment of Neurosyphilis Increase in serum VDRL or RPR titer by two dilutions (fourfold increase) at any time after therapy (repeat the test to confirm) Increase in CSF WBCs 3 mo after therapy Increase in CSF VDRL titer by two dilutions (fourfold increase) 3 mo after therapy CSF WBC > 5/μL 6 mo after therapy in an HIV-uninfected patient CSF WBC > 5/μL and no change in CSF VDRL or serum VDRL or RPR titer 6 mo after therapy in an HIV-infected patient Persistence of any CSF abnormality 2 yr after therapy in an HIV-uninfected patient Persistent CSF VDRL reactivity 2 yr after therapy in an HIV-infected patient Worsening neurologic symptoms or signs Development of new neurologic symptoms or signs VDRL, Venereal Disease Research Laboratory; RPR, rapid plasma reagin; CSF, cerebrospinal fluid; WBC, white blood cell count; HIV, human immunodeficiency virus.
persistently abnormal CSF protein concentration may not necessarily be an indication of treatment failure. Of note, we found that among the HIV-infected subjects, those with peripheral blood CD4+ T cell counts less than 200/μL were approximately four times less likely to normalize CSF VDRL than those with CD4+ cell counts higher than 200/μL. These results suggest that HIV-infected individuals, particularly those with low peripheral blood CD4+ T cell counts, might require more intensive therapy for neurosyphilis than those who are HIV uninfected. Previous case reports of neurosyphilis treatment failure in HIV-infected individuals underscore the need to carefully follow HIV-infected patients after neurosyphilis treatment. With these findings in mind, I suggest that serum VDRL or RPR titers be determined every 3 months and CSF be examined at 3 and 6 months, and then every 6 months thereafter, following treatment for neurosyphilis in both HIV-uninfected and HIV-infected individuals. Earlier follow-up than is recommended by the CDC will decrease the likelihood of loss to follow-up and will allow for earlier identification of treatment failure. Serial CSF examinations should continue until CSF pleocytosis and CSF VDRL reactivity normalize— by this I mean that the CSF WBC should be less than or equal to 5/μL and the CSF VDRL should revert to nonreactive, or the titer should drop by two dilutions (fourfold decline, such as a drop from 1:64 to 1:16). Serial serum examinations can be terminated when the serum VDRL or RPR becomes nonreactive or the titer drops by two dilutions. Although it is easy to devise such criteria for “cure,” we do not know if failure to meet these criteria is equivalent to treatment failure. Despite these limitations, suggested criteria for retreatment are listed in Table 3.
SELECTED READING Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002, MMWR Morb Mortal Wkly Rep 51:18-30, 2002. Golden MR, Marra CM, Holmes KK: Update on syphilis: resurgence of an old problem, JAMA 290:1510-1514, 2003. Katz DA, Berger JR, Duncan RC: Neurosyphilis: a comparative study of the effects of infection with human immunodeficiency virus, Arch Neurol 50:243-249, 1993. Lukehart SA, Hook EW III, Baker-Zander SA, et al: Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and therapy, Ann Intern Med 109:855-862, 1988. Marra CM, Boutin P, McArthur JC, et al: A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals, Clin Infect Dis 30:540-544, 2000. Marra CM, Maxwell CL, Smith SL, et al: Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features, J Infect Dis 189:369-376, 2004. Marra CM, Maxwell CL, Tantalo L, et al: Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 38:1001-1006, 2004. Marra CM, Tantalo LC, Maxwell CL, et al: Alternative cerebrospinal fluid tests to diagnose neurosyphilis in HIV-infected individuals, Neurology 63:85-88, 2004. Merritt HH, Adams RD, Solomon HC: Neurosyphilis, New York, 1946, Oxford University Press.
Lyme Disease Andrew R. Pachner, M.D.
Lyme borreliosis (LB) is a multisystemic illness caused by the tick-transmitted spirochete Borrelia burgdorferi. The neurologic manifestations of LB, often called Lyme neuroborreliosis (LNB), can be difficult to diagnose and treat. Many excellent reviews of LB and LNB are available, and this chapter focuses on practical aspects of management for the neurologist. Although ideally the diagnosis would be straightforward and management would be primarily focused on issues of therapy, the major efforts of the neurologist, and the most perplexing problems, lie in diagnosis. If diagnosis is approached in a rational manner, therapy and management are generally straightforward. Thus, this chapter addresses the diagnosis in depth first and then discusses therapy.
Diagnosis The diagnosis of LNB can occasionally be made purely from the history and neurologic examination. Usually, the diagnosis is considered as possible or probable on the initial evaluation and then confirmed by laboratory testing. Johnson: Current Therapy in Neurologic Disease (7/E)
Lyme Disease
HISTORY Travel to Endemic Areas It is important to get a travel history for three reasons. First, patients without exposure to field mice, generally in forested areas, are unlikely to have been infected. Secondly, European and American LNB may differ somewhat in clinical presentation in that a painful radiculitis is more common in the former, and thus a history of travel to Europe and outdoor activity there may be helpful. Third, there is a range of endemicity of the infection in the United States: from hyperendemic states in New England and the upper Midwest to states where LB is extremely rare such as Florida or Arizona. Travel to the former areas is more likely to be associated with infection.
TABLE 1 Erythema Migrans (EM) Versus Insect Bite Reaction Characteristic
EM
Insect Bite Reaction
General appearance Itchiness Diameter (cm) Time course
Raised erythema
Raised erythema
+/− >5 Increasing in size over 1 wk Frequent
++ 2 mo after onset Lack of detectable anti-B. bugdorferi antibodies in CSF > 2 mo after onset
Laboratory
CNS, Central nervous system; CSF, cerebrospinal fluid; PMN, polymorphonuclear leukocyte. Adapted from Hansen K: Lyme neuroborreliosis: improvements in the laboratory diagnosis and a survey of epidemiological and clinical features in Denmark 1985-1990, Acta Neurol Scand Suppl 151:5-44,1994.
Nonviral Infectious Disease
whereas American patients tend to be treated with IV antibiotics. The discussion of the therapy of LNB is divided into three parts: management of patients (1) with probable LNB, (2) without LNB, and (3) with possible LNB. The discussion also includes therapy of the inflammation associated with Lyme disease.
179
7
180
Lyme Disease
(NSAIDs) if over-the-counter agents do not work. I have needed to use corticosteroids in the rare patient, but this therapy was begun only after adequate antibiotic therapy and after failure of NSAIDs. Daily steroids are initiated, switched within a few weeks to every-other-day steroids, and then tapered over a few months. PATIENTS WITHOUT LNB Frequently in my practice patients are referred to me for therapy of LNB when there is little or nothing to suggest this diagnosis. The patient history outlined here is a particularly striking and tragic example. S.W. was a talented young artist who in June 1990 began to note some mild left arm tingling while summering with her other artist friends on Martha’s Vineyard, a highly
endemic area for Lyme disease. She had had a small round skin lesion on her calf 3 weeks earlier, consistent with an insect bite reaction, which had cleared within a few days. Her friends were convinced that she had Lyme disease and vociferously convinced both S.W. and the local physician. She was begun initially on doxycycline for 1 month, but when that had no lasting effect, she was given 3 weeks of intravenous ceftriaxone (Rocephin). A persistent trend of an initial few days of improvement coupled with long-term failure of response led to a multitude of oral and intravenous antibiotics by her physicians. By the time I first saw her in November, when she carried the diagnosis of “CNS Lyme disease refractory to multiple courses of antibiotics,” she had an unmistakable left hemiparesis. CT scan revealed a right temporoparietal mass, which on surgery was a glioblastoma.
FIGURE 1. Diagnosis and therapy of Lyme neuroborreliosis (LNB). CSF, Cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; PCN, penicillin; CEF, ceftriaxone; NSAID, nonsteroidal anti-inflammatory drug.
History and examination suggestive of LNB and absence of other diagnoses
Lumbar puncture
CSF lymphomonocytic pleocytosis Negative
Positive CSF anti-B. burgdorferi antibody
CSF anti-B. burgdorferi antibody Negative
Positive
Not LNB
Negative
sAb*
Negative
Positive sAb*
sAb* Positive
Negative
Negative Recheck CSF Ab
Positive
Positive Repeat sAb in 2 wks
Pleocytosis from other cause
Probable LNB
Therapy with PCN/CEF and NSAIDs 2–6 months later Treatment failure
Revisit diagnosis
Consider increasing anti-inflammatories
Treatment success
No further evaluation or Rx
*sAb = serum ELISA and immunoblot
Johnson: Current Therapy in Neurologic Disease (7/E)
Cerebral Malaria
PATIENTS WITH POSSIBLE LNB The group of patients with possible LNB has some features that may be consistent with LNB but do not meet diagnostic criteria. This is perhaps the most difficult variety of situations to manage. For instance, patients with viral (“aseptic”) meningitis have symptoms and CSF pleocytosis indistinguishable from those of LNB. The second series of tests outlined in Figure 1, antibody tests of CSF and serum, often are not available immediately after the LP. Thus, depending on the clinical suspicion of LNB and the degree of illness of the patient, I sometimes initiate doxycycline or ceftriaxone therapy. I do not do this in a patient with mild symptoms and nothing to implicate LNB other than lymphocytic pleocytosis. If positive serologies return after a few days on the latter type of patient, antibiotics can be initiated at that time. The “delay” of a few days does not adversely affect the outcome and saves the patient from potential adverse effects of the antibiotics. A similarly difficult presentation to treat is that of the patient with sudden onset of facial palsy without other indicators of LB. Most of these patients have idiopathic Bell’s palsies, and LP or antibiotics are not justified. In such patients I obtain an initial serum Lyme antibody. If that is negative, I treat the patient’s palsy as a routine Bell’s palsy but I repeat the serology in 3 weeks. If the patient seroconverts, or if the initial serology is positive, I obtain an LP and use the CSF results to guide therapy. Thus, patients with pleocytosis or a positive CSF antibody are treated with ceftriaxone, while those with a negative CSF profile but a positive serum antibody are treated with doxycycline. Given the complexity of the disease, and the complexity of the nervous system, there are many more potential scenarios that raise important management questions. In general, LNB is not a medical emergency, and there is time to evaluate data and obtain more information before making major management decisions. There has been a recent increase in the overdiagnosis of Johnson: Current Therapy in Neurologic Disease (7/E)
LNB and in its overtreatment, two mistakes that can be prevented by obtaining adequate studies and carefully considering treatment options. SUGGESTED READING Halperin JJ, Luft B, Anand AK, et al: Lyme neuroborreliosis: central nervous system manifestations, Neurology 39:753-759, 1989. Hansen K: Lyme neuroborreliosis: improvements in the laboratory diagnosis and a survey of epidemiological and clinical features in Denmark 1985-1990, Acta Neurol Scand Suppl 151:5-44, 1994. Pachner AR: Early disseminated Lyme disease: Lyme meningitis, Am J Med 98:4A30S-4A43S, 1995. Pachner AR, Dail D, Bai Y, et al: Genotype of infecting strain determines phenotype of infection in experimental Lyme borreliosis, Ann Neurol 56:361-370, 2004. Shadick NA, Phillips CB, Logigian EL, et al: The long-term clinical outcomes of Lyme disease: a population-based retrospective cohort study, Ann Intern Med 121:560-567, 1994.
Nonviral Infectious Disease
Surgery and irradiation were partially successful, but she died in the summer of 1991. The surgeons felt that surgery at an earlier date may have been curative. This patient, who had a number of “features casting doubt on the diagnosis of Lyme neuroborreliosis” (Table 2), should never have been given the diagnosis of CNS Lyme disease, since an evaluation for other causes would have yielded the correct diagnosis. Alternatively, there are patients who do not have clear diagnoses even after evaluation and have symptoms that might be attributable to LNB but are highly nonspecific, such as intermittent headache, numbness and tingling, and low-grade encephalopathy. Patients with protracted symptoms deserve thorough analysis, but if after serum and CSF analysis, there is nothing to implicate LNB, it is questionable medical judgment to treat these patients “to see what will happen.” Antibiotic therapy in patients without LNB has a low chance of success, a significant chance of side effects, and distracts diagnostic focus; it should thus not be done.
181
PATIENT RESOURCES American Lyme Disease Foundation Phone: 914-934-9155 Phone hotline: 800-876-5963 Centers for Disease Control and Prevention (CDC) Phone: 404-332-4555 New York State Health Department Phone: 518-474-4568
Cerebral Malaria Tom Solomon, M.D., Ph.D., and Tom Blanchard, M.D.
Cerebral malaria is an acute cerebral dysfunction (an encephalopathy) caused by infection with the parasite Plasmodium falciparum. The three other malaria parasites—Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale—do not cause cerebral malaria, though they may cause febrile seizures in children. P. falciparum can cause a range of severe complications affecting many organs of the body. Thus there are many potential causes of reduced consciousness in someone infected with P. falciparum, including hypoglycemia, acid-base disturbance, severe anemia, and seizures. For research purposes the World Health Organization has defined cerebral malaria as unrousable coma (i.e., a nonpurposeful response to a painful stimulus) in patients in whom these metabolic deficits and seizures have been corrected. However, for practical purposes, all patients with P. falciparum infection and altered consciousness, including those who are drowsy or irritable, should be treated as if they have severe disease. How P. falciparum infection causes cerebral malaria is not known, but sludging of parasitized red blood cells as they pass through the blood vessels of the brain (known as sequestration) is thought to be critically important.
7
Cerebral Malaria
PATIENTS WITH POSSIBLE LNB The group of patients with possible LNB has some features that may be consistent with LNB but do not meet diagnostic criteria. This is perhaps the most difficult variety of situations to manage. For instance, patients with viral (“aseptic”) meningitis have symptoms and CSF pleocytosis indistinguishable from those of LNB. The second series of tests outlined in Figure 1, antibody tests of CSF and serum, often are not available immediately after the LP. Thus, depending on the clinical suspicion of LNB and the degree of illness of the patient, I sometimes initiate doxycycline or ceftriaxone therapy. I do not do this in a patient with mild symptoms and nothing to implicate LNB other than lymphocytic pleocytosis. If positive serologies return after a few days on the latter type of patient, antibiotics can be initiated at that time. The “delay” of a few days does not adversely affect the outcome and saves the patient from potential adverse effects of the antibiotics. A similarly difficult presentation to treat is that of the patient with sudden onset of facial palsy without other indicators of LB. Most of these patients have idiopathic Bell’s palsies, and LP or antibiotics are not justified. In such patients I obtain an initial serum Lyme antibody. If that is negative, I treat the patient’s palsy as a routine Bell’s palsy but I repeat the serology in 3 weeks. If the patient seroconverts, or if the initial serology is positive, I obtain an LP and use the CSF results to guide therapy. Thus, patients with pleocytosis or a positive CSF antibody are treated with ceftriaxone, while those with a negative CSF profile but a positive serum antibody are treated with doxycycline. Given the complexity of the disease, and the complexity of the nervous system, there are many more potential scenarios that raise important management questions. In general, LNB is not a medical emergency, and there is time to evaluate data and obtain more information before making major management decisions. There has been a recent increase in the overdiagnosis of Johnson: Current Therapy in Neurologic Disease (7/E)
LNB and in its overtreatment, two mistakes that can be prevented by obtaining adequate studies and carefully considering treatment options. SUGGESTED READING Halperin JJ, Luft B, Anand AK, et al: Lyme neuroborreliosis: central nervous system manifestations, Neurology 39:753-759, 1989. Hansen K: Lyme neuroborreliosis: improvements in the laboratory diagnosis and a survey of epidemiological and clinical features in Denmark 1985-1990, Acta Neurol Scand Suppl 151:5-44, 1994. Pachner AR: Early disseminated Lyme disease: Lyme meningitis, Am J Med 98:4A30S-4A43S, 1995. Pachner AR, Dail D, Bai Y, et al: Genotype of infecting strain determines phenotype of infection in experimental Lyme borreliosis, Ann Neurol 56:361-370, 2004. Shadick NA, Phillips CB, Logigian EL, et al: The long-term clinical outcomes of Lyme disease: a population-based retrospective cohort study, Ann Intern Med 121:560-567, 1994.
Nonviral Infectious Disease
Surgery and irradiation were partially successful, but she died in the summer of 1991. The surgeons felt that surgery at an earlier date may have been curative. This patient, who had a number of “features casting doubt on the diagnosis of Lyme neuroborreliosis” (Table 2), should never have been given the diagnosis of CNS Lyme disease, since an evaluation for other causes would have yielded the correct diagnosis. Alternatively, there are patients who do not have clear diagnoses even after evaluation and have symptoms that might be attributable to LNB but are highly nonspecific, such as intermittent headache, numbness and tingling, and low-grade encephalopathy. Patients with protracted symptoms deserve thorough analysis, but if after serum and CSF analysis, there is nothing to implicate LNB, it is questionable medical judgment to treat these patients “to see what will happen.” Antibiotic therapy in patients without LNB has a low chance of success, a significant chance of side effects, and distracts diagnostic focus; it should thus not be done.
181
PATIENT RESOURCES American Lyme Disease Foundation Phone: 914-934-9155 Phone hotline: 800-876-5963 Centers for Disease Control and Prevention (CDC) Phone: 404-332-4555 New York State Health Department Phone: 518-474-4568
Cerebral Malaria Tom Solomon, M.D., Ph.D., and Tom Blanchard, M.D.
Cerebral malaria is an acute cerebral dysfunction (an encephalopathy) caused by infection with the parasite Plasmodium falciparum. The three other malaria parasites—Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale—do not cause cerebral malaria, though they may cause febrile seizures in children. P. falciparum can cause a range of severe complications affecting many organs of the body. Thus there are many potential causes of reduced consciousness in someone infected with P. falciparum, including hypoglycemia, acid-base disturbance, severe anemia, and seizures. For research purposes the World Health Organization has defined cerebral malaria as unrousable coma (i.e., a nonpurposeful response to a painful stimulus) in patients in whom these metabolic deficits and seizures have been corrected. However, for practical purposes, all patients with P. falciparum infection and altered consciousness, including those who are drowsy or irritable, should be treated as if they have severe disease. How P. falciparum infection causes cerebral malaria is not known, but sludging of parasitized red blood cells as they pass through the blood vessels of the brain (known as sequestration) is thought to be critically important.
7
182
Cerebral Malaria
The most common clinical picture in cerebral malaria is of a diffuse symmetrical encephalopathy, which may manifest as gradually increasing drowsiness, confusion, or agitation or may follow a seizure. Seizures are common in cerebral malaria, especially in children. Often there are no focal neurologic signs, but bruxism (teeth grinding), increased tone, decreased tone, flexor or extensor posturing, and opisthotonus may occur. In children coma may occur without any preceding fever or other symptoms. A characteristic retinopathy, which consists of patchy whitening of the fundus and small vessels, with retinal hemorrhages, may be seen on funduscopy.
Diagnosis The diagnosis of cerebral malaria should not be difficult, but there are some common pitfalls (Table 1). One of the biggest mistakes is in not thinking of the diagnosis in the first place; unless you ask about travel for every patient with an acute encephalopathy, you will miss some cases. Be wary of diagnosing flu in a returning traveler—an urgent examination of blood films is required to exclude malaria. Make sure that the laboratory does thick films, which have the maximum chance of seeing parasites, and thin films, which allow the Plasmodium species to be identified. Another common mistake is to assume that because a traveler took antimalarial chemoprophylaxis, malaria is not possible. Antimalarials do not provide complete protection, but unwary travelers may allow mosquitoes to bite them in the mistaken belief that they are protected. Furthermore antimalarial chemoprophylactic drugs can make the diagnosis harder; they lengthen the incubation period beyond the 1 to 2 weeks that is quoted in many textbooks, and they make it less likely that parasites will be
TABLE 1 Suspicion of Cerebral Malaria Category
Assessment
Caveats
Always take a travel history Beware of patients who “cannot” have malaria because they “took prophylaxis” or are “immune” Coma Score Seizures?—obvious or subtle Hyperventilation?—acidosis, pulmonary edema, or pneumonia Fluid balance—dehydration? Thick and thin blood film for parasites and pigment (repeated if necessary) Clues if blood film negative: thrombocytopenia? malaria pigment in neutrophils and monocytes? Blood glucose Complete blood count; urea and electrolytes; blood gases or venous lactate for acidosis; blood culture Lumbar puncture if no contraindication
Evaluations
Initial investigations
seen on a blood film. In a similar way, do not be misled by patients who “cannot have malaria” because they were brought up in Africa and have natural immunity. Such natural immunity wanes in those who have been living in nonendemic areas for awhile; the native African who has lived in the West for many years and then returns home for a holiday may well get malaria. However, because they have some immunity, the incubation period may again be prolonged, and diagnosis by blood film examination may again be difficult. Sometimes, in partially treated patients, malaria pigment within neutrophils or monocytes may be easier to see than parasites. Mild thrombocytopenia (1 lesion 1 lesion
Development of multiple sclerosis, %
60
Overall No lesions
50 40 30 20 10
0
1
2
3
4
5
6
7
8
9
10
11
12
Follow-up study, year Overall Patients at risk 388* Multiple sclerosis 33 15 Censored
340 17 6
317 23 4
290 18 1
271 13 5
253 12 9
232 8 6
218 4 4
210 3 0
207 6 2
199 2 35
162 2 79
Brain MRI: No lesion 191 Patients at risk 4 Multiple sclerosis 10 Censored
177 5 4
168 6 3
159 6 1
152 7 3
142 3 6
133 0 4
129 2 1
126 0 0
126 4 1
121 0 24
97 1 54
44 3 2
39 2 0
37 5 0
32 2 0
30 2 1
27 3 1
23 1 0
22 1 0
21 1 0
20 1 0
19 1 2
16 0 8
Brain MRI: >1 lesion 116 Patients at risk Multiple sclerosis 24 2 Censored
90 8 2
80 8 1
71 7 0
64 1 1
62 6 1
55 7 2
46 0 2
44 2 0
42 1 1
40 0 8
32 0 9
Brain MRI: 1 lesion Patients at risk Multiple sclerosis Censored
this time period, treatment decisions should be based on the potential benefits versus risks of therapy. The ONTT also demonstrated that MR imaging findings—specifically, the presence of two or more, or even one, white matter lesion(s) at baseline—are a powerful predictor of risk for a development of MS in patients with acute monosymptomatic optic neuritis (see Figure 1). This demonstration of increased MS risk in the subgroup of patients with optic neuritis and two or more MR imaging white matter lesions provided a rationale for clinical trials examining the potential role for early disease-modifying therapy in patients with clinically isolated syndromes, such as those discussed in the following sections. CONTROLLED HIGH-RISK AVONEX MS PREVENTION STUDY CHAMPS was a randomized trial of 383 patients who presented with clinically isolated syndromes (acute optic neuritis, brainstem syndromes, or incomplete transverse myelopathy) and brain MR imaging scans showing high risk for MS as per ONTT criteria (≥ 2 white matter lesions, ≥ 3 mm in diameter, at least 1 lesion periventricular or ovoid). All patients in CHAMPS received IV methylprednisolone 1 gm/day for 3 days, initiated within 14 days of symptom onset; this was followed by Johnson: Current Therapy in Neurologic Disease (7/E)
FIGURE 1. The cumulative probability of multiple sclerosis was statistically significantly higher in patients with one or more lesions seen on the baseline MRI scan of the brain than in patients with no brain lesions (p < 0.001, log rank test) but was not significantly different comparing patients with a single brain lesion and patients with multiple lesions (p = 0.22, log rank test). The numbers of patients at risk are the numbers who had not developed multiple sclerosis at the beginning of each year. The “multiple sclerosis” rows indicate the number of patients classified as having multiple sclerosis during each yearly interval. The “censored” rows indicate the number of patients not developing multiple sclerosis whose last available follow-up data occurred during each yearly interval. Asterisk indicates 37 patients who had no baseline MRIs. (From Optic Neuritis Study Group: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis, Arch Ophthalmol 121:944-949, 2003.)
oral prednisone (1 mg/kg/day for 11 days, with a 4-day taper). Patients were then randomized (within 27 days of symptom onset) to receive interferon beta-1a (Avonex) 30 μg intramuscularly weekly) or placebo. To minimize potential flulike side effects of interferon beta-1a, all patients were given 650 mg of acetaminophen prior to each injection and then every 6 hours for 24 hours. Results of CHAMPS demonstrated that interferon beta-1a significantly reduced the 3-year cumulative probability of MS versus placebo (probability of MS 35% for interferon beta-1a vs. 50% for placebo, rate ratio 0.56; p = 0.002, Kaplan-Meier analysis/Mantel log-rank test). Treated patients also had significantly reduced accumulation of new but clinically silent brain MR imaging white matter lesions (p < 0.001 for both T2-weighted and gadolinium-enhancing brain MR imaging lesions at 18 months). Results were similar in the CHAMPS subgroup that presented with optic neuritis as the first demyelinating event (192 patients), supporting the initiation of interferon beta-1a in optic neuritis patients at high risk for MS by MR imaging criteria. During the first 6 months in CHAMPS, an influenzalike syndrome (fever, chills, myalgias) was reported by 54% in the interferon beta-1a group, compared with 26% for placebo (p < 0.001). Depression was the only other adverse event whose incidence was at least 5 percentage
Other Inflammatory and Demyelinating Diseases
70
187
8
188
Optic Neuritis
1. Clinical features Typical for acute demyelinating optic neuritis? Yes
No MRI brain/orbits with gadolinium Consider CSF analysis/serologic studies Treatment as appropriate
2. MRI brain w/gadolinium High risk for MS? (≥ 2 white matter lesions, ≥ 3 mm diameter, at least 1 lesion periventricular or ovoid) No
Yes
Consider IV methylprednisolone on individual basis to hasten visual recovery
3. Consider treatment 1. Intravenous methylprednisolone sodium succinate (1 gram IV/day for 3 days) followed by oral prednisone (1 mg/kg/day for 11 days) with 4-day taper (20 mg on day 1, 10 mg on days 2 and 4), followed by: 2. Interferon beta 1-a (Avonex 30 μg intramuscularly [IM] weekly, or Rebif 22 μg subcutaneously [SQ] weekly) – demonstrated to significantly reduce the risk of MS and the development of clinically silent MRI lesions in high-risk patients within 2–5 years follow-up.
FIGURE 2. Management of acute monosymptomatic demyelinating optic neuritis. CSF, Cerebrospinal fluid; MS, multiple sclerosis; IV, intravenous. (From Balcer LJ, Galetta SL: Optic neuritis. In Conn’s current therapy, ed 56, Philadelphia, 2004, WB Saunders, 187-190.)
points higher in the interferon beta-1a group (20% vs. 13%; p = 0.05). Patients on interferon beta-1a should undergo laboratory testing prior to initiation and after 3 and 6 months (complete blood count with differential, platelet count, blood chemistries, liver function tests). Compliance rates in CHAMPS were high: more than 90% of patients receiving interferon beta-1a were compliant at least 80% of the time. Although the potential for long-term benefit of interferon beta-1a in high-risk patients with acute monosymptomatic demyelinating optic neuritis is not known, data from CHAMPS provide rationale for early therapy. An extension study of CHAMPS with all patients on active interferon beta-1a therapy, the Controlled High-Risk Avonex MS Prevention Surveillance (CHAMPIONS), has provided more data in support of early treatment. Five-year follow-up has shown that despite the fact that all patients in the extension study were placed on active treatment, those initially randomized to interferon beta-1a still had a lower cumulative probability of MS (21% for initially treated vs. 35% for former placebo patients; rate ratio, 0.65; 95% confidence interval, 0.43 to 0.97; p = 0.03). Thus, immediate
initiation of interferon beta-1a was associated with a 35% reduction in the risk of developing MS. A 42% reduction in the number of new T2-weighted or enlarging MR imaging lesions was also noted at 5 years in patients treated with interferon beta-1a from the time of study initiation. EARLY TREATMENT OF MULTIPLE SCLEROSIS STUDY Early interferon therapy following a first demyelinating event is also supported by results of the ETOMS, a randomized trial of interferon beta-1a (Rebif ) performed in Europe. Participants in ETOMS (n = 308) were randomized to interferon beta-1a (Rebif ) 22 μg subcutaneously weekly or placebo. Treatments were initiated within 3 months; many participants (40%), however, had multifocal neurologic deficits at presentation. Seventy percent of ETOMS patients received corticosteroids (variable dose and route of administration) prior to initiation of study medication. During the 2-year follow-up, a significantly lower proportion of patients in the interferon beta-1a group developed MS compared with placebo (52/154 [34%] vs. 69/154 [45%]; p = 0.047). The time to occurrence of a second demyelinating event (MS) in 30% of ETOMS participants in each treatment group was also significantly shorter for interferon beta-1a (569 vs. 252 days for placebo; hazard ratio, 0.65; p = 0.023, Cox proportional hazards model). With respect to MR imaging parameters, patients on interferon beta-1a had significantly fewer new lesions on T2-weighted images throughout follow-up (p < 0.001, analysis of covariance). Similarly, the proportion of patients without MR imaging activity (new T2 lesions) was significantly higher in the interferon beta-1a group (23/146 [16%] vs. 8/133 [6%]; p = 0.005). Side effects reported more frequently among patients receiving active treatment in ETOMS included injection site inflammation (60% for interferon beta-1a vs. 12% for placebo), fever (28% vs. 12%), myalgias (17% vs. 9%), and chills (11% vs. 5%). As suggested by the ETOMS Study Group, differences between CHAMPS and ETOMS with respect to interferon beta-1a dosage (22 μg vs. 30 μg), timing of initiation of therapy (3 months vs. 14 days following first demyelinating event), and patient population/disease severity (multifocal vs. unifocal neurologic deficits at presentation) may account for the slightly greater effet on delay of clinically definite MS observed in CHAMPS. Data from ETOMS nonetheless support initiation of early interferon beta-1a therapy in patients with acute optic neuritis or other clinically isolated syndromes. Figure 2 represents a potential treatment paradigm for patients with acute demyelinating optic neuritis and is likely applicable to patients with other clinically isolated syndromes. In monosymptomatic patients with less than two white matter lesions by MR imaging, and in patients for whom a diagnosis of MS has been established, IV methylprednisolone followed by oral prednisone should be considered on an individual basis and may hasten visual recovery but has not been demonstrated to affect long-term visual outcome. Johnson: Current Therapy in Neurologic Disease (7/E)
Multiple Sclerosis
SUGGESTED READING Balcer L J, Galetta SL: Optic neuritis. In Conn’s current therapy, ed 56, Philadelphia, 2004, WB Saunders, 187-190. Comi G, Fillippi M, Barkhof F, et al: Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study, Lancet 357:1576-1582, 2001. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis, N Engl J Med 343:898-904, 2000. Optic Neuritis Study Group: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis, Arch Ophthalmol 121:944-949, 2003. Optic Neuritis Study Group: Visual function more than 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial, Am J Ophthalmol 137:77-83, 2004.
Multiple Sclerosis Peter Calabresi, M.D.
Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic disability in young adults and affects between 250,000 and 400,000 persons in the United States. MS usually presents in young adults and affects women two to three times more commonly than men. Most patients start with a period of unpredictable relapses and remissions, which in most is followed by accumulation of neurologic dysfunction and a chronic, progressive course. The life expectancy has been shown to be only 6 to 7 years less than that for a control population without MS, but the emotional and economic costs to society as a result of the disability are enormous. Although the etiology of MS is unknown, it is thought to be an immune-mediated disease of the central nervous system (CNS), in which mononuclear cells (lymphocytes and macrophages) cause demyelination, followed by varying degrees of secondary axonal degeneration. The partial success of immunomodulatory agent (IMA) therapies in the treatment of MS supports a primary role of the immune system but does not exclude the possibility that neurodegenerative mechanisms are also critical. It is recognized that oligodendrocyte and neuronal apoptosis may also play an important role in the pathogenesis of the disease. Johnson: Current Therapy in Neurologic Disease (7/E)
MS is diagnosed clinically through the demonstration of CNS lesions disseminated in time and space and with no better explanation for the disease process. There is no single diagnostic test, and several other diseases can mimic MS. Therefore, diagnostic criteria based on clinical features supplemented by laboratory tests have been used. The new McDonald criteria were developed by a panel of world MS experts and were based on review of extensive supportive scientific studies focusing on the sensitivity and specificity of magnetic resonance (MR) imaging diagnostic criteria. The major change associated with the latest criteria is that a diagnosis of MS can be made early after a clinically isolated demyelinating syndrome if a follow-up MR imaging performed 3 months later demonstrates the formation of a new lesion. Clinical disease subtypes have been recognized for years, but recently pathologic subtypes of disease have been demonstrated and provide confirmation that different pathologic mechanisms may be occurring in individual MS patients. Whether noninvasive studies such as MR imaging or serum antibody titers could be used to predict these subtypes and guide therapy remains to be determined.
Nonpharmacologic Therapy The care of MS patients requires a health care team approach including experienced nurses, physical and occupational therapists, social workers, and mental health specialists, in addition to a neurologist. The importance of an appropriate support team should not be underestimated. Frequently, nonpharmacologic interventions are as effective as drugs in improving the quality of life for patients with MS. We have found that education and counseling at the time of diagnosis are critical and should be provided by the neurologist, nurse, and support staff from the National Multiple Sclerosis Society at MS specialty centers. There are several useful Web sites, which provide unbiased educational material (see Patient Resources). Counseling and discussion of psychological, social, work, and family-related issues are useful and should be continued throughout the changing stages of the disease. Physical and occupational therapy as well as education and formal assessment and training regarding the use of assistive devices and rehabilitative equipment should be a routine part of the care of patients with MS.
Immunomodulatory Therapies There are four U.S. Food and Drug Administration (FDA)-approved IMAs for relapsing-remitting MS (RRMS) (two interferon beta-1a drugs, interferon beta-1b, and glatiramer acetate [Copaxone]) and one chemotherapeutic agent approved for worsening forms of relapsing MS and secondary progressive MS (SPMS) (mitoxantrone) (Table 1). In addition, one of these drugs (Avonex) carries an indication for patients with a clinically isolated (demyelinating) syndrome and MR imaging suggestive of MS. In all situations the clinician
Other Inflammatory and Demyelinating Diseases
Although evidence for treatment of patients with one white matter lesion with immunomodulatory agents has not been established by class I studies, initiation of early therapy and/or continued MR imaging surveillance at 3 to 6 months following a first demyelinating event are not unreasonable. In all cases of typical acute monosymptomatic demyelinating optic neuritis, oral prednisone alone at a dose of 1 mg/kg/day, without prior treatment with IV methylprednisolone (1 gm/day for 3 days), may increase the risk for recurrent optic neuritis and should be avoided.
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SUGGESTED READING Balcer L J, Galetta SL: Optic neuritis. In Conn’s current therapy, ed 56, Philadelphia, 2004, WB Saunders, 187-190. Comi G, Fillippi M, Barkhof F, et al: Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study, Lancet 357:1576-1582, 2001. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis, N Engl J Med 343:898-904, 2000. Optic Neuritis Study Group: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis, Arch Ophthalmol 121:944-949, 2003. Optic Neuritis Study Group: Visual function more than 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial, Am J Ophthalmol 137:77-83, 2004.
Multiple Sclerosis Peter Calabresi, M.D.
Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic disability in young adults and affects between 250,000 and 400,000 persons in the United States. MS usually presents in young adults and affects women two to three times more commonly than men. Most patients start with a period of unpredictable relapses and remissions, which in most is followed by accumulation of neurologic dysfunction and a chronic, progressive course. The life expectancy has been shown to be only 6 to 7 years less than that for a control population without MS, but the emotional and economic costs to society as a result of the disability are enormous. Although the etiology of MS is unknown, it is thought to be an immune-mediated disease of the central nervous system (CNS), in which mononuclear cells (lymphocytes and macrophages) cause demyelination, followed by varying degrees of secondary axonal degeneration. The partial success of immunomodulatory agent (IMA) therapies in the treatment of MS supports a primary role of the immune system but does not exclude the possibility that neurodegenerative mechanisms are also critical. It is recognized that oligodendrocyte and neuronal apoptosis may also play an important role in the pathogenesis of the disease. Johnson: Current Therapy in Neurologic Disease (7/E)
MS is diagnosed clinically through the demonstration of CNS lesions disseminated in time and space and with no better explanation for the disease process. There is no single diagnostic test, and several other diseases can mimic MS. Therefore, diagnostic criteria based on clinical features supplemented by laboratory tests have been used. The new McDonald criteria were developed by a panel of world MS experts and were based on review of extensive supportive scientific studies focusing on the sensitivity and specificity of magnetic resonance (MR) imaging diagnostic criteria. The major change associated with the latest criteria is that a diagnosis of MS can be made early after a clinically isolated demyelinating syndrome if a follow-up MR imaging performed 3 months later demonstrates the formation of a new lesion. Clinical disease subtypes have been recognized for years, but recently pathologic subtypes of disease have been demonstrated and provide confirmation that different pathologic mechanisms may be occurring in individual MS patients. Whether noninvasive studies such as MR imaging or serum antibody titers could be used to predict these subtypes and guide therapy remains to be determined.
Nonpharmacologic Therapy The care of MS patients requires a health care team approach including experienced nurses, physical and occupational therapists, social workers, and mental health specialists, in addition to a neurologist. The importance of an appropriate support team should not be underestimated. Frequently, nonpharmacologic interventions are as effective as drugs in improving the quality of life for patients with MS. We have found that education and counseling at the time of diagnosis are critical and should be provided by the neurologist, nurse, and support staff from the National Multiple Sclerosis Society at MS specialty centers. There are several useful Web sites, which provide unbiased educational material (see Patient Resources). Counseling and discussion of psychological, social, work, and family-related issues are useful and should be continued throughout the changing stages of the disease. Physical and occupational therapy as well as education and formal assessment and training regarding the use of assistive devices and rehabilitative equipment should be a routine part of the care of patients with MS.
Immunomodulatory Therapies There are four U.S. Food and Drug Administration (FDA)-approved IMAs for relapsing-remitting MS (RRMS) (two interferon beta-1a drugs, interferon beta-1b, and glatiramer acetate [Copaxone]) and one chemotherapeutic agent approved for worsening forms of relapsing MS and secondary progressive MS (SPMS) (mitoxantrone) (Table 1). In addition, one of these drugs (Avonex) carries an indication for patients with a clinically isolated (demyelinating) syndrome and MR imaging suggestive of MS. In all situations the clinician
Other Inflammatory and Demyelinating Diseases
Although evidence for treatment of patients with one white matter lesion with immunomodulatory agents has not been established by class I studies, initiation of early therapy and/or continued MR imaging surveillance at 3 to 6 months following a first demyelinating event are not unreasonable. In all cases of typical acute monosymptomatic demyelinating optic neuritis, oral prednisone alone at a dose of 1 mg/kg/day, without prior treatment with IV methylprednisolone (1 gm/day for 3 days), may increase the risk for recurrent optic neuritis and should be avoided.
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TABLE 1 FDA-Approved Immunomodulatory Drugs: Indications and Side Effects Drugs
Dosage
Comments
Interferon beta-1a (Avonex)
30 μg IM weekly
Interferon beta-1a (Rebif)
22-44 μg SC three times/wk
Interferon beta-1b (Betaseron)
8 million IU SC qod
Glatiramer acetate (Copaxone)
20 mg SC qd
Mitoxantrone (Novantrone)
5-12 mg/m2 IV q 3 mo
Used in CIS, less aggressive presentations, patient preference/lifestyle, as platform agent in combination therapy Flulike side effects Monitor CBC and LFTs Low risk of NABs Used in aggressive presentations with two or more relapses, polysymptomatic onset, multiple enhancing lesions on MR imaging Flulike side effects Injection site reactions and local pain Monitor CBC and LFTs Moderate risk of NABs Used in aggressive presentations with two or more relapses, polysymptomatic onset, multiple enhancing lesions on MR imaging, or if Rebif shots too painful Flulike side effects Injection site reactions Monitor CBC and LFTs High risk of NABs Used in early RRMS with nonaggressive presentation, depressed patients, side effect–intolerant patients, or patients on interferon beta who have high-titer NABs or are poorly controlled Injection site reactions Rare benign systemic reaction lasting 15-20 min No blood monitoring necessary Carries indication for worsening RRMS and SPMS Mild chemotherapy-related side effects Cardiotoxicity (may occur asymptomatically in 1st yr) Small increased risk of leukemia
FDA, U.S. Food and Drug Administration; CIS, clinically isolated syndrome; CBC, complete blood count; LFT, liver function test; NAB, neutralizing antibody; RRMS, relaxing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.
should be extremely careful about making a diagnosis of MS and ruling out appropriate mimics of the disease as discussed elsewhere. Recent clinical trial evidence and immunologic studies suggest that an early diagnosis and initiation of IMA may afford the patient the best chance for disease stability because the changes in the immune response over time may become more difficult to halt, lesion burden accumulates and is not reversed by presently available drugs. Pathologic and MR imaging studies have shown that axonal injury and progressive degeneration of demyelinated axons occur early and may become more prominent with time. Several trials have shown that patients on an IMA have less accumulated disability over time, but this is probably the result of the anti-inflammatory effects of the drugs and prevention of relapses rather than any effect on the progressive aspects of the disease. There are situations in which the clinician might recommend not initiating an IMA. There are clearly cases of benign MS in which after 20 to 40 years the patient has minimal to no physical or cognitive disability. Unfortunately, there is a tendency to overestimate the number of patients who fall into this category because we either do not follow the patient long enough or have not examined all aspects of the disease adequately
(cognitive impairment, fatigue, and depression are often underestimated). If one has the luxury of knowing a patient’s history for 20 years or longer and the clinical course has been benign (e.g., optic neuritis at 20 years of age and paresthesias in the 40s), it is reasonable to continue to monitor such a patient without an IMA. However, more often than not we are faced with a young patient presenting with a first episode of demyelination, a clinically isolated syndrome. In this situation, it is difficult to know what course the patient may follow, and initiation of an IMA is indicated immediately or when there is evidence for disease activity either clinically or radiologically (new enhancing lesion on an MR imaging scan after 3 months), at which time a definite diagnosis of MS can be made, presuming alternative explanations have been appropriately excluded. The choice of IMA is highly controversial and fraught with inconclusive data. In general the interferon beta drugs have the most dramatic effect on decreasing permeability of the blood-brain barrier, and hence their effect can be monitored on a contrast-enhanced MR imaging scan. The more frequently dosed interferon beta drugs, Rebif and Betaseron, have been shown in 1- to 2-year head-to-head trials against Avonex, to have more immediate efficacy in reducing relapses and Johnson: Current Therapy in Neurologic Disease (7/E)
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Johnson: Current Therapy in Neurologic Disease (7/E)
We use glatiramer for RRMS in patients who are worried about or cannot tolerate interferon beta side effects and in patients with moderate or severe affective disease in whom interferon beta may aggravate their depression. The onset of action appears to be delayed in glatiramer such that in a monthly MR imaging trial there was no significant reduction in MR imaging activity until month 6. This suggests that the immunologic response and benefit of the drug may be delayed, and one should not consider switching patients off this drug in the first 6 to 12 months unless the patient is doing extremely poorly (two or more relapses or three or more active MR imaging lesions). The decision to pursue combination therapy or chemotherapy is even more challenging because the risk of side effects increases and less conclusive data exist. Nonetheless, the marked efficacy in MS of the FDA-approved immunosuppressive drug mitoxantrone in reducing relapses, disability, and MR imaging activity provides a strong rationale for considering more aggressive immunosuppression before the patient becomes permanently disabled. The simplest and most commonly employed strategy is to add on pulses of IV methylprednisolone at the time of relapse or at scheduled intervals (1 day a month or 3 days bimonthly). Some trials have provided support for this approach, but conclusive data are lacking. We have found that a subset of patients respond to this approach for a limited period. Several oral immunosuppressive drugs, such as azathioprine, methotrexate, and mycophenolate mofetil are being used in MS, based on preliminary efficacy in pilot studies, but double-blind, placebo-controlled trial data are not available. We use immunosuppressive drugs only in conjunction with interferon beta drugs because it may counteract the benefit of glatiramerreactive T cells. The ease of use and minimal toxicity of the oral drugs make them more acceptable than chemotherapy to the less disabled breakthrough patient. We frequently use oral immunosuppressive drugs in combination with interferon beta therapy before initiating high-dose chemotherapy or as part of a maintenance regimen following chemotherapy as has been done in lupus. Oral methotrexate starting at 10 mg once weekly and then 20 mg weekly, is well tolerated except for nausea and is the simplest combination therapy to use. Methotrexate can be given at 20 mg weekly intramuscularly to avoid the gastrointestinal side effects. Mycophenolate mofetil can be started at 500 mg twice daily and increased to 1000 mg twice daily as tolerated and is also a useful adjunct to interferon beta in our experience. Azathioprine is a less expensive alternative and should be started gradually at one half a 50-mg tablet daily and increased to either 2 or 3 mg/kg in split doses or until the white blood cell count (WBC) is 4000/μL or lower, because of the known heterogeneity in genetic metabolism of this drug. Although mitoxantrone has proven efficacy in worsening and early SPMS, the risk of therapy-related leukemias and cardiotoxicity has limited its use. There are several reports suggesting that a significant subset of patients (10% to 25%) may have an asymptomatic reduction in
Other Inflammatory and Demyelinating Diseases
MR imaging activity and therefore may be preferred in very active patients in whom a rapid effect is desirable. Unfortunately, these two drugs also seem to carry the highest risk for development of neutralizing antibodies (NABs) against interferon beta (Rebif ~20%, Betaseron ~33%), which, depending on the NAB titer and duration, may partially or completely negate the efficacy of the drug. Since NABs tend to develop at year 1, the detrimental effects of NAB may not be entirely evident at year 2, but after 3 years persistent NAB appears to reduce the benefit of the drug. There is no consensus on what is considered a high titer, but NABs greater than 100 are likely to persist for long enough to be detrimental. In this situation, there is no known strategy for clearing NABs, and because NABs cross-react between all interferon beta agents, it is recommended to switch to a noninterferon. Avonex has the lowest incidence of NAB (3% to 5%) and may therefore provide a more sustained benefit. Patients fail interferon beta therapy for reasons other than NABs; therefore, if a patient has had two relapses in a year or develops more than three new lesions on a yearly follow-up MR imaging, one should consider switching IMAs regardless of NABs. The interferon beta drugs also commonly cause a flulike reaction characterized by low-grade fever, chills, myalgias, and asthenia 6 to 24 hours after each injection. These symptoms improve after 3 to 6 months and, with the use of appropriate prophylactic medications, become tolerable in most patients. We start the more frequently dosed interferon beta drugs (Rebif and Betaseron) at quarter dose and titrate up by quarter doses each week as tolerated to the full dose if possible. For Avonex, we initiate treatment at one-half dose for 2 weeks and then increase to full dose if it is being tolerated. We recommend two acetaminophen 325 mg and 400 to 800 mg of ibuprofen or 500 mg naproxen prior to injection in the evening and again the next morning if needed. These agents can gradually be tapered off if the patient is tolerating the interferon beta well. We have also found that starting interferon beta immediately following a course of intravenous (IV) methylprednisolone, sometimes during the prednisone taper, helps mask some of the side effects. The propensity of interferon beta to aggravate underlying depression is an issue, in our experience, and careful attention to the patient’s mood is important. Interferon beta can also aggravate migraine headaches and contribute to fatigue or menstrual irregularity. Rarely, patients feel remarkably better after discontinuation of interferon beta therapy, presumably because of unrecognized side effects. Glatiramer acetate is also an effective drug in RRMS and has an entirely different side effect profile. Glatiramer seems to work differently than interferon beta drugs and does not have its predominant effect at the blood-brain barrier and therefore has a less dramatic effect on reducing contrast-enhancing lesions. Animal and in vitro data suggest that the drug may work inside the CNS and could have some neuroprotective properties through release of brain-derived neurotrophic factor by glatiramer-reactive T cells, but whether glatiramerreactive T cells access the CNS and are neuroprotective in MS patients remains uncertain.
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left ventricular ejection fractions after only 1 year of therapy. We therefore prefer cyclophosphamide, an older chemotherapy drug, which has a rapid onset of action and is also highly effective in reducing relapses and MR imaging activity but causes more acute side effects such as nausea, mild alopecia, and neutropenia than does mitoxantrone. It does not have cardiotoxicity at conventional pulse doses (800 to 1200 mg/m2), and the risk of hematologic malignancy appears to be less than mitoxantrone. We initiate treatment at 800 mg/m2 and titrate upward each month based on the 10-day WBC nadir. After 6 to 12 months of monthly pulses, we reconsider alternative maintenance regimens or continue with bimonthly pulses. Bladder toxicity and malignancy have been reported at high doses acutely, but with the pulse regimen used earlier, malignancy rarely occurs and only after many years, presumably due to the oncogenic potential of human papilloma virus in a chronically immunosuppressed host. Yearly urine collections for cytology should be obtained. Intravenous immunoglobulin (IVIg) given monthly has been shown in some clinical trials to reduce relapses. We rarely use this approach because of its cost and unproven efficacy. Plasma exchange has been advocated in steroid-refractory fulminant cases of demyelination. We have seen dramatic improvement in isolated cases and reserve this approach for acute severe and refractory cases. Perhaps the presence of serum antibodies will allow us to prospectively identify responders to plasma exchange in the future. Two novel monoclonal antibody approaches have shown promise in phase II trials: (1) daclizumab (Zenapax) (FDA approved to avoid transplantation rejection), which targets the interleukin 2 receptor; and (2) natalizumab (Antegren), which blocks the leukocyte adhesion molecule VLA-4. Natalizumab was recently shown to be markedly effective in reducing relapses (66%), Gd-enhancing MRI lesions (92%), and in slowing disease progression in RRMs versus placebo. It was FDA approved in late 2004 and then suspended in February 2005 because of 2 cases of PML in patients treated with natalizumab and Avonex in combination. The future use of this drug will depend on the results of the risk of JC virus in treated patients.
Treatment of Exacerbations (Table 2) The first response to exacerbation of MS symptoms is to determine if there are any provoking factors, specifically infection and/or elevation of body temperature. Occasionally treating these is all that is required to ameliorate the symptoms. For disabling attacks characterized by visual loss greater than 20/60, impaired ambulation, pain, or extremely active MR imaging (two or more enhancing lesions or single lesion > 1 cm), we initiate IV methylprednisolone (or equivalent) 1 gm daily in the morning for 5 days. We usually do not use a prednisone taper unless the patient has a history of difficulty withdrawing from high-dose steroids.
TABLE 2 Treatment of Multiple Sclerosis Exacerbations Rule out treatable infection (e.g., urinary tract infection, sinusitis, bronchitis) Five-day course of IV methylprednisolone, 1 gm, or equivalent corticosteroid if the patient is having acute disability from the episode; prednisone taper optional Supportive care, physical and occupational therapy, social work, temporary disability status MR imaging (prior to steroids, if possible) to assess extent of disease activity and exclude alternative process Consider additional 5 days of IV methylprednisolone or plasma exchange for refractory and severely disabling exacerbations
Careful attention to blood glucose levels and bone density is necessary especially after repeated usage.
Symptomatic Therapy (Table 3) FATIGUE Fatigue is one of the most common and disabling symptoms of MS. Our algorithm for the management of fatigue includes first ruling out alternative etiologies including thyroid disease (thyroid-stimulating hormone), iron deficiency anemia (complete blood count, iron, ferritin, total iron-binding capacity), and infections (urinalysis, possibly chest radiograph, erythrocyte sedimentation rate, Epstein-Barr virus IgM, ELISA for Lyme disease). A detailed sleep history can also help discriminate fatigue from impaired sleep secondary to depression, spasticity, pain, or nocturia. Our first-line drug treatment for fatigue is a trial of amantadine (100 mg on awakening and again in the early afternoon) for 2 weeks. Sometimes amantadine stops working after 6 months and a drug holiday is indicated. We therefore target its use to winter months, when its anti-influenza A properties are most beneficial. Modafinil, 200 mg in the morning, is a nonaddictive stimulant with a good safety profile and can be useful for MS fatigue. Some patients feel jittery at this dose and can tolerate only 100 mg/day. Occasionally, activating selective serotonin receptor inhibitor (SSRI) antidepressants (see later) can have positive effects on fatigue in the absence of overt depression. DEPRESSION Depression is a major treatable complication of MS and interferon beta therapy. A combination of counseling and drug therapy is often required. We use many of the available antidepressants depending on the specific features of the individual’s symptoms, but in general we often start with an activating SSRI in the morning (fluoxetine, citalopram, escitalopram). Paroxetine may be useful for anxious depression and sometimes is best given in the evening because it can be sedating. If sexual side effects are a problem even with escitalopram (least offensive of the SSRIs), then we switch to bupropion. Venlafaxine has noradrenergic properties and is a good alternative for some patients. Low doses Johnson: Current Therapy in Neurologic Disease (7/E)
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Symptom
Therapeutic Approach
Fatigue
Amantadine (100 mg bid) can cause rash and edema; modafinil (100-200 mg q AM) can cause jittery sensation and palpitations SSRIs (e.g., fluoxetine 10-80 mg, sertraline 50-200 mg, citalopram 20-60 mg, escitalopram 10-20 mg) preferred once in the morning because of activating properties Discuss sexual side effects Alternative is bupropion 150-400 mg SR Oxybutynin 5-20 mg/day and tolterodine 2-4 mg bid for urgency cause dry mouth and can exacerbate glaucoma or worsen urinary retention Baclofen 10-40 mg tid-qid or tizanidine 2-8 mg tid; both can cause weakness and fatigue in excessive dosing Antiepileptic drugs such as gabapentin 300-1200 mg tid-qid cause fatigue at high doses; carbamazepine 100-600 mg tid requires CBC and LFT monitoring, causes rash and neurologic side effects at high doses; can load with IV phenytoin in severe cases in hospital setting
Depression
Bladder Spasticity Paroxysmal symptoms and pain
Other Inflammatory and Demyelinating Diseases
TABLE 3 Symptomatic Therapies in Multiple Sclerosis
SSRI, Selective serotonin receptor inhibitor; CBC, complete blood count; LFT, liver function test.
of tricyclic antidepressants amitriptyline, nortriptyline (less anticholinergic side effects), or trazodone are useful in patients with concomitant insomnia or nocturnal pain. Combination antidepressants may be required, but such patients are usually referred to our neuropsychiatry team. One must pay careful attention to the possibility of unmasking bipolar disease, and valproic acid and other antiepileptic drugs can be useful mood stabilizers. NEUROGENIC BLADDER The first step in treating a neurogenic bladder is determining whether the problem is one of failure to empty, failure to store, or a combination of both, as in detrusor external sphincter dyssynergia. Urinary frequency, urgency, and incontinence are the most common symptoms. After a careful history in which there are no symptoms of retention or hesitancy, and exclusion of a urinary tract infection, we initiate a trial of oxybutynin at a 5-mg dose and warn the patient to discontinue if they have trouble voiding. Higher doses 10 to 20 mg/day, long-acting variations and alternatives (tolterodine), or dermal patches are often useful. Failure to empty is difficult to treat medically, but a trial of an alpha1-adrenergic receptor antagonist such as terazosin, doxazosin, or tamsulosin is worthwhile prior to initiating catheterization. Inhaled desmopressin acetate (DDAVP) may be useful for nocturnal incontinence, but it causes rebound symptoms in the morning and is contraindicated in patients with hypertension. Patients who require chronic catheterization or are refractory to these medical therapies are referred to a urologist. BOWEL SYMPTOMS Constipation is common in MS and should be managed aggressively to avoid long-term complications. Fortunately, fecal incontinence is rare, but when it occurs the addition of fiber in the form of Metamucil Johnson: Current Therapy in Neurologic Disease (7/E)
twice a day can provide enough bulk to the stool to allow a partially incompetent sphincter to hold in the bowel movement long enough to allow the patient to reach a bathroom. The use of anticholinergics or antidiarrheal agents may be effective for short periods to combat incontinence associated with diarrhea. SEXUAL SYMPTOMS A careful sexual history, sometimes done by a health care provider of the same sex, may reveal several problematic sexual issues. These include feelings of sexual inadequacy, impaired libido, and direct sexual dysfunction from erectile dysfunction, impaired lubrication, spasticity, or heat-related sensory dysesthesias. Counseling, review of sexual side effects of medication, and medical therapy may be appropriate. Erectile dysfunction in MS can be effectively managed in some patients with sildenafil (50 to 100 mg). SPASTICITY Mild spasticity may be managed by stretching and exercise programs such as aqua therapy and yoga. Drug therapy is indicated when stiffness, spasms, or clonus interfere with function or sleep. We start treatment with baclofen 10 mg at bedtime, then add 5-mg doses in the morning and afternoon, and increase as tolerated, almost always with higher doses at night. Some patients, especially those requiring chronic therapy, may need up to 160 mg of baclofen a day. Limiting side effects include fatigue and weakness from loss of muscle tone. The addition of tizanidine using 2-mg tablets often provides a synergistic effect in those who cannot tolerate higher doses of baclofen. Alternative adjunct agents include gabapentin and benzodiazepines. Intrathecal baclofen has had a major impact on medically intractable spasticity, but we rarely use this approach because the implantable pump obviates further MR imaging scans and can be uncomfortable.
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PAROXYSMAL DISORDERS AND PAIN Dystonic spasms respond well in most instances to gabapentin (100 to 300 mg) or carbamazepine (100 to 200 mg), sometimes at very low doses. Paroxysmal pain or electrical burning sensations can be effectively treated with these antiepileptics or amitriptyline. We use gabapentin starting at 300 mg at bedtime the first day, twice daily the second day, and three times a day on the third day. If after 1 week there is no benefit, we double the dose every week until benefit or intolerable side effects occur (usually fatigue). Some patients require extremely high doses (up to 5600 mg/day) for complete pain control. TREMOR We have found tremor to be extremely refractory to medical therapy. Clonazepam sometimes appears to provide benefit, but perhaps more through its sedating and muscle-relaxing properties. COGNITIVE PROBLEMS Difficulty with concentration, short-term memory loss, and mental fatigue are common in MS. Some patients may benefit from stimulant drugs used for fatigue or attention deficit disorder, including modafinil, methylphenidate, or protriptyline. We also try acetylcholinesterase inhibitors such as donepezil (5 to 10 mg at bedtime) despite mixed results in clinical trials. ALTERNATIVE AND COMPLEMENTARY THERAPIES We actively discuss alternative therapies so that we know what else our patients are taking. We discourage the use of expensive or potentially dangerous regimens with unproved efficacy (bee stings). Some herbal remedies (St. John’s wart) are mildly effective but should not be used to the exclusion of prescription drugs if necessary. Some of our patients report benefit from marijuana and acupuncture for pain and spasticity. Nonmedical approaches such as yoga, tai chi, and meditation can be quite useful and are encouraged. We do not advocate a specific diet but recommend a multivitamin and specific supplementation of calcium and vitamin D. PATIENT RESOURCES National Multiple Sclerosis Society http://www.nmss.org/ The Consortium of Multiple Sclerosis Centers Website for organization of MS healthcare professionals. The Consortium publishes the International Journal of MS Care, available online http://www.mscare.org/ Hablemos de Esclerosis Múltiple—Let’s Talk about Multiple Sclerosis http://www.hablemosdeem.com/ MSWorld, the National MS Society’s collaborative partner, provides the official chat and bulletin board site for the Society http://www.msworld.org/communications.htm/ The Brain Matters Neurology Patient Education, including MS http://www.thebrainmatters.org/
Transverse Myelitis David Irani, M.D.
The clinical entity of transverse myelitis (TM) is broadly defined as any acute inflammatory process affecting the spinal cord having a clear rostral border of involvement. In many cases only a focal area of tissue is affected; however, other patients have more extensive cord pathology below this defined upper level. In addition to the salient clinical features that accompany spinal cord dysfunction, current diagnostic criteria define acute TM as having a duration from onset to nadir of between 4 hours and 21 days. Likewise, these criteria mandate that cord inflammation be presumptively identified by finding inflammatory changes in the cerebrospinal fluid (CSF) or by demonstrating gadolinium enhancement of the involved cord region using magnetic resonance (MR) imaging techniques. TM is distinguished to some degree from transverse myelopathy that encompasses other noncompressive syndromes such as vascular events involving the spinal cord that can reach clinical nadir in less than 4 hours or that fail to reveal any evidence of an underlying inflammatory pathology. TM is rare (1 to 4 cases per million population per year); affects individuals of all ages; and shows no predisposition to known ethnic, gender, or environmental factors. Multiple systemic conditions have been identified as causes underlying acute TM, but most patients have no predisposing disorder identified at presentation and remain categorized as idiopathic cases. Serial imaging data suggest that the acute cord inflammation in most TM patients resolves over a period of a few weeks, implying that long-term neurologic sequelae are dictated largely by the degree of collateral injury to adjacent neuronal cell bodies and their axonal extensions. Overall, about one third of patients make a good functional recovery after the initial episode, one third recover partially but are left with a moderate level of disability, and one third have no meaningful recovery and remain severely impaired. A poorer prognosis can be indicated by clinical features noted in the acute phase (rapid progression of symptoms, prominent back pain, and early spinal shock), by electrophysiologic measures (absent central conduction on somatosensory evoked potentials), and by detection of the 14-3-3 protein in CSF. In keeping with all these disease features, the therapeutic interventions I advocate in acute TM focus largely on terminating spinal cord inflammation as soon as possible to minimize collateral nerve injury. On the other hand, there is usually little role for such interventions beyond the acute stage of disease (cord inflammation has often resolved at this point), and my focus shifts to managing the numerous complications of chronic spinal cord dysfunction. Restoring function to the injured spinal cords of TM patients is an exciting prospect, but it also remains quite distant on the therapeutic horizon. Johnson: Current Therapy in Neurologic Disease (7/E)
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PAROXYSMAL DISORDERS AND PAIN Dystonic spasms respond well in most instances to gabapentin (100 to 300 mg) or carbamazepine (100 to 200 mg), sometimes at very low doses. Paroxysmal pain or electrical burning sensations can be effectively treated with these antiepileptics or amitriptyline. We use gabapentin starting at 300 mg at bedtime the first day, twice daily the second day, and three times a day on the third day. If after 1 week there is no benefit, we double the dose every week until benefit or intolerable side effects occur (usually fatigue). Some patients require extremely high doses (up to 5600 mg/day) for complete pain control. TREMOR We have found tremor to be extremely refractory to medical therapy. Clonazepam sometimes appears to provide benefit, but perhaps more through its sedating and muscle-relaxing properties. COGNITIVE PROBLEMS Difficulty with concentration, short-term memory loss, and mental fatigue are common in MS. Some patients may benefit from stimulant drugs used for fatigue or attention deficit disorder, including modafinil, methylphenidate, or protriptyline. We also try acetylcholinesterase inhibitors such as donepezil (5 to 10 mg at bedtime) despite mixed results in clinical trials. ALTERNATIVE AND COMPLEMENTARY THERAPIES We actively discuss alternative therapies so that we know what else our patients are taking. We discourage the use of expensive or potentially dangerous regimens with unproved efficacy (bee stings). Some herbal remedies (St. John’s wart) are mildly effective but should not be used to the exclusion of prescription drugs if necessary. Some of our patients report benefit from marijuana and acupuncture for pain and spasticity. Nonmedical approaches such as yoga, tai chi, and meditation can be quite useful and are encouraged. We do not advocate a specific diet but recommend a multivitamin and specific supplementation of calcium and vitamin D. PATIENT RESOURCES National Multiple Sclerosis Society http://www.nmss.org/ The Consortium of Multiple Sclerosis Centers Website for organization of MS healthcare professionals. The Consortium publishes the International Journal of MS Care, available online http://www.mscare.org/ Hablemos de Esclerosis Múltiple—Let’s Talk about Multiple Sclerosis http://www.hablemosdeem.com/ MSWorld, the National MS Society’s collaborative partner, provides the official chat and bulletin board site for the Society http://www.msworld.org/communications.htm/ The Brain Matters Neurology Patient Education, including MS http://www.thebrainmatters.org/
Transverse Myelitis David Irani, M.D.
The clinical entity of transverse myelitis (TM) is broadly defined as any acute inflammatory process affecting the spinal cord having a clear rostral border of involvement. In many cases only a focal area of tissue is affected; however, other patients have more extensive cord pathology below this defined upper level. In addition to the salient clinical features that accompany spinal cord dysfunction, current diagnostic criteria define acute TM as having a duration from onset to nadir of between 4 hours and 21 days. Likewise, these criteria mandate that cord inflammation be presumptively identified by finding inflammatory changes in the cerebrospinal fluid (CSF) or by demonstrating gadolinium enhancement of the involved cord region using magnetic resonance (MR) imaging techniques. TM is distinguished to some degree from transverse myelopathy that encompasses other noncompressive syndromes such as vascular events involving the spinal cord that can reach clinical nadir in less than 4 hours or that fail to reveal any evidence of an underlying inflammatory pathology. TM is rare (1 to 4 cases per million population per year); affects individuals of all ages; and shows no predisposition to known ethnic, gender, or environmental factors. Multiple systemic conditions have been identified as causes underlying acute TM, but most patients have no predisposing disorder identified at presentation and remain categorized as idiopathic cases. Serial imaging data suggest that the acute cord inflammation in most TM patients resolves over a period of a few weeks, implying that long-term neurologic sequelae are dictated largely by the degree of collateral injury to adjacent neuronal cell bodies and their axonal extensions. Overall, about one third of patients make a good functional recovery after the initial episode, one third recover partially but are left with a moderate level of disability, and one third have no meaningful recovery and remain severely impaired. A poorer prognosis can be indicated by clinical features noted in the acute phase (rapid progression of symptoms, prominent back pain, and early spinal shock), by electrophysiologic measures (absent central conduction on somatosensory evoked potentials), and by detection of the 14-3-3 protein in CSF. In keeping with all these disease features, the therapeutic interventions I advocate in acute TM focus largely on terminating spinal cord inflammation as soon as possible to minimize collateral nerve injury. On the other hand, there is usually little role for such interventions beyond the acute stage of disease (cord inflammation has often resolved at this point), and my focus shifts to managing the numerous complications of chronic spinal cord dysfunction. Restoring function to the injured spinal cords of TM patients is an exciting prospect, but it also remains quite distant on the therapeutic horizon. Johnson: Current Therapy in Neurologic Disease (7/E)
Transverse Myelitis
All patients suspected of having acute spinal cord dysfunction require emergent evaluation. Furthermore, because few of these patients present with the full clinical constellation of motor, sensory, and autonomic disturbances at disease onset, clinicians must have a low threshold for pursuing disease processes affecting the spinal cord. Many patients with a rapidly progressive paraparesis are incorrectly diagnosed with GuillainBarré syndrome; unlike with TM, these patients often have cranial nerve involvement and usually do not manifest early bladder dysfunction or bandlike sensory complaints. When in doubt, a spinal MR scan is easily justified and should always take precedent over more elective imaging studies. Conversely, the consequences of failing to perform a timely scan and missing a spinal cord lesion can be catastrophic for the patient. The initial evaluation of a patient with a new myelopathy must include a search for evidence of a structural lesion causing spinal cord compression. The diagnostic procedure of choice, a gadolinium-enhanced spinal MR scan, should ideally be completed within a few hours of presentation. Computed tomography (CT) with myelography is another option if MR imaging is not immediately available, but this modality has a much more limited capacity to identify intramedullary spinal cord lesions. If no imaging study can immediately be performed, I suggest treating all patients with evolving neurologic deficits and short symptom durations as if they have acute traumatic spinal cord compression by administering high-dose intravenous (IV) methylprednisolone according to defined protocols. Here, a 30 mg/kg bolus over 1 hour followed by a 5.4 mg/kg/hr continuous infusion for the next 23 hours is given to patients within 3 hours of symptom onset, whereas a 30 mg/kg bolus over 1 hour followed by a 5.4 mg/kg/hr continuous infusion for the next 47 hours is given to patients between 3 and 8 hours of symptom onset. Any structural lesion identified by MR imaging (e.g., vertebral fracture, herniated disk, epidural hematoma or abscess, spondylolisthesis) mandates immediate neurosurgical consultation regarding the options for mechanical decompression of the cord. Following the exclusion of a compressive cord lesion, the next step in the proper evaluation of a patient with suspected TM is to perform a lumbar puncture and undertake a complete CSF analysis. This can help to confirm an inflammatory process, facilitate the search for a possible underlying cause, and may even generate information that can be of long-term prognostic significance. The CSF sample should be sent for routine studies (cell count and differential, total protein and glucose levels), as well as for oligoclonal bands, immunoglobulin G (IgG) index, polymerase chain reaction (PCR)-based assays for viral nucleic acids, syphilis serology, and Lyme and mycoplasma antibodies. Since the CSF cell count and differential should be available within a few hours of sample acquisition, one can begin the therapeutic decision-making process right away. Again, any gadolinium enhancement of the cord on MR imaging or the discovery of a CSF pleocytosis is considered Johnson: Current Therapy in Neurologic Disease (7/E)
presumptive evidence of TM and should point strongly toward the initiation of acute therapy.
Acute Therapy Planning therapeutic interventions for a patient with suspected acute TM should happen in parallel to the initial diagnostic evaluation being undertaken. If an inflammatory basis for the acute spinal cord dysfunction is identified, I urge the immediate initiation of IV methylprednisolone at a dose of 1000 mg in an adult (30 mg/kg for a child) as a single daily infusion over 60 to 90 minutes for a period of 5 to 7 days. Although a prospective, randomized, placebo-controlled trial documenting the benefit of such an intervention in acute TM has never been performed, there are enough published reports documenting the utility of highdose methylprednisolone in shortening the time to independent ambulation and in enhancing the degree of eventual motor recovery that this has become the de facto intervention of choice in this setting. Indeed, I believe that corticosteroids should be withheld only in those patients with some absolute contraindication to the drug. Prophylaxis against gastrointestinal ulceration should always accompany these treatments. Although some cases of acute TM occur as a result of direct infection of the spinal cord by an infectious pathogen (certain viruses and bacteria, in particular, are culprits), the prophylactic use of antimicrobial therapies in all cases is not advised. I do not, as a rule, start an empirical antibiotic or antiviral agent in patients with acute TM unless there is some clear evidence of recent viral or bacterial infection (e.g., shingles, genital herpes, mycoplasma pneumonia). Nevertheless, I do advocate a thorough search for such infectious agents, and if a serologic screen or a CSF PCR assay reveals evidence of such a process, then starting the appropriate antimicrobial agent is advised. Finding an infectious cause for acute TM should not, however, dissuade one from continuing the aggressive use of IV corticosteroids. Other cases of acute TM occur in patients with previously known or newly identified connective tissue disorders. The acute diagnostic investigation of new patients should always include serologic screening for such processes, in addition to a search for historical features that might suggest a systemic vasculitis or a prothrombotic state resulting from antiphospholipid antibodies. In these cases, starting IV corticosteroids is still highly appropriate, but the presence of antiphospholipid antibodies may also require consideration of both acute and chronic anticoagulation. Once again, the decision to anticoagulate a patient in the acute setting should not supersede the need for ongoing corticosteroid therapy.
Follow-Up to Acute Interventions The management of patients with acute TM who fail to respond to high-dose corticosteroids is both difficult and controversial. In my opinion, however, other acute
Other Inflammatory and Demyelinating Diseases
Acute Evaluation
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interventions should be strongly considered within a week of completing corticosteroid infusions if there is no reasonable evidence of improvement. At this point, my preferred strategy is to give alternate-day cycles of plasmapheresis over a total of 14 days. Weinshenker and colleagues (see Selected Reading) were the first to show favorable results using this treatment modality in patients with acute inflammatory demyelinating events (including acute TM) that did not respond to steroids, and we have since found that nearly 50% of patients in our TM center who fail steroid therapy derive significant and sustained benefit from plasmapheresis. Indeed, one can often see noticeable clinical improvement in many patients after the second or third exchange. Another option worth considering in steroidnonresponsive TM patients who are still in the acute phase of disease is the use of IV cyclophosphamide at a dose of 750 to 1000 mg/m2. This approach may, in fact, be optimal for the patient with a previously known or a newly identified connective tissue disorder. Indeed, many patients with active systemic lupus erythematosus require monthly cyclophosphamide pulses for the next 4 to 6 months, aiming for a white blood cell count nadir of 3000 to 4000 cells/mm3 to achieve adequate control of the presumed disease flare. Although fraught with substantial risk, both plasmapheresis and cyclophosphamide have the advantage of working rapidly during a time when spinal cord inflammation is presumably still active. I do not advocate IV immune globulin in this situation, because my personal experience suggests that it is quite ineffective in these patients. I also suggest obtaining a second gadolinium-enhanced spinal MR scan within 4 to 6 weeks of clinical nadir to look for resolution of cord inflammation and to determine whether any loss of cord caliber has developed. Ongoing cord inflammation (persistent enhancement on MR imaging or a continued CSF pleocytosis) with sustained neurologic deficits should be aggressively treated with repeated plasmapheresis or monthly pulses of IV cyclophosphamide to make every effort that collateral injury to motor, sensory, and autonomic pathways in the spinal cord is minimized. On the other hand, there is no role for any of these aggressive immunotherapies in patients whose inflammatory component has largely resolved.
Long-Term Considerations Although many patients with acute TM make good functional recoveries from their illnesses, most are left with moderate or severe disability due to irreversible injury of the spinal cord. As these patients transition out of the acute phase of disease with active cord inflammation, chronic management focuses on addressing the wide range of symptoms that accompany these lesions. Standard physical and occupational rehabilitation strategies can prevent complications and promote meaningful improvement over time. Some patients with less severe disability report motor and autonomic improvement with 4-aminopyridine (fampridine), a potassium channel blocker that can enhance conduction in damaged nerve fibers. This drug, which is not approved by the U.S. Food and Drug Administration and must be obtained from compounding pharmacies, can be started at a dose of 10 mg/day and slowly increased to a dose of 0.5 to 0.7 mg/kg/day. It may cause a host of adverse effects, most notably seizures when used at higher doses, limiting its long-term usefulness. Chronic symptoms following acute TM are extremely common, and it is mandatory to ask patients about such things as bowel, bladder, and sexual function; pain; disturbed mood; fatigue; and spasticity in muscles of their extremities. All of these complaints may respond to various medications that can significantly improve the quality of their lives. Although space limitations preclude me from being able to outline a detailed approach for every symptom, the medications I most commonly use are outlined in Table 1. We are fortunate to have physicians from many other disciplines available to help us manage patients in our TM Center, and I firmly believe that complex pain management and urological, psychiatric, or rehabilitative issues are best addressed by involving the appropriate specialist. Having said this, all patients benefit from maintaining a relationship with their primary care physician, who ideally can help to coordinate care between multiple specialists and who can maximize the vigilance for various complications of disability including pneumonia, venous thrombosis, decubitus ulcers, osteoporosis, and the like.
TABLE 1 Management of Chronic Symptoms in Patients Having Experienced Previous Acute Transverse Myelitis Symptom
Suggested Therapy
Alternative Treatments
Pain, dysesthesias
Gabapentin
Fatigue Spasticity Urinary urgency Constipation
Amantadine Baclofen Oxybutynin Bisacodyl, senna
Nortriptyline, carbamazepine, tramadol, TENS unit, intrathecal opioids Modafinil, methylphenidate Tizanidine, diazepam, intrathecal baclofen Hyoscyamine, tolterodine, propantheline Mineral oil enemas, manual disimpaction
TENS, Transcutaneous electrical nerve stimulation.
Johnson: Current Therapy in Neurologic Disease (7/E)
Urinary and Sexual Dysfunction in Multiple Sclerosis and Myelitis
Most episodes of acute TM are isolated clinical events that result in varying degrees of injury to the cord with attendant disability but show no evidence of ongoing disease progression or future relapse. In the experience at our TM Center, that has seen well over 250 cases, however, a small proportion of patients ( 3 hr before administration
Severe neurologic deficits (e.g., National Institutes of Health Stroke Scale Score > 22) Midline shift or mass effect on CT or MR imaging
Evidence of infarct > 1/3 of middle cerebral artery territory on CT scan Evidence of intracranial hemorrhage Suspected subarachnoid hemorrhage Recent previous stroke, serious head injury, or intracranial surgery Uncontrolled hypertension (>185 mm Hg systolic or >110 mm Hg diastolic) at time of administration Active internal bleeding Seizure at stroke onset Known bleeding diathesis (e.g., heparin within 48 hr, elevated PTT or INR, platelet count < 100,000)
Cerebrovascular Disease
TABLE 2 Contraindications for Intravenous Thrombolysis
PTT, Partial thromboplastin time; INR, international normalized ratio.
improving stroke outcome has been demonstrated. However, anticoagulation may prevent recurrent stroke (and perhaps extension of stroke) in cases where there is a known embolic source of infarct, arterial dissection, or sinus thrombosis. However, in the case of embolic stroke, anticoagulation is generally delayed for at least 5 or 6 days, when a repeat CT scan is done to rule out hemorrhagic transformation of the infarct. Hemorrhage occurs when there is recanalization allowing blood flow to the infarct and so is a particular risk in embolic stroke. IV anticoagulation may worsen hemorrhagic transformation, which can lead to increased edema.
Medical Management that Improves Outcome Whether a patient receives intervention to re-establish cerebral perfusion, careful monitoring and control of other clinical conditions related to the stroke can markedly influence outcome. For this reason, many stroke patients are being cared for in dedicated stroke units, which have now been associated with better outcomes. Whether the benefit of such units is due to protocols for treatment, closer monitoring, better communication between care providers, or specialized training of nurses and physicians is unclear. However, it is clear that close attention to the following issues can improve clinical outcome. BLOOD PRESSURE The optimum blood pressure range for patients who do not receive thrombolytics has been a matter of intense debate. Although high blood pressure is among the strongest risk factors for stroke, the best management of blood pressure in the first few days following stroke probably depends on the etiology and size of stroke. Several studies have indicated that a relatively high blood pressure in the first few days of stroke may be beneficial and that lowering blood pressure acutely may be harmful. Current guidelines from the American Johnson: Current Therapy in Neurologic Disease (7/E)
Stroke Association specify that antihypertensive medications should initially be withheld from patients who have not received thrombolytics unless systolic blood pressure rises above 220 mm Hg or diastolic blood pressure rises above 120 mm Hg. Symptomatic hypertension (e.g., associated with cardiac ischemia or congestive heart failure) should also be treated. Even in these cases, blood pressure should not be lowered precipitously, but cautiously using IV labetalol or nicardipine, aiming for an initial reduction of 10% to 15%. GLUCOSE Several studies have provided evidence that hyperglycemia is associated with worse outcome in ischemic stroke in humans, and animal studies suggest that tight glucose control may lead to better outcome. Patients with known diabetes or elevated serum glucose at admission should have glucose monitoring and sliding scale insulin to maintain glucose in the range of 80 to 120 mg/dL. TEMPERATURE There is also strong evidence that hyperthermia can worsen outcome after stroke. Close monitoring of temperature and aggressive treatment of both fever and infections are therefore essential. NUTRITION Large hemispheric strokes, bilateral strokes, or brainstem strokes can severely compromise swallowing function. Typically, thin liquids are more likely to be aspirated than thick liquids, soft solids, or purees in patients with neurogenic dysphagia. To reduce the risk of aspiration, swallowing should be assessed before allowing the patient to eat or drink by mouth. A simple bedside swallowing evaluation by observing for coughing, choking, or change in voice quality (wet-hoarse phonation) after swallowing 2 oz of water can identify patients at greatest risk for aspiration. Patients who show signs of dysphagia in this bedside assessment or
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FIGURE 1. Procedures to follow in patients who meet the criteria for intravenous recombinant tissue plasminogen activator (IV r-TPA) (see Table 2). BP, Blood pressure.
IV r-TPA 0.9 mg/kg up to 90 mg; 10% over 1 minute; remaining over 60 minutes (must be started within 3 h of onset of symptoms)
Measure BP every 15 min for 2 h, then every 30 min for 6 h; then hourly for 18 h
Yes
Systolic BP 230 mm Hg or Yes diastolic BP >120 (2 readings)
IV labetalol 20 mg over 1–2 min, then every 10 min prn or infusion 2–8 mg/min until goal BP
No Systolic BP >180 mm Hg or Yes diastolic BP >105 (2 readings)
IV labetalol 10 mg over 1–2 min, then every 10–20 min prn or infusion 2–8 mg/min until goal BP
Monitor BP every 15 minutes during antihypertensive therapy
No anticoagulants or antiplatelets for 24 h
Intracranial hemorrhage suspected
Yes
Discontinue r-TPA; stabilize patient; head CT
No Follow-up head CT before starting any antiplatelet or anticoagulant
who have an absent gag reflex accompanied by dysarthria or dysphonia should have a swallowing evaluation by a speech-language pathologist prior to oral alimentation or hydration. Nutrition and fluids can be given for short periods via a nasogastric tube, but a percutaneous gastrostomy or jejunostomy tube should be considered if the patient is expected to be kept from oral intake longer than a week.
should have pulse oximetry at least at admission. Supplemental oxygen should be given as necessary to keep oxygen saturation above 95%, except in cases of chronic obstructive lung disease (in which case oxygen saturation should be kept at the patient’s optimum baseline). Arterial blood gas may be required for appropriate evaluation and management.
OXYGEN
Prevention of Complications
Hypoxia can increase intracranial pressure (ICP) and worsen stroke outcome. Large strokes or brainstem strokes can cause both hypoventilation and aspiration and thus may demand intubation in the acute stage to protect the airway and prevent hypoxia. Most patients
ELEVATED INTRACRANIAL PRESSURE The most devastating complication of stroke is increased ICP, which generally occurs only in large strokes or stroke in the posterior fossa, when there is significant edema. Johnson: Current Therapy in Neurologic Disease (7/E)
Acute Ischemic Stroke
SEIZURES Seizures in the first week after stroke have been reported in 4% to 43% of cases, and recurrent seizures are seen in 20% to 80% of patients. Although seizures do not alter long-term outcome, they can increase ICP and should be treated when observed. Patients with fluctuating level of consciousness should have an electroencephalogram to rule out nonconvulsive status epilepticus, which is treated with anticonvulsants. Blood levels of unbound anticonvulsants (e.g., phenytoin) should be monitored. DEEP VEIN THROMBOSIS AND PULMONARY EMBOLUS Limb paresis and immobility present a high risk for deep vein thrombosis (DVT) and pulmonary embolus. All nonambulatory patients should have DVT prophylaxis from the time of admission with subcutaneous heparin (5000 units twice a day), low-molecular-weight heparin, and/or sequential compression devices, as long as they are not anticoagulated for another reason. In addition, progressive mobility with physical therapy and occupational therapy should begin as soon as possible to prevent DVT, pulmonary embolus, contractures, and atelectasis. ASPIRATION PNEUMONIA Patients with dysphagia have a high risk of aspiration pneumonia. Oral alimentation and hydration should be undertaken only after ruling out significant aspiration (see earlier). Additionally, keeping the head elevated 45 degrees, and propping the head slightly forward in flexed position (never hyperextended), can also reduce the risk for aspiration.
PRESSURE SORES Immobility can cause pressure sores (decubitus ulcers) in just 2 hours. The best prevention is turning immobile patients every 2 hours. Special beds that keep pressure off one place can also be helpful. Since urinary and bowel incontinence can exacerbate or infect pressure sores, urinary incontinence should be treated (see earlier), and a bowel regimen should be established using daily suppositories if necessary. Wet-to-dry dressing can be helpful to prevent worsening of pressure sores. A large number of later complications, such as depression, contractures, spasticity, and pain, require monitoring, prevention, and treatment after the first few days of stroke, but their management is beyond the scope of this chapter.
Prevention of Recurrent Stroke Rapid evaluation of the etiology of ischemic stroke is a first step toward preventing recurrence. Tests that are frequently used to determine the most likely cause of stroke are listed in Table 1. Patients with 70% to 99% carotid stenosis as the suspected cause of stroke should be evaluated for potential carotid endarterectomy or stenting, although the procedure is generally delayed for at least 6 weeks after stroke to prevent hemorrhagic conversion or edema. After new carotid occlusion, anticoagulation for 6 weeks can prevent embolism from the thrombus. Intracranial large vessel stenosis is generally treated with antiplatelet agents, but when severe stenosis is associated with persistent symptomatic hypoperfusion, other investigational interventions described earlier may be considered. The standard secondary prevention of ischemic stroke due to intracranial large or small-vessel disease is aspirin (≥50 mg). Patients whose stroke occurred while on aspirin can be offered other antiplatelet medications such as clopidogrel (or dipyridamole in addition to aspirin). Evaluation and management of vasculitis and cerebral embolism are described in other chapters. Risk factor reduction is also essential. Hypercholesterolemia should be aggressively treated. High-dose statins may help reduce the risk of embolism from plaque in patients with severe atherosclerosis. Tight control of diabetes, healthy diet, smoking cessation, and treatment of drug or alcohol abuse are also important. Many of these issues can be initially addressed in the acute hospitalization and reinforced during rehabilitation or as an outpatient.
Summary URINARY TRACT INFECTIONS Urinary tract infections are common in patients with “neurogenic bladder” due to incomplete emptying of the bladder and use of indwelling catheters for bladder incontinence. Assisting the patient to the toilet or offering a bedpan or urinal every few hours while awake can prevent the need for catheterization in many cases. Johnson: Current Therapy in Neurologic Disease (7/E)
Cerebrovascular Disease
Edema typically is highest 3 to 5 days after onset of stroke. Hyperthermia, hypoxia, or hypercapnia can worsen edema and should be aggressively corrected. Elevating the head of the bed, reducing excess fluids, eliminating hypo-osmolar fluids, and eliminating any restrictions on venous outflow (e.g., tape on the neck) can be helpful. Urgent interventions to reduce ICP to prevent or reverse herniation include increasing the osmolarity of the blood with mannitol or hypertonic saline, hyperventilation to reduce PCO2 by 5 to 10 mm Hg, hypothermia, or barbiturates administered in an intensive care environment. Insertion of an intraventricular catheter to drain cerebrospinal fluid is used primarily when edema results in obstructive hydrocephalus. Benefits of hemicraniectomy or temporal lobectomy for malignant brain edema are also under investigation.
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Management of acute ischemic stroke has changed radically in the last decade and is likely to continue to evolve with further progress in the domains of imaging, interventional neuroradiology, and neuroprotection. Interventions to salvage the ischemic penumbra begin as soon as possible after onset of stroke. Inpatient management to reduce complications, prevent recurrent stroke,
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Emboli of Cardiac Origin
and begin rehabilitation is equally important. Most patients recover substantial function in the first few days to weeks, but many will continue to improve over many years, particularly with appropriate rehabilitation. SUGGESTED READING Adams HP Jr, Adams R J, Brott T, et al: Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association, Stroke 34:1056-1083, 2003. Adams HP Jr, Brott TG, Crowell RM, et al: Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 25:1901-1914, 1994. Biller J, Feinberg WM, Castaldo JE, et al: Guidelines for carotid endarterectomy: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 29:554-562, 1998. Fisher M, Albers GW: Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke, Neurology 52: 1750-1756, 1999. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke, N Engl J Med 333:1581-1587, 1995.
Identification of Cardiac Sources of Embolization According to the American Heart Association guidelines, all patients being evaluated for cerebral ischemia should have a routine electrocardiogram performed (Figure 1). Additionally, 24 hours of cardiac rhythm monitoring should be performed in all patients with stroke and transient ischemic attack (TIA) admitted to the hospital. For those with a normal cardiac examination, normal electrocardiogram, no history of cardiac symptoms or disease, and brain imaging not suggestive of an embolic event, echocardiography is not likely to identify a cardiac source of embolization. Echocardiography should be performed in all others. A detailed discussion of the selection of transthoracic versus transesophageal echocardiography (TEE) is beyond the scope of this chapter.
Primary Prevention of Cardioembolism
PATIENT RESOURCES
NONVALVULAR ATRIAL FIBRILLATION
American Heart Association’s Stroke Connection 7272 Greenville Avenue Dallas, TX 75231 Phone: 800-553-6321 Fax: 214-706-2139 E-mail:
[email protected] http://www.americanheart.org
AF is the most common sustained arrhythmia, affecting approximately 2 million Americans. Its prevalence increases with age, with 10% of those over 80 affected. AF accounts for approximately half of all cardioembolic strokes. Overall, the annual stroke rate of those with nonvalvular AF not treated with an antithrombotic agent is 5%, with a range of approximately 1% to 25%, depending on the individual’s risk classification related to comorbidities. Patients with AF should be treated the same regardless of whether it is persistent or paroxysmal. Likewise, those with atrial flutter and those with AF should be treated equivalently. Most patients with AF require anticoagulation with a goal international normalized ratio (INR) of 2 to 3 for stroke and other thromboembolism prophylaxis. Unfortunately, studies have shown that warfarin is currently being underutilized for primary stroke prophylaxis in AF patients. Warfarin has been shown to be superior to aspirin for stroke prophylaxis, although the benefits and risks must be weighed carefully. In patients with AF, aspirin reduces stroke risk by 19%, whereas warfarin reduced it by 68%. In patients with nonvalvular AF, increased age, prior thromboembolism, hypertension, heart failure, and diabetes appear to be independent risk factors for stroke. There are several systems for scoring stroke risk related to AF. One such example is the CHADS2 score, standing for congestive heart failure, hypertension, age older than 75 years, and prior history of stroke. Each risk factor is ascribed one point, with the exception of history of stroke, to which two points are ascribed. For each point increase in the CHADS2 score, there is an approximate 1.5-fold increase in stroke rate. An understanding of AF risk factors can allow for risk stratification; however, in general, those with AF should be treated with warfarin unless there is a clear contraindication. Those who have a contraindication to
National Stroke Association 96 Inverness Drive, E., Suite 1 Englewood, CO 80112 Phone: 800-787-6537 Fax: 303-649-1328 E-mail:
[email protected] http://www.stroke.org
Emboli of Cardiac Origin Devin L. Brown, M.D., and Lewis B. Morgenstern, M.D.
Cardioembolism is typically due to thrombus formation from intracardiac blood stasis. Atrial fibrillation (AF) can lead to left atrial and, more specifically, left atrial appendage clots, whereas depressed left ventricular function due to cardiac ischemia or other causes may result in ventricular thrombi. Cardioembolism is a common cause of stroke, accounting for approximately 20% of all ischemic stroke.
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Emboli of Cardiac Origin
and begin rehabilitation is equally important. Most patients recover substantial function in the first few days to weeks, but many will continue to improve over many years, particularly with appropriate rehabilitation. SUGGESTED READING Adams HP Jr, Adams R J, Brott T, et al: Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association, Stroke 34:1056-1083, 2003. Adams HP Jr, Brott TG, Crowell RM, et al: Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 25:1901-1914, 1994. Biller J, Feinberg WM, Castaldo JE, et al: Guidelines for carotid endarterectomy: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Stroke 29:554-562, 1998. Fisher M, Albers GW: Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke, Neurology 52: 1750-1756, 1999. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke, N Engl J Med 333:1581-1587, 1995.
Identification of Cardiac Sources of Embolization According to the American Heart Association guidelines, all patients being evaluated for cerebral ischemia should have a routine electrocardiogram performed (Figure 1). Additionally, 24 hours of cardiac rhythm monitoring should be performed in all patients with stroke and transient ischemic attack (TIA) admitted to the hospital. For those with a normal cardiac examination, normal electrocardiogram, no history of cardiac symptoms or disease, and brain imaging not suggestive of an embolic event, echocardiography is not likely to identify a cardiac source of embolization. Echocardiography should be performed in all others. A detailed discussion of the selection of transthoracic versus transesophageal echocardiography (TEE) is beyond the scope of this chapter.
Primary Prevention of Cardioembolism
PATIENT RESOURCES
NONVALVULAR ATRIAL FIBRILLATION
American Heart Association’s Stroke Connection 7272 Greenville Avenue Dallas, TX 75231 Phone: 800-553-6321 Fax: 214-706-2139 E-mail:
[email protected] http://www.americanheart.org
AF is the most common sustained arrhythmia, affecting approximately 2 million Americans. Its prevalence increases with age, with 10% of those over 80 affected. AF accounts for approximately half of all cardioembolic strokes. Overall, the annual stroke rate of those with nonvalvular AF not treated with an antithrombotic agent is 5%, with a range of approximately 1% to 25%, depending on the individual’s risk classification related to comorbidities. Patients with AF should be treated the same regardless of whether it is persistent or paroxysmal. Likewise, those with atrial flutter and those with AF should be treated equivalently. Most patients with AF require anticoagulation with a goal international normalized ratio (INR) of 2 to 3 for stroke and other thromboembolism prophylaxis. Unfortunately, studies have shown that warfarin is currently being underutilized for primary stroke prophylaxis in AF patients. Warfarin has been shown to be superior to aspirin for stroke prophylaxis, although the benefits and risks must be weighed carefully. In patients with AF, aspirin reduces stroke risk by 19%, whereas warfarin reduced it by 68%. In patients with nonvalvular AF, increased age, prior thromboembolism, hypertension, heart failure, and diabetes appear to be independent risk factors for stroke. There are several systems for scoring stroke risk related to AF. One such example is the CHADS2 score, standing for congestive heart failure, hypertension, age older than 75 years, and prior history of stroke. Each risk factor is ascribed one point, with the exception of history of stroke, to which two points are ascribed. For each point increase in the CHADS2 score, there is an approximate 1.5-fold increase in stroke rate. An understanding of AF risk factors can allow for risk stratification; however, in general, those with AF should be treated with warfarin unless there is a clear contraindication. Those who have a contraindication to
National Stroke Association 96 Inverness Drive, E., Suite 1 Englewood, CO 80112 Phone: 800-787-6537 Fax: 303-649-1328 E-mail:
[email protected] http://www.stroke.org
Emboli of Cardiac Origin Devin L. Brown, M.D., and Lewis B. Morgenstern, M.D.
Cardioembolism is typically due to thrombus formation from intracardiac blood stasis. Atrial fibrillation (AF) can lead to left atrial and, more specifically, left atrial appendage clots, whereas depressed left ventricular function due to cardiac ischemia or other causes may result in ventricular thrombi. Cardioembolism is a common cause of stroke, accounting for approximately 20% of all ischemic stroke.
Johnson: Current Therapy in Neurologic Disease (7/E)
Emboli of Cardiac Origin
Stroke/TIA
History, exam, EKG, brain imaging, echocardiography
Cardiac source identified
No cardiac source found
Cerebrovascular Disease
FIGURE 1. Treatment algorithm for emboli of cardiac origin transient ischemic attack (TIA). EKG, Electrocardiogram; Afib, atrial fibrillation.
219
Risk factor modification Antiplatelet agent, risk factor modification TIA
Small infarct
Large infarct
Immediate anticoagulation
Warfarin after ~2 days
Warfarin after ~7–10 days
Recurrence while adequately anticoagulated Assess for alternative causes, including endocarditis
No endocarditis
Afib
Mechanical valve
Endocarditis
Stop anticoagulation, start antibiotics, cardiology consult, antiplatelet agent
Add aspirin
anticoagulation should be given aspirin, 325 mg per day. Patients with lone AF (typically defined as patients younger than 60 years of age, without heart disease, without risk factors for thromboembolism, and with evidence of normal ventricular function by echocardiography) should be treated with aspirin rather than warfarin because they are at lower risk of thromboembolism.
Detection of an atrial thrombus without associated AF is uncommon. Those with AF should be treated as discussed earlier. Surprisingly, there are few data dictating treatment for atrial thrombi. We use warfarin to treat these patients for at least 3 months. If the thrombus has resolved, and the patient does not have AF, we then switch to antiplatelet therapy.
stroke prophylactic agents have a 1% to 2% stroke risk per year for mechanical valves and a little less than 1% per year for bioprosthetic valves. Patients with mechanical valves are at high risk for cardioembolic stroke if not treated with anticoagulation. The American College of Cardiology has guidelines that should be followed for the use of anticoagulation for patients with mechanical valves, depending on the valve type and the valve position. Most require warfarin with a goal INR of 2.5 to 3.5. Patients with new bioprosthetic valves should be treated with warfarin for the first 3 months, followed by antiplatelet therapy. In patients at high risk of thromboembolism, such as those with previous thromboembolism, an ejection fraction (EF) less than 30%, or a hypercoaguable state, life-long warfarin with a goal INR of 2 to 3 is likely indicated.
PROSTHETIC VALVES
DEPRESSED EJECTION FRACTION
Patients with prosthetic valves are at increased risk of cardioembolism. Even those treated with appropriate
Patients with depressed left ventricular function secondary to ischemic cardiomyopathy appear to be at
ATRIAL THROMBI
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Emboli of Cardiac Origin
an elevated risk of stroke and other thromboembolism. The degree of risk elevation appears to be proportional to the degree of left ventricular dysfunction. Those treated with warfarin may have lower stroke rates than those treated with antiplatelet therapy, although no prospective, randomized trials to assess this as a primary endpoint have yet been completed. In the Survival and Ventricular Enlargement (SAVE) trial, a prospective study where patients post-myocardial infarction (MI) with an EF less than 40% were randomized to captopril or placebo, stroke was a prespecified endpoint. The estimated cumulative rate of stroke over 5 years was 8.1%. For each 5% decrease in EF, there was an 18% increase in stroke risk. Those with an EF less than 28% had almost double the risk of those with an EF 35% to 40%. Both aspirin and warfarin were associated with lower stroke risk, with warfarin having a stronger association. The Studies of Left Ventricular Dysfunction (SOLVD), another trial in which patients were randomized to an angiotensin-converting enzyme inhibitor or placebo, showed lower mortality associated with warfarin use in those with depressed left ventricular function (EF < 35%). In patients with a depressed EF, stroke prophylactic selection should be tailored to the individual patient and performed in conjunction with the patient’s cardiologist. Those who have a TIA or stroke on an antiplatelet agent typically should be switched to warfarin. POST-MYOCARDIAL INFARCTION In general, patients who are post-MI have about a 1% to 2% risk of stroke per year, although the risk is likely greatest in the first few months. It seems clear that patients who are post-MI and who also have AF or a left ventricular thrombus, and those with an anterior Q wave MI, should be anticoagulated. For all others, data are somewhat conflicting. Warfarin is likely superior to aspirin in post-MI stroke prevention but is associated with a significant increase in bleeding complications. The use of warfarin post-MI should typically be reserved for those at higher risk of embolization, including those with significant cardiac wall motion abnormalities and depressed left ventricular function. We typically anticoagulate these patients for at least 3 months. Post-MI stroke prevention choices are best determined in conjunction with the patient’s cardiologist.
Secondary Prevention of Cardioembolism ATRIAL FIBRILLATION Transient Ischemic Attack Patients who present with transient cerebral ischemia who are found in their evaluation to have a clear cardioembolic source, such as AF, require anticoagulation. If no infarction is seen on diffusion-weighted imaging (DWI), immediate anticoagulation should be undertaken, barring a contraindication, with either intravenous unfractionated heparin or low-molecular-weight heparinoid, while
awaiting adequate anticoagulation with warfarin. The heparin should be discontinued after the patient reaches a therapeutic INR. If the patient clinically has a TIA but is found to have DWI changes consistent with parenchymal ischemia, we forego using immediate anticoagulation with heparin/ heparinoid and proceed with immediate initiation of warfarin. Patients with known protein C or protein S deficiency, theoretically, should be therapeutically anticoagulated on heparin prior to initiation of warfarin. Stroke The decision to anticoagulate a patient immediately following a stroke from a cardioembolic source requires balancing the risk of recurrent infarction with the risk of symptomatic intracerebral hemorrhage. Data from the International Stroke Trial (IST) and the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) suggest that patients not anticoagulated after a stroke associated with nonvalvular AF have a low risk of recurrent stroke within the first 14 days (well less than 1% per day). Given this low risk of recurrence, we delay anticoagulation after a new stroke. The size of the infarction (or of the individual infarctions if multiple) dictates the length of delay. Typically, we initiate warfarin after 2 to 3 days for a small infarction, and after 7 to 10 days for a large infarction, without first using heparin. Prior to full anticoagulation with warfarin, we use aspirin in these patients. The aspirin is discontinued after a therapeutic INR is achieved. MECHANICAL VALVES Some patients develop embolization from a mechanical valve despite therapeutic warfarin. For these patients, the dose of warfarin should not be escalated to exceed the recommended INR, but rather aspirin, 81 mg/day, should be added. This does increase the risk of hemorrhagic complications; however, the benefits appear to outweigh the risks. Patients with stroke and a mechanical valve require blood cultures and an evaluation for endocarditis. ENDOCARDITIS It is essential to have a high index of suspicion for endocarditis. Patients with valvular abnormalities and/or a new murmur and those with recent infections should arouse particular suspicion. Although fever and an elevated leukocyte count are suggestive of the diagnosis, it is important to recall that elderly patients may have neither sign. Patients with endocarditis and stroke are at risk for further cerebral ischemic events. The embolic material may contain bacterial vegetation, platelet-fibrin clot that has formed on the vegetation, or a combination thereof. Risk of further events is reduced by treatment with antibiotics. If a second embolic event occurs, valvular surgery may become indicated. Bacterial material may embolize to cerebral vessels and create mycotic aneurysms, which are typically distal and multiple in the middle cerebral artery branches. With rupture, the resulting subarachnoid hemorrhage can be fatal. Johnson: Current Therapy in Neurologic Disease (7/E)
Intracerebral Hemorrhage
PATENT FORAMEN OVALE By autopsy and TEE studies, approximately 20% to 30% of the population has a patent foramen ovale (PFO). If a PFO is to be implicated as causative, venous thrombosis with paradoxical embolization must be inferred, suggesting the need to assess for deep venous thrombosis. One study suggests that 10% of stroke patients with a PFO have a deep venous thrombosis. These patients should be treated with anticoagulation. In the PFO in Cryptogenic Stroke Study (PICSS), stroke patients who had TEEs were randomized to receive warfarin, with a goal INR of 2 to 3, or aspirin 325 mg/day. Time to recurrent stroke in those with a PFO was not different between the two treatment groups. Those with a PFO were not at a higher risk than those without a PFO in this study, regardless of the presence of an atrial septal aneurysm or the size of the PFO. As the mean age of patients in PICSS was around 59, the best agent for secondary stroke prophylaxis in younger patients with PFOs remains uncertain. OTHER There are several other more rare causes of cardioembolism, including atrial myxomas and other intracardiac tumors, and nonbacterial thrombotic endocarditis (NBTE). For these more rare causes, evidence-based recommendations are not possible. Complete resection of atrial myxomas is recommended for stroke prophylaxis and to alleviate any direct cardiac effects. For NBTE, supported by the American College of Chest Physicians consensus conferences, heparin should be used for stroke prophylaxis. Addressing the primary medical process, such as cancer or sepsis, is of course critical in this setting. SUGGESTED READING ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation) Developed in Collaboration with the North American Society of Pacing and Electrophysiology, Circulation 104:2118-2150, 2001. Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association), Stroke 33:1934-1942, 2002. Johnson: Current Therapy in Neurologic Disease (7/E)
Intracerebral Hemorrhage Gene Sung, M.D., M.P.H.
Spontaneous intracerebral hemorrhage (ICH) encompasses hemorrhage in the parenchyma of the brain and may include hemorrhage into the ventricles and subarachnoid space. This accounts for approximately 15% to 20% of all strokes. The underlying cause of hemorrhage can be varied and is often divided into primary and secondary ICH. The former tends to result from the rupture of smaller vessels in patients with poorly controlled hypertension or amyloid angiopathy. The latter is more often the result of gross structural lesions such as aneurysms, arteriovenous malformations, and tumors. This chapter is a discussion of primary ICH. ICH has a significantly higher mortality rate and has not benefited from the same kind of proven advances documented for the treatment of ischemic stroke. Nonetheless, more continues to be discovered about ICH, which should ultimately lead to improved therapeutics.
Diagnosis Clinical diagnosis is difficult because of the inability to distinguish ICH with ischemic strokes based solely on clinical symptoms. The neurologic symptoms can be identical to ischemic stroke, though there is more likelihood of headache, vomiting, and unconsciousness in the setting of ICH. The sensitivity and specificity of these clinical features are insufficient for a meaningful positive predictive value. Typically, a radiographic test is necessary to complete the diagnosis, and currently computed tomographic (CT) scanning remains the preferred initial test, because of availability, cost, familiarity, and sensitivity. Magnetic resonance (MR) imaging technology has improved significantly, and many believe that the sensitivity to detect even small amounts of subarachnoid hemorrhage approaches CT, but availability, cost, and familiarity remain issues. Besides the diagnosis of ICH, the CT scan can be used to give an initial prognosis for the patient. Care must be considered in discussions of prognosis, since these can be self-fulfilling prophecies, such that the prediction of a bad outcome can lead to limited care, which will then lead to a guaranteed bad outcome. Furthermore, these prognostic scales are based on retrospective data and do not take into account new advances in care, nor do they measure or predict the quality of life of a patient. So, in actuality, it is impossible to definitely predict a patient’s outcome; however, these scales remain useful at least as a measure of severity of the clinical picture. There have been several studies of prognostic factors, and the common denominators always include hematoma size and clinical condition. Other variables that have been found to influence the prognosis
Cerebrovascular Disease
Delivery of a full antibiotic course for endocarditis can cure the aneurysms. Although these aneurysms are uncommon, we recommend cerebral angiography in patients with stroke from endocarditis who have reasonable neurologic and medical recovery, prior to discontinuation of antibiotics. Aneurysms that do not resolve with antibiotic therapy and are accessible may be amenable to surgical treatment. We do not anticoagulate patients with endocarditis secondary to the risk of intracerebral hemorrhage, but instead use an antiplatelet agent for stroke prophylaxis.
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Intracerebral Hemorrhage
PATENT FORAMEN OVALE By autopsy and TEE studies, approximately 20% to 30% of the population has a patent foramen ovale (PFO). If a PFO is to be implicated as causative, venous thrombosis with paradoxical embolization must be inferred, suggesting the need to assess for deep venous thrombosis. One study suggests that 10% of stroke patients with a PFO have a deep venous thrombosis. These patients should be treated with anticoagulation. In the PFO in Cryptogenic Stroke Study (PICSS), stroke patients who had TEEs were randomized to receive warfarin, with a goal INR of 2 to 3, or aspirin 325 mg/day. Time to recurrent stroke in those with a PFO was not different between the two treatment groups. Those with a PFO were not at a higher risk than those without a PFO in this study, regardless of the presence of an atrial septal aneurysm or the size of the PFO. As the mean age of patients in PICSS was around 59, the best agent for secondary stroke prophylaxis in younger patients with PFOs remains uncertain. OTHER There are several other more rare causes of cardioembolism, including atrial myxomas and other intracardiac tumors, and nonbacterial thrombotic endocarditis (NBTE). For these more rare causes, evidence-based recommendations are not possible. Complete resection of atrial myxomas is recommended for stroke prophylaxis and to alleviate any direct cardiac effects. For NBTE, supported by the American College of Chest Physicians consensus conferences, heparin should be used for stroke prophylaxis. Addressing the primary medical process, such as cancer or sepsis, is of course critical in this setting. SUGGESTED READING ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation) Developed in Collaboration with the North American Society of Pacing and Electrophysiology, Circulation 104:2118-2150, 2001. Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association), Stroke 33:1934-1942, 2002. Johnson: Current Therapy in Neurologic Disease (7/E)
Intracerebral Hemorrhage Gene Sung, M.D., M.P.H.
Spontaneous intracerebral hemorrhage (ICH) encompasses hemorrhage in the parenchyma of the brain and may include hemorrhage into the ventricles and subarachnoid space. This accounts for approximately 15% to 20% of all strokes. The underlying cause of hemorrhage can be varied and is often divided into primary and secondary ICH. The former tends to result from the rupture of smaller vessels in patients with poorly controlled hypertension or amyloid angiopathy. The latter is more often the result of gross structural lesions such as aneurysms, arteriovenous malformations, and tumors. This chapter is a discussion of primary ICH. ICH has a significantly higher mortality rate and has not benefited from the same kind of proven advances documented for the treatment of ischemic stroke. Nonetheless, more continues to be discovered about ICH, which should ultimately lead to improved therapeutics.
Diagnosis Clinical diagnosis is difficult because of the inability to distinguish ICH with ischemic strokes based solely on clinical symptoms. The neurologic symptoms can be identical to ischemic stroke, though there is more likelihood of headache, vomiting, and unconsciousness in the setting of ICH. The sensitivity and specificity of these clinical features are insufficient for a meaningful positive predictive value. Typically, a radiographic test is necessary to complete the diagnosis, and currently computed tomographic (CT) scanning remains the preferred initial test, because of availability, cost, familiarity, and sensitivity. Magnetic resonance (MR) imaging technology has improved significantly, and many believe that the sensitivity to detect even small amounts of subarachnoid hemorrhage approaches CT, but availability, cost, and familiarity remain issues. Besides the diagnosis of ICH, the CT scan can be used to give an initial prognosis for the patient. Care must be considered in discussions of prognosis, since these can be self-fulfilling prophecies, such that the prediction of a bad outcome can lead to limited care, which will then lead to a guaranteed bad outcome. Furthermore, these prognostic scales are based on retrospective data and do not take into account new advances in care, nor do they measure or predict the quality of life of a patient. So, in actuality, it is impossible to definitely predict a patient’s outcome; however, these scales remain useful at least as a measure of severity of the clinical picture. There have been several studies of prognostic factors, and the common denominators always include hematoma size and clinical condition. Other variables that have been found to influence the prognosis
Cerebrovascular Disease
Delivery of a full antibiotic course for endocarditis can cure the aneurysms. Although these aneurysms are uncommon, we recommend cerebral angiography in patients with stroke from endocarditis who have reasonable neurologic and medical recovery, prior to discontinuation of antibiotics. Aneurysms that do not resolve with antibiotic therapy and are accessible may be amenable to surgical treatment. We do not anticoagulate patients with endocarditis secondary to the risk of intracerebral hemorrhage, but instead use an antiplatelet agent for stroke prophylaxis.
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Intracerebral Hemorrhage
include patient age and presence of intraventricular hemorrhage. One measure of hematoma volume is using the formula for the volume of an ellipsoid [4/3 • π • (Α/2) • (Β/2) • (C/2)]; making approximation that π = 3, this is simplified to: (A × B × C) ÷ 2 where A is the longest length of the hemorrhage, B is the largest width of the hemorrhage, and C is depth of the hemorrhage (determined by the number of CT slices in which hemorrhage is present times the slice thickness).
Acute onset of neurologic deficits
Protecting airway or GCS>8? Yes
No
Ventilation and oxygenation adequate?
No
Intubate
Yes
Evaluation and Management (Figure 1)
No
The initial evaluation and management of the patient with ICH are the same as for any patient in the emergency or critical care setting, which starts with the ABC (airway, breathing, circulation) assessment. ABCs In reference to A, determine whether the patient’s airway is protected. Is there a lack of gag reflex either from depressed level of consciousness or brainstem/ cranial nerve dysfunction? Or is there an obstruction, such as the tongue or other foreign objects such as food or dentures, and so forth? Obstructions should be removed, and intubation is indicated for those patients who cannot protect their airway or will need breathing assistance. Induction should be accomplished only with short-acting anesthetics so that the clinician is able to monitor the neurologic status as quickly as possible after intubation. In reference to B, determine whether there is an impediment to breathing/gas exchange, from depressed respiratory drive, mechanical respiratory failure or lung parenchymal disease (e.g., chronic obstructive pulmonary disease), pulmonary edema, or aspiration pneumonia. Intubation and mechanical ventilation are also indicated for these patients as well. Finally, in reference to C, determine whether the circulation is adequate. Is the intravascular volume sufficient to maintain adequate blood pressure and cerebral perfusion pressure? Generally, though, most ICH patients’ blood pressure will be raised and in the early stage will need to be lowered. BLOOD PRESSURE A discussion of blood pressure leads to the somewhat controversial dilemma of hemodynamic management. Typically a patient with ICH has elevated blood pressure, but there had been concern in treating this blood pressure aggressively because the blood pressure may simply be a response to the acute insult, and, more important, because of the fear of decreasing collateral perfusion and worsening the presumed ischemic penumbra around the hematoma. However, in a variety of studies
Hypotension Yes
Obtain CT or MRI to confirm ICH No
IV fluids and vasopressors
Yes
End ICH algorithm
ICH seen on imaging study
Go to part 2 of ICH algorithm
Yes
External ventricular drainage
Yes Acute hydrocephalus? No Is it a cerebellar hematoma (>30 ml or GCS 160 or MAP >120 Yes
Neurosurgical evacuation
No
IV antihypertensive infusion
– Consider seizure prophylaxis – Euvolemia – Normothermia – Normotensive – Early mobilization
FIGURE 1. Algorithm for the treatment of intracranial hemorrhage (ICH). GCS, Glasgow Coma Scale.
Johnson: Current Therapy in Neurologic Disease (7/E)
Intracerebral Hemorrhage
TABLE 1 Hemodynamic Management Drug and Type of Blood Pressure Hypertension Labetalol Esmolol Hydralazine Enalapril Nitroprusside Nicardipine Hypotension IV fluids Dopamine Phenylephrine Norepinephrine
Dosage
5-40 mg IV q 15 min or 5-200 mg/h continuous infusion 500 μg/kg IV load, then 50-200 μg/kg/min 10-20 mg IV q 6-8 h 0.625-1.25 mg IV q 10 min (not to exceed 5 mg/6 h) 0.5-10 μg/kg/min (doses > 4μg/kg/min or prolonged infusion may lead to cyanide toxicity) 5-15 mg/h IV infusion Maintain euvolemia, preferably with isotonic saline 2-20 μg/kg/min IV infusion Up to 200 μg as a bolus, then 2-10 μg/kg/min IV infusion 0.05-0.2 μg/kg/min, then titrate to effect
Johnson: Current Therapy in Neurologic Disease (7/E)
VENTRICULOSTOMY AND SURGERY A severe complication of ICH is an increase in intracranial pressure (ICP), either in the acute setting because of the large size of the hematoma, or delayed ICP elevation because of perihematoma edema or because of hydrocephalus caused from either an intraventricular hemorrhage component to the ICH or from obstruction of ventricular outflow by compression of the third or fourth ventricles, depending on the location of the ICH. Obstructive hydrocephalus is fairly easily treated with external ventricular drainage; however, there may be continued compression of other brain elements that may lead to the decision of surgical evacuation of the hematoma. Though there is no evidence that evacuation of supratentorial hemorrhage can consistently lead to improved clinical outcomes, it is often attempted at most institutions with neurosurgical support. Certainly there has been successful outcome in isolated cases. In the instance of cerebellar hematoma, there is evidence that surgical evacuation will lead to improved outcome in those cases where the hematoma is larger than 40 mL or where there has been neurologic decline. INTRACRANIAL PRESSURE Though there is no concrete evidence that monitoring and treatment actually lead to an improved outcome, if ICP is to be treated, it makes sense to monitor ICP. When ICP is known, then the cerebral perfusion pressure (CPP) can be calculated as CPP = MAP − ICP and hemodynamic therapy can also be modified to maintain CPP at adequate levels, typically greater than 60 mm Hg. Occasionally, blood pressure needs to be raised with hypertensive agents to meet these goals (see Table 1 for agents treating hypotension). Treatment of ICP (Table 2) consists of (1) improving venous drainage by elevating the head of the bed to 30 degrees above horizontal, (2) hyperventilation to cause vasoconstriction and decrease cerebral blood volume, (3) diuretics to decrease intravascular blood volume, and (4) hyperosmolar therapy, typically with mannitol and sometimes hypertonic saline, to maintain an elevated serum osmolarity to draw off interstitial fluid and edema from the brain into the vasculature and then excretion through the renal system. Except for raising the head of the bed, these interventions are short lived
TABLE 2 Treatment of Elevated Intracranial Pressure 1. Raise head of bed > 30 degrees. 2. Treat hyperventilation by increasing set respiratory rate to meet PCO2 goals of 25-30 mm Hg. 3. Administer diuretic dose with furosemide (Lasix) 10 mg (in patients with adequate renal function). 4. Administer mannitol 1 gm/kg IV to meet serum osmolarity goals of 300-320 mOsm (in patients with adequate renal function).
Cerebrovascular Disease
using single-photon emission CT (SPECT), positron emission tomography (PET), and diffusion MR imaging, no such ischemic penumbra has been demonstrated. Since chronic and acute hypertension are known risk factors for ICH, and there is high probability of early recurrent ICH and no ischemic penumbra has been proven, at our institution we believe in early blood pressure reduction. Blood pressure reduction can be accomplished in a variety of means. In an informal survey of neurointensivists, I have found that approximately half used the mean arterial blood pressure (MAP) and half used the systolic blood pressure as the measurement of choice to set patient care goals and monitoring. At our institution, we use systolic blood pressure goals of 130 to 160 mm Hg, since approximately two thirds of the MAP value is based on the diastolic blood pressure and we feel that the higher systolic blood pressure is the likely instigator in recurrent hemorrhage. MAP goals are perhaps better for those patients where consistent perfusion is more of a concern, and typical MAP goals might be in the range of 100 to 120 mm Hg. After setting the chosen goals, specific agents must be chosen to meet those goals. In Table 1 there is a list of typical antihypertensive agents and doses used in acute ICH. A caveat to the use of nitroprusside is that arterial line monitoring is recommended because of the chance of acute severe hypotension and hemodynamic instability. At our institution, we prefer intravenous infusions of nicardipine because of more consistent blood pressure response and tighter blood pressure control, compared with either nitroprusside or boluses of antihypertensive medications, such as labetalol.
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and should be reserved for the acutely deteriorating patient. Steroids should be avoided since they have not been found to be effective in randomized, controlled trials.
Complications A major complication of ICH is seizures, usually developing within 24 hours of the hemorrhage. The risk is higher when blood invades or is adjacent to the cerebral cortex, so for those patients with cortical hemorrhages or those who have had seizures, it is reasonable to begin immediate prophylactic therapy with anticonvulsants such as phenytoin or valproate that can be given intravenously or orally (Table 3). If no seizures have occurred, it is agreed to discontinue prophylactic therapy, though there is some discrepancy on the timeline, anywhere from 1 to 6 months after the ICH has been espoused. Certainly those with later seizures will need long-term therapy. Systemic factors that have been associated with poorer outcome in stroke patients are consistently dehydration, elevated serum glucose levels, and fever. So though not proven to be a causal relationship, it certainly makes sense to aggressively maintain euvolemia, euthermia, and normal serum glucose levels.
Upcoming Therapies and Trials There remains little high-level clinical trial evidence to help determine the best management of the patient with ICH. Some of the difficult issues in ICH management that are targets of active investigation include (1) a study on blood pressure management of ICH patients that stratifies patients to high, low, and “normal” blood pressure control; (2) minimally invasive removal of hematoma through stereotactic approaches; (3) hypothermia treatment for ICH; (4) accelerating removal of intraventricular hemorrhage through aggressive drainage and thrombolytic agents; and (5) preventing recurrent hemorrhage with recombinant VIIa factors.
TABLE 3 Seizure Prophylaxis Drug
Dosage
Phenytoin
Loading dose 15-20 mg/kg IV (not to exceed 50 mg/min) or orally in divided doses Maintenance 300 mg/day in divided doses Loading dose 10-20 mg PE/kg IV (not to exceed 150 mg PE/min) or IM Maintenance dose 4 to 6 mg PE/kg/day IV or IM IV loading dose 10-15 mg/kg/day (≤20 mg/min) Maintenance titrated to meet therapeutic goals
Fosphenytoin
Valproate
PE, Phenytoin sodium equivalent units.
SUGGESTED READING Broderick JP, Adams HP Jr, Barsan W, et al: 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 30:905-915, 1999. Broderick JP, Brott TG, Duldner JE, et al: Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality, Stroke 24:987-993, 1993. Qureshi AI, Tuhrim S, Broderick JP, et al: Spontaneous intracerebral hemorrhage, N Engl J Med 344:1450-1460, 2001. Tuhrim S, Horowitz DR, Sacher M, Godbold JH: Validation and comparison of models predicting survival following intracerebral hemorrhage, Crit Care Med 23:950-954, 1995.
Management of Subarachnoid Hemorrhage Joao A. Gomes, M.D., and Wendy C. Ziai, M.D.
Overall, craniocerebral trauma is the most common cause of subarachnoid hemorrhage (SAH), whereas aneurysmal rupture (saccular or berry) accounts for more than 80% of nontraumatic SAH. Other less common etiologies include perimesencephalic (presumably venous) hemorrhages, arterial dissections, vascular malformations, drug abuse, coagulopathies, and sickle cell disease. In this review we concentrate primarily on the management of aneurysmal SAH. The estimated annual incidence of SAH varies greatly with the population studied and with other demographic and geographic factors. In a recent meta-analysis, the pooled incidence of SAH was 10.5 per 100,000 personyears, and in the United States alone 30,000 new cases are reported every year. The relative risk of developing SAH is increased with alcohol intake, hypertension, smoking, and history of a first-degree relative with SAH. The prevalence of intracranial aneurysm in the general U.S. population is 0.5% to 1%. After an episode of aneurysmal SAH, 80% of patients reach the hospital alive, 30% die during their hospital admission, and only about 16% ultimately regain independence without cognitive deficits. Overall, fewer than 50% of independent patients return to their prior level of work after SAH. At presentation patients typically complain of a sudden-onset, severe headache (“worse headache of my life”), accompanied by nausea, vomiting and photophobia. In 19% of cases, however, the headache progresses gradually over minutes or rarely longer. A warning “leak,” called a sentinel hemorrhage, occurs in approximately 70% of patients and is usually indicated by a previous episode of milder symptoms. Alterations of consciousness, including coma (occurring in ≤ 25% of patients), and focal neurologic deficits (in 33%), are also frequent manifestations. The nonspecific nature of these symptoms leads to initial misdiagnosis in 23% to 37% Johnson: Current Therapy in Neurologic Disease (7/E)
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and should be reserved for the acutely deteriorating patient. Steroids should be avoided since they have not been found to be effective in randomized, controlled trials.
Complications A major complication of ICH is seizures, usually developing within 24 hours of the hemorrhage. The risk is higher when blood invades or is adjacent to the cerebral cortex, so for those patients with cortical hemorrhages or those who have had seizures, it is reasonable to begin immediate prophylactic therapy with anticonvulsants such as phenytoin or valproate that can be given intravenously or orally (Table 3). If no seizures have occurred, it is agreed to discontinue prophylactic therapy, though there is some discrepancy on the timeline, anywhere from 1 to 6 months after the ICH has been espoused. Certainly those with later seizures will need long-term therapy. Systemic factors that have been associated with poorer outcome in stroke patients are consistently dehydration, elevated serum glucose levels, and fever. So though not proven to be a causal relationship, it certainly makes sense to aggressively maintain euvolemia, euthermia, and normal serum glucose levels.
Upcoming Therapies and Trials There remains little high-level clinical trial evidence to help determine the best management of the patient with ICH. Some of the difficult issues in ICH management that are targets of active investigation include (1) a study on blood pressure management of ICH patients that stratifies patients to high, low, and “normal” blood pressure control; (2) minimally invasive removal of hematoma through stereotactic approaches; (3) hypothermia treatment for ICH; (4) accelerating removal of intraventricular hemorrhage through aggressive drainage and thrombolytic agents; and (5) preventing recurrent hemorrhage with recombinant VIIa factors.
TABLE 3 Seizure Prophylaxis Drug
Dosage
Phenytoin
Loading dose 15-20 mg/kg IV (not to exceed 50 mg/min) or orally in divided doses Maintenance 300 mg/day in divided doses Loading dose 10-20 mg PE/kg IV (not to exceed 150 mg PE/min) or IM Maintenance dose 4 to 6 mg PE/kg/day IV or IM IV loading dose 10-15 mg/kg/day (≤20 mg/min) Maintenance titrated to meet therapeutic goals
Fosphenytoin
Valproate
PE, Phenytoin sodium equivalent units.
SUGGESTED READING Broderick JP, Adams HP Jr, Barsan W, et al: 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 30:905-915, 1999. Broderick JP, Brott TG, Duldner JE, et al: Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality, Stroke 24:987-993, 1993. Qureshi AI, Tuhrim S, Broderick JP, et al: Spontaneous intracerebral hemorrhage, N Engl J Med 344:1450-1460, 2001. Tuhrim S, Horowitz DR, Sacher M, Godbold JH: Validation and comparison of models predicting survival following intracerebral hemorrhage, Crit Care Med 23:950-954, 1995.
Management of Subarachnoid Hemorrhage Joao A. Gomes, M.D., and Wendy C. Ziai, M.D.
Overall, craniocerebral trauma is the most common cause of subarachnoid hemorrhage (SAH), whereas aneurysmal rupture (saccular or berry) accounts for more than 80% of nontraumatic SAH. Other less common etiologies include perimesencephalic (presumably venous) hemorrhages, arterial dissections, vascular malformations, drug abuse, coagulopathies, and sickle cell disease. In this review we concentrate primarily on the management of aneurysmal SAH. The estimated annual incidence of SAH varies greatly with the population studied and with other demographic and geographic factors. In a recent meta-analysis, the pooled incidence of SAH was 10.5 per 100,000 personyears, and in the United States alone 30,000 new cases are reported every year. The relative risk of developing SAH is increased with alcohol intake, hypertension, smoking, and history of a first-degree relative with SAH. The prevalence of intracranial aneurysm in the general U.S. population is 0.5% to 1%. After an episode of aneurysmal SAH, 80% of patients reach the hospital alive, 30% die during their hospital admission, and only about 16% ultimately regain independence without cognitive deficits. Overall, fewer than 50% of independent patients return to their prior level of work after SAH. At presentation patients typically complain of a sudden-onset, severe headache (“worse headache of my life”), accompanied by nausea, vomiting and photophobia. In 19% of cases, however, the headache progresses gradually over minutes or rarely longer. A warning “leak,” called a sentinel hemorrhage, occurs in approximately 70% of patients and is usually indicated by a previous episode of milder symptoms. Alterations of consciousness, including coma (occurring in ≤ 25% of patients), and focal neurologic deficits (in 33%), are also frequent manifestations. The nonspecific nature of these symptoms leads to initial misdiagnosis in 23% to 37% Johnson: Current Therapy in Neurologic Disease (7/E)
Management of Subarachnoid Hemorrhage
General Management Noncontrast CT scanning of the brain has a sensitivity of 85% to 90% for the diagnosis of SAH. The location of clot on CT scan can be indicative of the location of the ruptured aneurysm. If the CT result is negative for SAH, a lumbar puncture is mandatory to look for the presence of blood or xanthochromia in the cerebrospinal fluid (CSF). Four-vessel cerebral angiography remains the gold standard for detection of aneurysms, although 10% to 30% of cases may not reveal an aneurysm, and repeat angiography should be performed in 1 to 2 weeks (10% to 20% of cases are then positive). Helical CT angiography provides multiplanar views or three-dimensional images that have a sensitivity of 77% to 97% (specificity, 87% to 100%) and is a reasonable alternative for patients who cannot tolerate an angiogram and require surgery. Initial stabilization of patients with SAH requires admission to a monitored critical care setting. After assessing the basic ABCs (airway, breathing, circulation), one of the earliest interventions that relieves patient distress and may control hypertension and agitation is adequate pain control. Oral or rectal acetaminophen or intravenous (IV) short-acting narcotics such as fentanyl can be used until pain control is achieved. The sedating effect of narcotic agents may limit their use in patients with impaired consciousness and/or higher SAH grades. Although frequent neurologic assessments are required during this period, excessive stimulation should be reduced to a minimum. If the patient requires intubation, general anesthetic induction should be used to blunt the hemodynamic stress of laryngoscopy. Adequate IV access is also mandatory, and although peripheral venous lines are usually sufficient in the early stages, central venous access is often required, particularly if the patient requires hypertonic fluids or prolonged use of vasopressor agents. The presence of a central venous line also helps with hemodynamic monitoring and the assessment of fluid status by continuous measurement of central venous pressure. Fever in this setting is a common occurrence and may play a role in the pathophysiology of cerebral vasospasm. Experimental data suggest that fever is associated with worse outcomes after brain trauma or ischemia; therefore, it is important to aggressively maintain normothermia. Although adequate microbiologic cultures should be obtained, including CSF in patients with
TABLE 1 Hunt-Hess Grading Scale for Subarachnoid Hemorrhage* Grade
Criteria
1
Asymptomatic or minimal headache and slight nuchal rigidity Moderate-to-severe headache, nuchal rigidity, no neurologic deficit other than cranial nerve palsy Drowsiness, confusion, or mild focal deficit Stupor, moderate-to-severe focal deficit (hemiparesis); vegetative disturbances Deep coma, decerebrate posturing
2 3 4 5
*Significant comorbidity raises the Hunt-Hess score by 1 point.
Johnson: Current Therapy in Neurologic Disease (7/E)
TABLE 2 World Federation of Neurological Surgeons Grading Scale for Subarachnoid Hemorrhage Grade
Criteria
1 2 3 4 5
GCS GCS GCS GCS GCS
score score score score score
GCS, Glasgow Coma Scale.
15, no motor deficit 13-14, no motor deficit 13-14, with motor deficit 7-12, with or without motor deficit 3-6, with or without motor deficit
Cerebrovascular Disease
of patients. Findings on physical examination include nuchal rigidity, papilledema, subhyaloid hemorrhage, cranial nerve palsy (especially cranial nerves III and VI), bilateral leg weakness, abulia, nystagmus, hemiparesis, ataxia, aphasia, and neglect. The three baseline variables that best predict poor outcome after SAH are neurologic status of the patient on admission, age, and amount of subarachnoid blood on the initial computed tomographic (CT) scan. Several clinical and radiologic grading scales have been proposed, and the most commonly used in routine practice are shown in Tables 1 to 3. These scales have some prognostic value (i.e., an SAH with a grade V in the Hunt-Hess scale has an estimated mortality of close to 100%) and to some extent can help dictate further management. They are, however, far from perfect because they include subjective terminology, they have undocumented or imperfect interobserver reliability, the prognostic value may not be the same for all of the elements included, and they fail to consider the presence of reversible conditions such as hydrocephalus that may initially suggest a worse prognosis. In the past, rebleeding was a major cause of morbidity and mortality following the initial hemorrhage. With the current practice of early aneurysm clipping, the incidence of rebleeding is more limited and vasospasm and delayed ischemic deficits have become the most significant and feared complications following SAH. Although classically the presence of thick clot on the initial CT scan was considered a major determinant of vasospasm, this view has been recently challenged. The pathophysiology of cerebral vasospasm is currently not fully understood, but both inflammation and endothelial dysfunction seem to play a major role in its development. The management of patients with SAH remains a major challenge for physicians involved in the care of these patients. In this review we focus on the initial management of patients after SAH (i.e., the acute phase up to the time of aneurysm clipping), and then review the management of various complications associated with SAH.
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TABLE 3 Fisher Grading Scale for Subarachnoid Hemorrhage Grade
Criteria
1 2
No subarachnoid blood detected on CT scan Diffuse subarachnoid blood or vertical layer 1 mm thick Intracerebral or intraventricular clot in absence of significant subarachnoid blood
3 4
intraventricular catheters or following craniotomy, fever in these patients may occur without any identifiable infectious etiologies (“central fever”). Oral or rectal acetaminophen and surface cooling techniques (i.e., cooling blankets, ice packs, and alcohol rubs) are routinely used to maintain core body temperature below 37.5°C. Intravascular cooling catheters have also been successfully used for this purpose; however, cost and potential side effects due to their invasive nature may limit their widespread use. Nimodipine, a calcium channel blocker, has been shown to improve outcomes in patients with SAH, but it is unclear if it does so by decreasing vasospasm or through other neuroprotective mechanisms. We routinely start nimodipine at 60 mg every 4 hours (or 30 mg every 2 hours if hypotension is induced with the larger dose), and continue treatment for 3 weeks. IV nimodipine is available in some countries. The incidence of rebleeding from the aneurysm during the first 24 hours is likely underestimated. It ranges from 4% to as high as 15%. During the first 2 weeks about 20% of patients experience an episode of rebleeding, which is a major factor contributing to poor outcome. In the past, administration of antifibrinolytic agents (epsilon aminocaproic acid) was associated with a decreased rate of rebleeding, but at the expense of an increased risk of ischemic complications. More recently, activated recombinant factor VII has been tested in a small cohort of patients. No episodes of rebleeding were documented, but the trial was stopped pending the adjudication of a thrombotic complication. In retrospective studies, up to 20% of patients had at least one seizure during the first 2 weeks following SAH, whereas only 6% to 8% developed late seizures and epilepsy. Persistent postoperative neurologic deficits, loss of consciousness for more than 1 hour at ictus, subdural hematoma, and cerebral infarction were associated with the development of epilepsy. All patients should receive seizure prophylaxis with an IV bolus of phenytoin or fosphenytoin (20 mg/kg) on arrival to the hospital, and therapeutic levels (15 to 20 ng/dL) should be maintained throughout their admission. Common side effects such as skin rash, hypotension during the infusion, hyponatremia, and drug fever should be monitored for. Valproate is also a reasonable alternative if phenytoin is contraindicated and is available in an IV formulation. In uncomplicated cases the antiepileptic agent can be stopped after the first month but may be continued
longer if there is a high likelihood of developing late epilepsy, for example, after cerebral infarction or brain abscess. Because of the ability of corticosteroids to suppress inflammation, inhibit prostanoid actions, and prevent lipid peroxidation, their use has been tested extensively in SAH, particularly as a means of preventing vasospasm. In a trial involving 22 patients, those treated with corticosteroids were twice as likely to have an excellent outcome and half as likely to die. Unfortunately these results have not been replicated, and despite a reasonable rationale for their use, good clinical data are lacking. In our unit patients are treated with dexamethasone 4 mg every 6 hours IV in the perioperative period, but rarely for more than a few days. The rationale is for control of pain and inflammation. Between 10% and 34% of patients with SAH develop hypovolemia associated with a negative sodium balance, known as cerebral salt wasting. Fluid restriction in patients with hyponatremia and SAH is associated with an increased risk of cerebral ischemia. Therefore, maintaining normal intravascular volume is an important strategy to prevent the development of delayed ischemic deficits. Two nonrandomized studies support this view and advocate the daily intake of at least 3 L of fluid. Normal saline is usually the fluid of choice, and if a central line is in place, the central venous pressure should be maintained between 8 and 12 cm H2O. Fludrocortisone is sometimes used to promote sodium and water retention, particularly if cerebral salt wasting has developed (see later). Another important consideration is hemoglobin and hematocrit levels. To optimize oxygen delivery to brain tissue, the hemoglobin level should be kept between 10 and 11 gm/dL and hematocrit should be in the 30% to 34% range. Blood transfusions should be used as needed, but consideration should also be given to recombinant erythropoietin for patients with severe anemia. Blood transfusion thresholds in the SAH population have recently been challenged in view of lower hemoglobin thresholds used in other intensive care unit populations where blood transfusion may be an independent predictor of worse outcome. Arterial hypertension is a common occurrence in this initial period and may be the result of anxiety, pain, increased intracranial pressure, or agitation. On the one hand, uncontrolled hypertension can theoretically lead to rerupture of the aneurysm, whereas aggressive blood pressure lowering may compromise cerebral perfusion pressure, particularly if elevated intracranial pressure is present. Although the optimal range of blood pressure in this setting is unknown, in an observational study, lowering blood pressure did not reduce the rate of rerupture but increased the risk of cerebral ischemia. Our usual practice is to maintain a systolic blood pressure below 160 mm Hg prior to aneurysm clipping or coiling (diastolic blood pressure, < 80 mm Hg, and mean arterial pressure [MAP] < 110 mm Hg), and to treat aggressively only if end organ damage is evident. The preferred IV agents include labetalol, hydralazine, and nicardipine. The latter has the added advantage of reducing the incidence of vasospasm. Johnson: Current Therapy in Neurologic Disease (7/E)
Management of Subarachnoid Hemorrhage
Complications Angiographic vasospasm is documented in about 60% of patients following SAH but becomes symptomatic in only half of them. Ultimately, delayed ischemic deficits develop in about 16% of subjects with SAH. Typically, vasospasm has its onset 3 to 5 days following the initial bleed, peaks at 7 to 10 days, and resolves spontaneously over 2 to 4 weeks. Vasospasm is a proliferative vasculopathy that results from a variety of vasoactive mediators including oxyhemoglobin, free radicals, prostaglandins, decreased action of nitric oxide, inflammatory immune mediators, and vasoconstrictive peptides such as endothelin. The clinical manifestations of vasospasm include decreased responsiveness, abulia, focal neurologic deficits including paraparesis, and apraxia. Without adequate supportive care, the result is mortality in 30% and disability in 35% of patients. The best predictor of vasospasm is the amount of blood detected on head CT scan (Fisher grade) within the first 3 days after SAH. Structural complications should be ruled out by CT scan when vasospasm is suspected. Although conventional angiography is considered the gold standard for the diagnosis of vasospasm, daily screening of cerebral blood flow (CBF) velocities in the large arteries comprising the circle of Willis by means of transcranial Doppler (TCD) ultrasound is routinely performed in an attempt to detect it. Overall, the sensitivity of TCD for detecting vasospasm ranges from 65% to 80%, with velocities less than 120 cm/sec having a negative predictive value of 94% and greater than 200 cm/sec Johnson: Current Therapy in Neurologic Disease (7/E)
a positive predictive value of almost 90%. Unfortunately, most CBF velocities during vasospasm actually fall in the range between 120 and 200 cm/sec, making TCD somewhat less useful. The ratio of the mean velocity of the middle cerebral artery to the mean velocity recorded in the extracranial carotid artery (Lindegaard index [LI]) helps differentiate hyperemia (LI < 3) from vasospasm (LI > 3). An increment in mean CBF velocities by more than 50 cm/sec in a 24-hour period is considered a specific marker of vasospasm. The combination of hypervolemia, hemodilution, and hypertension (“triple-H therapy”) was first introduced in the 1970s and remains the mainstay of therapy for cerebral vasospasm, even though its effectiveness has never been documented in a randomized, controlled trial. In the presence of arterial narrowing, cerebral autoregulation is impaired and blood flow may become pressure dependent. This is the rationale for blood pressure augmentation in symptomatic vasospasm. It is also thought that hemodilution decreases blood viscosity and enhances blood flow through spastic blood vessels. Besides aggressive hydration with IV normal saline with a target central venous pressure of 8 to 12 cm H2O, the use of vasopressor agents is recommended for ongoing symptoms suggestive of cerebral ischemia. Phenylephrine is usually the first agent of choice, but development of reflex bradycardia may limit its use. MAP is usually increased by 20% up to a MAP of 140 mm Hg, and the patient is reassessed frequently. Pulmonary edema and myocardial infarction are the main complications associated with this therapy, and daily chest radiographs and electrocardiograms should be obtained in all patients. Some groups advocate the routine insertion of a pulmonary artery catheter to guide therapy, never allowing the pulmonary capillary wedge pressure to exceed the calculated colloid oncotic pressure. Increasing cardiac output independent of blood pressure has also been used successfully to increase CBF and treat vasospasm following SAH. This is usually achieved by using primarily inotropic agents such as dobutamine and has the added advantage of being potentially beneficial in the setting of cardiac dysfunction. If maximal medical therapy fails to produce clinical improvement after 2 to 4 hours, an angiogram should be obtained and endovascular interventions considered. Percutaneous transluminal angioplasty has been advocated as an effective and relatively safe procedure to mechanically dilate large intracranial vessels increasing distal CBF (rarely vessel rupture or dissection can occur), but no controlled trials have documented its value. If the spasm is diffuse or present in smaller arterial branches, the infusion of papaverine, verapamil, or nicardipine is then considered, but their effect tends to be short lasting. Hyponatremia occurs in as many as 30% of patients with SAH and is often associated with intravascular volume depletion and cerebral ischemia. In most instances this is due to cerebral salt wasting (CSW), a syndrome thought to be mediated by a natriuretic factor that is released as a consequence of the initial brain insult as well as decreased rennin and aldosterone. It is most commonly seen in aneurysms involving the
Cerebrovascular Disease
The respiratory status of the patient should be assessed periodically, supplemental oxygen provided as required, and the airway secured if there is evidence of aspiration, neurogenic pulmonary edema with compromised oxygenation, or poor mental status with inability to protect the airway. Baseline chest radiograph and arterial blood gases should be obtained and repeated if the patient status changes. Adequate prophylaxis for pulmonary embolism should be instituted with compressive stockings and sequential compression devices initially and subcutaneous heparin after the aneurysm has been secured. An effective bowel regimen is paramount to prevent stress ulcers and avoid constipation, particularly in patients taking narcotic analgesics. Proton pump inhibitors, H2 blockers, or sucralfate, and a variety of medications to keep a regular bowel schedule should be implemented early. Nausea should also be aggressively treated with the standard medications (i.e., metoclopramide, prochlorperazine, dolasetron, or ondansetron). Patients should not be fed for the first 24 to 48 hours in preparation for surgery or endovascular interventions. Patients with inadequate swallowing mechanisms should have a nasogastric or orogastric tube placed and tube feeds started postoperatively to provide adequate nutrition. Concentrated feeds with less free water and higher sodium content may be preferable for these patients.
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anterior cerebral artery complex and typically peaks in the first 7 to 10 days. It manifests as natriuresis, hyponatremia, and hypovolemia. CSW needs to be differentiated from the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In the latter, there are no signs of dehydration because patients are usually euvolemic or slightly hypervolemic. Serum uric acid concentration (decreased in SIADH), plasma osmolality (decreased in SIADH), and CVP (increased or normal in SIADH) may also help differentiate between these two conditions. Volume repletion and maintenance of a positive sodium balance are the cornerstones of therapy. Multiplying the deficit in sodium concentration by the total body water (TBW) helps estimate the amount of sodium required to achieve normonatremia, as shown in the following equation: Na+ replacement = (ideal Na+ − measured Na+) × TBW Oral sodium chloride tablets (2 gm every 6 hours), 2% or 3% hypertonic saline (when serum Na+ < 130), and fludrocortisone (a mineralocorticoid agent) all are useful in correcting the sodium deficit. Although a rapid decrease in sodium plasma levels can lead to cerebral edema, overtly aggressive correction of hyponatremia (>20 mEq/L per day) can lead to central pontine myelinolysis. Fluid restriction is contraindicated in patients with vasospasm. Hydrocephalus following SAH can be either noncommunicating (usually acute) or communicating (typically subacute or delayed). Usually patients develop decline in alertness, confusion, disorientation, and inattention. In the acute period if the CT scan shows enlarged ventricles, an intraventricular catheter is inserted to drain CSF and relieve symptoms, but the pop-off (the set pressure above which CSF would drain) is set at a high level (15 to 20 mm Hg) to avoid changes in the transmural differential pressure across the aneurysm wall and to prevent sagging of the brain against the floor of the anterior cranial fossa, which may theoretically lead to rerupture. Once the aneurysm is secured (clipped), this is no longer a consideration and the pop-off can be lowered to optimize treatment of hydrocephalus. In instances of communicating (nonobstructive) hydrocephalus, lumbar drain insertion for continuous CSF drainage or serial large volume lumbar punctures are less invasive options. If these interventions are unsuccessful and chronic hydrocephalus develops, ventriculoperitoneal or ventriculopleural shunts are required. It is estimated that about 20% of patients following SAH require a ventriculoperitoneal shunt within the first 30 days. Although not all aneurysms necessarily require treatment, in the setting of SAH, the predicted natural history of the aneurysm is a 50% risk of rerupture in the subsequent 6 months. Rupture of an aneurysm that has previously bled has a significantly higher mortality risk (≥75%), usually justifying the risks of intervention. The goal of surgical management of aneurysms is to isolate the aneurysm fully from the intracranial circulation to remove the risk of rehemorrhage. This can be accomplished through a craniotomy with direct
visualization of the aneurysm that is clipped, or occasionally “trapped” or wrapped for less favorable aneurysms. Endovascular obliteration of aneurysms is performed by an interventional team and involves insertion of thrombogenic wire coils into the aneurysm that are detached from the guide wire and left in place. Occasionally balloons or stents are used with the coils. Endovascular treatment, although less invasive than direct surgery, is currently limited by specific aneurysm characteristics such as neck-to-dome ratio and aneurysm location. In addition, this technique achieves complete aneurysm obliteration in only about 60% to 70% of cases, making recurrence a potential risk. SUGGESTED READING McKhann GM II, Le Roux PD: Perioperative and intensive care unit care of patients with aneurysmal subarachnoid hemorrhage, Neurosurg Clin North Am 9:595-613, 1998. Treggiari-Venzi M, Suter PM, Romand J: Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care, Neurosurgery 48:249-262, 2001. van Gijn J, Rinkel GJE: Subarachnoid hemorrhage: diagnosis, causes, and management, Brain 124:249-278, 2001.
Management of Intracranial Aneurysms and Other Vascular Malformations S. Claiborne Johnston, M.D., Ph.D.
Vascular malformations of the brain, such as aneurysms, cavernous malformations, and arteriovenous malformations (AVMs) and fistulas, are complicated to manage. Patients presenting with hemorrhage due to a vascular malformation are some of the sickest in the hospital, with high risk of serious complications and short-term mortality rates approaching 50%. For those whose lesions are discovered for other reasons (e.g., incidentally or in the work-up of seizures, headache, or focal neurologic symptoms), it is difficult to balance the risk of complications from surgical or endovascular treatment with the expected natural history if left untreated; the balance between risk and benefit “turns on a dime,” at least as we understand it today. Given all these issues, management by a multidisciplinary team is essential. A fully complemented team includes a vascular or intensive-care neurologist, a vascular neurosurgeon, and a neurointerventionalist. Since these specialists are biased to exaggerate the benefits of their own approach, a balanced team is essential in making the best decisions, particularly given the scarcity of evidence and necessary reliance on judgment and experience. Several studies have shown that outcomes are better at centers that treat more patients with these conditions and provide Johnson: Current Therapy in Neurologic Disease (7/E)
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anterior cerebral artery complex and typically peaks in the first 7 to 10 days. It manifests as natriuresis, hyponatremia, and hypovolemia. CSW needs to be differentiated from the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In the latter, there are no signs of dehydration because patients are usually euvolemic or slightly hypervolemic. Serum uric acid concentration (decreased in SIADH), plasma osmolality (decreased in SIADH), and CVP (increased or normal in SIADH) may also help differentiate between these two conditions. Volume repletion and maintenance of a positive sodium balance are the cornerstones of therapy. Multiplying the deficit in sodium concentration by the total body water (TBW) helps estimate the amount of sodium required to achieve normonatremia, as shown in the following equation: Na+ replacement = (ideal Na+ − measured Na+) × TBW Oral sodium chloride tablets (2 gm every 6 hours), 2% or 3% hypertonic saline (when serum Na+ < 130), and fludrocortisone (a mineralocorticoid agent) all are useful in correcting the sodium deficit. Although a rapid decrease in sodium plasma levels can lead to cerebral edema, overtly aggressive correction of hyponatremia (>20 mEq/L per day) can lead to central pontine myelinolysis. Fluid restriction is contraindicated in patients with vasospasm. Hydrocephalus following SAH can be either noncommunicating (usually acute) or communicating (typically subacute or delayed). Usually patients develop decline in alertness, confusion, disorientation, and inattention. In the acute period if the CT scan shows enlarged ventricles, an intraventricular catheter is inserted to drain CSF and relieve symptoms, but the pop-off (the set pressure above which CSF would drain) is set at a high level (15 to 20 mm Hg) to avoid changes in the transmural differential pressure across the aneurysm wall and to prevent sagging of the brain against the floor of the anterior cranial fossa, which may theoretically lead to rerupture. Once the aneurysm is secured (clipped), this is no longer a consideration and the pop-off can be lowered to optimize treatment of hydrocephalus. In instances of communicating (nonobstructive) hydrocephalus, lumbar drain insertion for continuous CSF drainage or serial large volume lumbar punctures are less invasive options. If these interventions are unsuccessful and chronic hydrocephalus develops, ventriculoperitoneal or ventriculopleural shunts are required. It is estimated that about 20% of patients following SAH require a ventriculoperitoneal shunt within the first 30 days. Although not all aneurysms necessarily require treatment, in the setting of SAH, the predicted natural history of the aneurysm is a 50% risk of rerupture in the subsequent 6 months. Rupture of an aneurysm that has previously bled has a significantly higher mortality risk (≥75%), usually justifying the risks of intervention. The goal of surgical management of aneurysms is to isolate the aneurysm fully from the intracranial circulation to remove the risk of rehemorrhage. This can be accomplished through a craniotomy with direct
visualization of the aneurysm that is clipped, or occasionally “trapped” or wrapped for less favorable aneurysms. Endovascular obliteration of aneurysms is performed by an interventional team and involves insertion of thrombogenic wire coils into the aneurysm that are detached from the guide wire and left in place. Occasionally balloons or stents are used with the coils. Endovascular treatment, although less invasive than direct surgery, is currently limited by specific aneurysm characteristics such as neck-to-dome ratio and aneurysm location. In addition, this technique achieves complete aneurysm obliteration in only about 60% to 70% of cases, making recurrence a potential risk. SUGGESTED READING McKhann GM II, Le Roux PD: Perioperative and intensive care unit care of patients with aneurysmal subarachnoid hemorrhage, Neurosurg Clin North Am 9:595-613, 1998. Treggiari-Venzi M, Suter PM, Romand J: Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care, Neurosurgery 48:249-262, 2001. van Gijn J, Rinkel GJE: Subarachnoid hemorrhage: diagnosis, causes, and management, Brain 124:249-278, 2001.
Management of Intracranial Aneurysms and Other Vascular Malformations S. Claiborne Johnston, M.D., Ph.D.
Vascular malformations of the brain, such as aneurysms, cavernous malformations, and arteriovenous malformations (AVMs) and fistulas, are complicated to manage. Patients presenting with hemorrhage due to a vascular malformation are some of the sickest in the hospital, with high risk of serious complications and short-term mortality rates approaching 50%. For those whose lesions are discovered for other reasons (e.g., incidentally or in the work-up of seizures, headache, or focal neurologic symptoms), it is difficult to balance the risk of complications from surgical or endovascular treatment with the expected natural history if left untreated; the balance between risk and benefit “turns on a dime,” at least as we understand it today. Given all these issues, management by a multidisciplinary team is essential. A fully complemented team includes a vascular or intensive-care neurologist, a vascular neurosurgeon, and a neurointerventionalist. Since these specialists are biased to exaggerate the benefits of their own approach, a balanced team is essential in making the best decisions, particularly given the scarcity of evidence and necessary reliance on judgment and experience. Several studies have shown that outcomes are better at centers that treat more patients with these conditions and provide Johnson: Current Therapy in Neurologic Disease (7/E)
Management of Intracranial Aneurysms and Other Vascular Malformations
Unruptured Intracranial Aneurysms Unruptured intracranial aneurysms are common, with a prevalence estimated at greater than 1% among adults. Most are asymptomatic, incidentally discovered in a work-up for unrelated headache, vertigo, or other neurologic symptoms. Some headaches and focal neurologic signs are produced by aneurysms, particularly when large aneurysms compress neighboring nerves or brain, but these represent fewer than half those discovered. As more data have become available from large cohort studies, such as the International Study of Unruptured Intracranial Aneurysms (ISUIA), treatment decisions about incidentally discovered aneurysms have gotten much more complicated. We previously treated all unruptured aneurysms, motivated by the devastating consequences of subarachnoid hemorrhage from aneurysm rupture and confident that results of surgery and endovascular treatment were favorable. However, recent data suggest that the risks of treatment are not inconsequential and that, for many aneurysms, the risk of rupture is much lower than expected. Furthermore, results of endovascular therapy have been improving and, in the short term, appear better than for surgery, although long-term occlusion remains a concern. Now we are much more careful about who gets referred for an intervention. The first questions are, who should have the aneurysm treated and who can be followed medically? This is a rapidly evolving area with new data published monthly, but the chart represents our interpretation of the best data available today (Figure 1). The decision is based on a number of factors that affect natural history and surgical risk. These include aneurysm size and location, history of subarachnoid hemorrhage from a different aneurysm, age, and whether the aneurysm is producing symptoms. The bottom line is that most aneurysms probably should be treated; however, intervention is not justified in patients with no history of subarachnoid hemorrhage with asymptomatic aneurysms smaller than 7 mm in diameter (in the anterior circulation but not in the posterior communicating artery). The risk of rupture is so low in that group that treatment would need to be nearly completely without complications to justify it. Given the preponderance of evidence supporting greater safety of endovascular therapy, even with limited information on long-term follow-up, we generally favor endovascular coil embolization over surgical clipping. Still, there are many in whom surgery is the best option. Patients best treated with surgical clipping include those with a strong preference for a single treatment procedure, those with aneurysms with wide necks or arising from the middle cerebral artery, and those in whom follow-up is questionable. In addition, other particular characteristics of an aneurysm on imaging may reveal that it is not safely treated by endovascular Johnson: Current Therapy in Neurologic Disease (7/E)
therapy, which can only be determined by a neurointerventionalist reviewing the images or attempting treatment. For difficult cases, representatives of endovascular therapy, neurology, and vascular neurosurgery converge in the angiography suite to discuss the best approach to treatment. After endovascular therapy, we generally recommend a follow-up angiogram at 6 months. Subtotal occlusion or recanalization is common and often necessitates further attempts at placing coils. Follow-up angiography is continued about every 6 months until the aneurysm appears completely and stably occluded. For those receiving surgery, a postoperative angiogram is recommended because incomplete occlusion may occur, necessitating further treatment or closer follow-up. If an aneurysm is completely occluded by surgical clipping on a postoperative angiogram, we generally do not perform further angiography or other vascular imaging during follow-up. For those not treated invasively, we generally recommend either computed tomographic (CT) angiography or magnetic resonance angiography 1 year after first diagnosis. If the aneurysm is stable in appearance, the duration between images can be rapidly increased (e.g., year 3, year 6, year 12). Since the literature suggests that most aneurysms expand suddenly before rupturing, the usefulness of follow-up imaging, beyond reassurance of the patient and physician, is questionable. Regardless of how the aneurysm is treated, we recommend secondary prevention through reduction of risk factors. This includes smoking cessation counseling and careful control of blood pressure. We do not recommend cessation of strenuous exercise or straining.
Ruptured Aneurysms Subarachnoid hemorrhage from ruptured aneurysms is devastating, with 50% mortality and 30% major morbidity. Much of the mortality is due to the initial hemorrhage and its resultant elevation in intracranial pressure. Management can be divided into acute stabilization, treatment of the aneurysm to prevent another rupture, and treatment of complications. An acute head CT scan confirms the diagnosis in most patients and identifies whether hydrocephalus is present, which should be treated by placement of an extraventricular drain. If there is no hydrocephalus or once it is treated with drainage, we generally lower the blood pressure (but maintain a cerebral perfusion pressure of at least 70 mm Hg) in an attempt to reduce risk of rehemorrhage. To reduce the risk of symptomatic vasospasm, we immediately initiate nimodipine 60 mg every 4 hours in all patients. Patients are lightly sedated, and any early complications, such as seizures or aspiration pneumonia, are treated. Patients with any intraparenchymal blood are treated with phenytoin (17 mg/kg load followed by 100 mg every 8 hours) as prophylaxis at least until 24 hours after the aneurysm is treated, and those presenting with seizures are continued on anticonvulsants at least for the duration of the acute hospitalization.
Cerebrovascular Disease
multidisciplinary care, so transfer should be considered if local expertise is limited.
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FIGURE 1. Treatment algorithm for unruptured intracranial aneurysms. This simplistic flowchart undervalues important characteristics that are likely to influence treatment decisions, including characteristics of the aneurysm other than size, patient age, the presence of symptoms from the aneurysm, and overall patient preference. Rigid application of this algorithm would be inappropriate. Treatment decisions are complex and require input from the patient and a multidisciplinary team. SAH, Subarachnoid hemorrhage; PCom, posterior communicating artery; Post Circ, posterior circulation.
Unruptured intracranial aneurysm
No
2 wk
FIGURE 1. Electrophysiologic assessment of peripheral nerve injuries. NCS, Nerve conduction studies; EMG, electromyography; MUP, motor unit potential.
Neurapraxia Axonotmesis Neurotmesis
Response present distally
MUP’s in muscles distal to lesion
Stimulate proximal to lesion
No response distally
EMG
NCS
sympathetic or sensory loss
Traction/stretch/contusion
Laceration/severe traction Complete sensory and motor loss distally
Electrophysiology Johnson: Current Therapy in Neurologic Disease (7/E)
Variable loss of motor, sensory, and sympathetic function
Trauma
of the affected nerve. Following complete distal peripheral nerve injury, a small area of total anesthesia is generally surrounded by areas of either hypesthesia or increased sensitivity, the latter representing a zone of overlap between the injured and adjacent intact nerves. Because of overlap, the sensory loss is rarely as extensive as is expected from the anatomic distribution of the injured nerve. If the lesion is distal to the dorsal root ganglia (DRG), the sensory axon is disconnected from the cell body in the DRG and will undergo wallerian degeneration; sensory NCSs reveal reduction of sensory nerve action potential (SNAP) amplitudes. Loss of SNAP amplitude lags behind reductions in motor amplitudes by 2 or 3 days. Conversely, if the lesion is proximal to the DRG (i.e., at the root level), the axon remains connected to the cell body, no wallerian degeneration takes place in sensory fibers, and SNAP will be normal. Sensory NCSs, therefore, help the physician to discriminate between a root lesion and a more distal lesion (see Table 1).
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Similarly, the severity of injury may vary across fascicles in an injured nerve.
Time Elapsed Since Nerve Injury Nerve conduction and EMG findings may vary depending on the time from injury. Three time phases can be identified: (1) an acute phase, within the first week of injury; (2) the period 1 to 2 weeks after injury; and (3) the period beyond 2 weeks (see Figure 1). NCS findings may also be influenced by the site of the injury, the distance between the injury site and recording site, and the type of fibers affected. During the first week of injury, sensory and motor NCS in the distal nerve stump remain normal, even with severe nerve injuries. It has been shown that CMAP amplitudes can continue to be recorded for up to 7 days after the injury and sensory amplitudes for up to 10 days. Thus, in the acute phase, NCS cannot distinguish between neurapraxia, axonotmesis, or neurotmesis. However, in the first week of injury, NCS may help establish whether the lesion is complete or incomplete. The nerve is stimulated proximal to the site of the nerve injury and the response is recorded from the nerve or muscle distal to the injury site: if there is a response, the lesion is incomplete; if there is no response, the lesion is complete. Similarly, on needle EMG examination of the innervated muscles distal to the nerve injury, volitional motor units will be absent if the lesion is complete. If any volitional motor units can be recorded, one can assume that the lesion is incomplete. A further advantage of studying nerve conduction in the first week of injury is to establish a baseline value. On serial nerve conductions, if the sensory and motor amplitudes improve or remain unchanged, one can conclude that the lesion is neurapraxic. If amplitudes progressively fall, the conclusion is that wallerian degeneration has begun and the injury is class 2 or worse. During the second phase (1 to 2 weeks), if axonal discontinuity has occurred (injury classes 2 to 5), then NCSs show evidence of axonal loss first in the motor fibers and later in the sensory fibers. Therefore, stimulation of the injured nerve distal to the injury site shows reduced or absent SNAP and/or CMAP responses if the lesion is axonotmetic or neurotmetic but normal responses if the lesion is neurapraxic. Needle EMG may not detect any abnormal spontaneous activity during this phase. The interpretation of volitional MUPs resemble those seen during the first week of injury. During the third phase (≥ 2 weeks after injury), NCS findings resemble those in the second phase, with absent (in complete injuries) or reduced SNAP/CMAP amplitudes (in incomplete injuries in the distal nerve stump). NCS findings become established by the second week, but EMG findings become established just beyond the second week after injury. It is during the third phase that NCS and EMG studies are most reliable in classifying the severity of the lesion, localizing the lesion, and suggesting a prognosis. We therefore recommend waiting 3 weeks after injury before getting an electrophysiologic evaluation. In axonotmesis and
neurotmesis, needle EMG shows abnormal spontaneous activity in the form of fibrillation potentials and positive sharp waves in the denervated muscle fibers. These EMG findings are length dependent, being seen earlier in muscles closer to the lesion than in those farther away from the lesion. As in the earlier two phases, volitional EMG activity either shows no units or a reduced recruitment of motor units, depending on the severity of the lesion.
Mechanism of Injury The mechanism of injury is critical in determining the severity of the injury, its management, and its prognosis. Table 3 shows the common modes of injury for the peripheral nerves most often injured. The mechanisms of injury can be classified as follows: injuries due to laceration; stretch, traction, or contusion; ischemia; and acute compression. NERVE LACERATION Common causes of nerve laceration include from knife wounds, glass, propeller and fan blades, chainsaws, bullets, fractured bones, or surgical instruments. These injuries usually result in neurotmesis and are followed by wallerian degeneration. By their location, many peripheral nerves are particularly vulnerable, but virtually any nerve is susceptible to such injuries. Nerve transsection injuries of this kind are often good candidates for early surgical repair. STRETCH, TRACTION, AND CONTUSION Stretch, traction, and contusion may be associated with fractures, motor vehicle accidents, birth, and bullets. The degree of injury is determined by the magnitude of the insult and the length of time that the deforming force has to inflict its damage. Hence the severity of injury may vary from transient, neurapraxic damage to neurotmesis. Stretch or traction of a mixed nerve results in numbness or paresthesias, with or without weakness. Severe stretch and traction injuries are difficult to treat because the intrafunicular rupture of nerve fibers occurs over considerable lengths (or at multiple locations) of the nerve. Therefore, even if the lesion is in continuity (axonotmesis), regenerating fibers may have difficulty navigating through long lengths of fibrosis to their targets. Nerve injuries associated with closed fractures or dislocations may be missed in the acute setting due to preoccupation with the bone or joint injury that often dominates the clinical picture. IATROGENIC INJURIES Examples of iatrogenic injuries include injection injuries commonly seen in the sciatic nerve at the buttock or in the radial nerve in the lateral upper arm. Generally the patient complains of electric shock-like sensations at the time of the injection. The spinal accessory nerve is at risk during cervical lymph node biopsy or resection in the posterior triangle of the neck. Nerve injuries may also Johnson: Current Therapy in Neurologic Disease (7/E)
TABLE 3 Mechanisms of Nerve Injury for Peripheral Nerves Common Modes of Injury
Facial
Traction/contusion*: temporal bone fractures, blunt trauma, GSW Laceration: stab wounds Iatrogenic: during ear surgery, parotid surgery, acoustic neuroma surgery Iatrogenic: surgery in the posterior triangle of the neck, e.g., lymph node resection, carotid endarterectomy cyst removal Laceration: stab wounds Traction/contusion: blunt injuries Stretch/traction/contusion: MVA, motorcycle accidents, GSW, shoulder fracture/dislocations, contact sports (“stingers” and “burners”), birth injury Laceration: stab wounds Iatrogenic: improper positioning during anesthesia, excessive sternal retraction (cardiac surgery) External compression: prolonged compression during narcotic coma, excessive supraclavicular pressure from weight of heavy backpack Stretch/traction/contusion: traction injuries in falls, MVA, motorcycle accidents, fracture of scapula; intensive exercise such as weightlifting, repair work on ceiling, associated with rotator cuff tear Stretch/traction/contusion: traction injury (accidents), direct blows (contact sports), overuse of shoulder (chopping, weightlifting) Iatrogenic: during surgery—first rib resection, thoracotomy, axillary lymph node resection Stretch/traction/contusion: fracture humerus, crutch use, missile wounds, posterior interosseous nerve—fracture or dislocation of radius (Monteggia fracture) External compression: pressure from head of a sleeping person; tight handcuffs, wristwatches, or plaster casts Laceration: axilla, wrist Iatrogenic: upper arm (tourniquets, injections) Stretch/traction/contusion: fractures or dislocations of shoulder, crutch palsy Iatrogenic: injection injury Stretch/traction/contusion: rarely damaged alone but involved with brachial plexus injuries or axillary nerve after shoulder dislocation; sudden or violent extension of forearm with strenuous exercise; sensory branch injured at the elbow by carrying heavy objects supported at the elbow crease, e.g., strap of a handbag Iatrogenic: venipuncture—sensory branch injured at the elbow Lacerations: upper arm or wrist Stretch/traction/contusion: fracture of humerus, GSW, crutches, tourniquet, rifle sling palsy; anterior interosseous damage by fractures at elbow External compression: pressure from head of a sleeping partner External compression: at axilla, upper arm, elbow, wrist (prolonged bicycle riding), or hand lacerations Stretch/traction/contusion: penetrating injuries, dislocation/fracture of elbow, fractures at wrist or distal radius Iatrogenic: improper position during anesthesia Stretch/traction/contusion: fracture of pelvic girdle, GSW Iatrogenic: hematomas in patients on anticoagulants; during parturition compressed against rim of pelvis by fetal head of forceps Iatrogenic: stretch during lithotomy position for childbirth, or vaginal hysterectomy; other surgical procedures (abdominal hysterectomy, renal transplant, hernia repair, hip arthroplasty, femoral artery cannulation, angioplasty, hip operations) Laceration: stab wounds Stretch/traction/contusion: GSW, hematoma, abscesses, fractures of pelvis or femur External compression: gymnasts and dancers performing hyperextension hip exercises Iatrogenic: injured by the fetal head or forceps during prolonged or difficult labor; during hip replacement Stretch/traction/contusion: blunt sports injuries, car seat belts Iatrogenic: external pressure during anesthesia; during operation for harvesting iliac bone crest graft; lower abdominal surgeries, misplaced injections Stretch/traction/contusion: trauma—pelvic and hip joint fractures or dislocations, GSW Laceration: stab wounds Iatrogenic: hip surgery; arthroscopic surgery, total hip replacement, gluteal injections External compression: coma; prolonged sitting in lotus position, on bicycles Stretch/traction/contusion: closed tibial fracture, trauma at the ankle Laceration: in the popliteal fossa Iatrogenic: pressure during anesthesia, bedridden patients, improper casts External compression: coma, sleep, prolonged squatting; deep peroneal nerve-anterior compartment syndrome; excessive exercise, soft tissue trauma, hemorrhage Laceration: skate blade in hockey players Stretch/traction/contusion: fractures of femur, tibia, or fibula; ankle inversion injury and minor athletic trauma in runners; blunt injury (contact sports)
Spinal accessory
Brachial plexus
Suprascapular Long thoracic Radial
Axillary Musculocutaneous Median
Ulnar
Lumbosacral plexus Femoral
Obturator Lateral cutaneous Sciatic Tibial Peroneal
*
Mechanisms in boldface type represent the most frequently seen modes of injury for that particular nerve. GSW, Gunshot wound; MVA, motor vehicle accident.
Johnson: Current Therapy in Neurologic Disease (7/E)
Trauma
Peripheral Nerve
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occur during surgical procedures owing to the patient being in the same position for prolonged periods, from retractors used during surgery, from tight plaster casts, and so on. Iatrogenic injuries need to be recognized and dealt with in a timely and professional manner. ISCHEMIA AND ACUTE COMPRESSION Tourniquets or a surgical patient’s maintenance of a constant position can compress nerves; however, damage generally results from mechanical distortion rather than from ischemia per se. Mild compression leads to paranodal or segmental demyelination (neurapraxic injury); more severe compression for longer periods produces crush, which can also damage the axon. Most palsies associated with focal compression due to anesthesia, coma, drug narcosis, undisturbed sleep of the fatigued, intoxication, or improper application of plaster casts fall into this category. In acute compressive neuropathies, muscle weakness is far more striking than sensory loss. Brachial plexus, radial, ulnar, sciatic, and peroneal nerves are particularly vulnerable. The prognosis is good for compressive injuries; most compression injuries are managed nonoperatively. Compartment syndromes occur when the pressure within a confined space increases such that compression or ischemic injury results. The anterior compartment of the lower leg is a common site of involvement and can lead to peroneal nerve palsy. Compartment syndromes are often missed until irreversible damage has occurred. Diagnosis rests with clinical examination and measurement of pressures. Early fasciotomy is indicated to prevent progressive wallerian degeneration in compartment syndrome. OTHER MODES OF INJURY Other modes of injury include thermal, electrical, and irradiation injuries. In patients with severe thirddegree burns, long lengths of nerve are often involved,
which necessitates nerve grafts or tendon transfers. Concomitant damage to soft tissues and muscles worsens the prognosis. Electrical injury, like thermal injury, may involve long nerve segments with extensive damage, resulting in a poor prognosis. Irradiation injuries in the brachial or lumbosacral plexus need to be distinguished from direct neoplastic infiltration. Imaging and electrophysiologic studies are often helpful. EMG may show myokymic discharges specific for radiation-induced injuries. The upper brachial plexus is more likely to be affected by irradiation, whereas the lower brachial plexus is more commonly infiltrated or compressed by cancer.
Therapy Management of a nerve lesion requires precise localization of the injury, confirmation of time interval since injury, and definition of the nature and severity of the injury. Surgical procedures for nerve injuries are presented in Table 4. We recommend the stepwise approach to management shown in Figure 2 and discussed in the following sections. COMPLETE VERSUS INCOMPLETE INJURIES If the clinical and electrophysiologic examinations suggest a complete injury, and if the mechanism of injury is known to be a sharp laceration, then surgical repair should be considered within 24 hours. An endto-end suture is the traditional method of choice for repairing a transected nerve. Recently we have begun to use fibrin glue as a substitute for epineural sutures. Fibrin glue shortens the duration of the procedure and produces less intraneural scar than do nerve sutures. At follow-up visits, the physician evaluates for evidence of nerve regeneration. Tinel’s sign should progress
TABLE 4 Peripheral Nerve Surgical Procedures Procedure
Description
External neurolysis Internal neurolysis End-to-end repair Nerve grafts
Dissection of nerve free from the surrounding and investing tissues, including scar; required prior to all peripheral nerve procedures Separation of the nerve into its individual fascicles; performed when injury is more severe to one portion of the nerve than to others; may be followed by split repair Generally performed to coapt nerves that have been transected or for lesions in continuity that are relatively short Use of healthy nerve to bridge the gap between a distal nerve stump and proximal stump of the injured nerve or a donor nerve; required for relatively long lesions in continuity Joining together of two parts of a divided nerve; includes end-to-end repair, and nerve grafts Regeneration of axons into tissues such as a distal nerve stump or a motor end plate; may occur spontaneously or result from end-to-end repair, nerve grafting, or nerve transfer Use of proximal healthy nerves (“donor nerves”) to reinnervate distal stump of injured nerve Repair of select fascicles after internal neurolysis Some injuries result in a painful neuroma; treatment involves resection of the neuroma and relocation of the proximal nerve stump away from scar tissue to location where it will be protected from mechanical stimulation (in muscle or bone)
Neurorrhaphy Neurotization Nerve transfer Split repair Resection of neuroma
Johnson: Current Therapy in Neurologic Disease (7/E)
Peripheral Nerve Injury
Trauma
FIGURE 2. Algorithm for the management of peripheral nerve injuries. NCS, Nerve conduction studies; EMG, electromyography; MUP, motor unit potential.
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Peripheral nerve injury
Complete No sensory or motor function No motor units in muscles
Laceration or open injury (neurotmesis)
Closed injury (neurapraxia or neurotmesis)
Neurorrhaphy as soon as possible
NCS and EMG at 3 wk
Incomplete
Mixed (fascicular injury)
NCS and EMG at 3 wk
NCS and EMG at 3 wk
Neurapraxia
Axonotmesis
MUPs in all innervated muscles
MUPs absent in some innervated muscles
Follow at 1 mo intervals
Follow monthly for 3 mo
Follow at 1 mo intervals
Follow at 1 mo intervals
10 Spontaneous recovery
No evidence of recovery of function distally
Spontaneous recovery
Surgery: Neurorrhaphy or neurolysis
distally at the expected rate of 1 inch of regeneration per month. Early evidence of reinnervation can be seen by EMG changes in muscles closest to the nerve repair site. Distal progression of muscle reinnervation should mirror that of Tinel’s progression at about 1 inch per month. For complete injuries caused by contusion, stretch, traction, or compression, we suggest waiting 3 weeks and then performing NCSs to determine whether the lesion is neurapraxic or axonotmetic. Lack of muscle denervation with loss of muscle power indicates a neurapraxic injury. Approximately 80% of closed injuries recover spontaneously because these lesions are in continuity. If neurapraxic, a return of function can be expected provided care is taken to ensure that no ongoing compressive injury is occurring. Axonotmetic injuries should be followed at 1- to 3-month intervals. An advancing Tinel’s sign in the distribution of the injured nerve indicates that the nerve is in continuity and justifies postponement of surgery. Lack of advancing Tinel’s sign or failure of muscle to show EMG evidence of reinnervation at the expected time course suggests neurotmetic injury and need for surgical exploration. Johnson: Current Therapy in Neurologic Disease (7/E)
No progress
Spontaneous recovery
Surgery: Neurorrhaphy or neurolysis
TIMING OF SURGERY The stepwise approach just described is useful when the physician sees a patient immediately after the patient has been injured, but this approach must be altered if the physician first sees the patient weeks or months after the injury. As mentioned, for clean lacerations of nerve, end-to-end nerve suturing or gluing should be performed as soon as local conditions are judged favorable for repair. Delays within the first few months of injury may necessitate nerve grafts that offer less chance of success. The chances of a successful recovery of motor function decline after 6 months, although severed axons retain their capacity to sprout for several years. The critical period for muscle reinnervation is about 18 to 24 months. Beyond this period, denervated muscles atrophy irreversibly and are replaced by connective tissue. After 18 to 24 months, tendon transfers are the preferred treatment for nerve injuries. No such time limits exist for the restoration of sensory function. INTRAOPERATIVE MONITORING Intraoperative electrophysiologic techniques have proved especially useful in the management of closed
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nerve injuries. Axonal continuity is established by the technique of intraoperative stimulation and recording across the area on injury. If compound nerve action potentials are present, external neurolysis is performed. If action potentials are absent, an internal neurolysis is then performed in the nonconducting region of the nerve. A neuroma in continuity is often identified. The nerve is then resected both proximal and distal until a healthy fascicular anatomy is identified. The gap is spanned by application of nerve cable grafts. When there is a question of nerve root avulsion, the use of proximal recordings can be of value. A stimulating electrode is placed on the nerve in question followed by an attempt at recording an averaged somatosensory potential from the contralateral cerebral hemisphere. Because of confounding issues such as level or type of anesthetic being employed, it is best to have access to a control nerve to ensure the system is functioning.
Complications after Injury PAIN A patient may develop pain after nerve injury due to several different mechanisms. COMPLEX REGIONAL PAIN SYNDROME Partial nerve injury may lead to the development of complex regional pain syndrome (CRPS) previously referred to as reflex sympathetic dystrophy. The pain is usually burning in quality (causalgia) and disproportionately severe with respect to the extent of injury. The pain often persists well after the injury has been presumed to have healed. If not treated early and aggressively, the pain often expands outside of the boundaries of the area of injured tissue. Allodynia to light touch and cooling are common symptoms. The skin may be warm and red or cold and cyanotic. Over time, the skin may have a smooth, glossy appearance with loss of skin folds and wrinkles. Excessive sweating is common. Decreased range of motion due to swelling and pain may eventually lead to permanent joint stiffness and contractures. Muscle wasting, osteoporosis, and tapering of the distal digits may occur in severe cases. Sympathetic block or sympathectomy in combination with physical therapy often relieves these symptoms (see Chapter 17). DENERVATION AND REGENERATION PAIN During the acute phase of nerve injury, patients may experience pain due to muscle denervation, joint stiffness, and/or contracture formation. The use of analgesics, awareness of the possibility of contracture, and the avoidance of prolonged immobilization are usually all that are necessary to manage these pains. As the nerve regenerates, paresthesias or dysesthesias may travel in the direction of regeneration. If such symptoms are bothersome, tricyclic antidepressants and anticonvulsants (gabapentin [Neurontin], pregabalin)
are helpful. Fortunately, regeneration pain is often self-limited and ceases once reinnervation is complete. NEUROPATHIC PAIN Severe pain may arise in the distribution of the injured nerve. Patients may experience spontaneous shooting electrical pains or hypersensitivity to stimulation of the skin in the distribution of the injured nerve. First-line therapy consists of anticonvulsants, tricyclic antidepressants, and strong analgesics. If the pain is refractory to pharmacologic treatment, surgical repair may be needed. AVULSION PAIN Avulsion of nerve roots may lead to the development of severe pain in the distribution of the injured nerve root. The pain is described as constant burning or crushing pain with paroxysmal burning or shooting pain. The unpredictable nature of the shooting pains often adds much distress. Nonoperative treatment consisting of extensive physical rehabilitation and polypharmacy is often required. The natural history of the avulsion pain is that about one half of patients are pain free or able to cope with their pain within 1 year, and most are pain free within 3 years. Unfortunately, avulsion-related pain can become exceedingly severe and bring a patient to suicide. Refractory pain can be managed by making a series of lesions at the dorsal root entry zone of the traumatized spinal cord (DREZ procedure). PAINFUL NEUROMAS When an axon is severed, the proximal end will form sprouts that attempt to grow down the distal endoneurial tube. If the forward progress of regenerating sprouts is blocked, they form a tangled mass of nerve fiber and connective tissue, a neuroma. A small proportion of these become pain generators. If medication management fails, surgical resection is performed with placing the proximal end away from sources of trauma. BONES, JOINTS, AND CONTRACTURES A nerve injury, even when uncomplicated by extensive soft tissue damage or wound infection, may be followed by changes in the bones, joints, and tendon sheaths of the affected limb. Changes are most common at and below the wrist and ankle. In adult bones, osteoporosis sets in; in growing bones, bone growth may be altered. In either case, arthritic changes, joint stiffness, or deformity may follow. Maintaining range of motion of joints, muscles, and tendons is of utmost importance. Patients should be educated as to the passive and active range of motion of the paralyzed joint. While awaiting nerve recovery and muscle activity, the patient must be engaged in an aggressive stretching program. Splints and other mechanical appliances in addition to physical and occupational therapy can be used to help with maintenance of musculoskeletal integrity. Johnson: Current Therapy in Neurologic Disease (7/E)
Peripheral Nerve Injury
Loss of protective sensation increases the risk for tissue damage due to burn or noxious chemicals. Trophic changes are uncommon unless the injury is severe. Injuries occurring in the median, ulnar, sciatic, and particularly the tibial component are the most likely to give rise to trophic changes. They are confined to the hand or foot and, in particular, to the digits. If the injury is complete, the skin becomes cold and cyanotic, the digital pads become atrophic and deformed, and the nails become brittle. If the injury is partial and irritative, causalgia and severe vasomotor disturbances add to the trophic changes. Treatment should aim to avoid recurrent trauma to insensate structures.
develop depression, which may magnify their degree of suffering. Care must be taken to identify psychological symptoms and obtain appropriate mental health consultations.
Trauma
SKIN AND SUBCUTANEOUS TISSUE
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SUGGESTED READING Aids to the examination of the peripheral nervous system, London, 1986, Bailliere Tindall. Chaudhry V, Glass JD, Griffin JW: Wallerian degeneration in peripheral nerve disease, Neurol Clin 10:613-627, 1992. Kline DG, Hudson AR: Nerve injuries: operative results for major nerve injuries, entrapments, and tumors, Philadelphia, 1995, WB Saunders. Sunderland S: Nerve injuries and their repair, New York, 1991, Churchill Livingstone.
DEPRESSION Loss of function, pain, or the slow process of recovery may be quite distressing for patients. Many patients
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SECTION 11 ●
Neoplastic Disease Childhood Brain Tumors Kaleb Yohay, M.D., and Kenneth Cohen, M.D., M.B.A.
Brain tumors are the most common solid malignancy of childhood, with an annual incidence of approximately 3.9 cases per 100,000 person-years according to data from the Central Brain Tumor Registry of the United States (CBTRUS). Each year, approximately 3000 children within the United States are newly diagnosed with a primary brain tumor. Though improvements in diagnosis and treatment have resulted in overall improvement in survival, morbidity and mortality remain high. The overall survival rate at 5 years following diagnosis for children with a primary malignant brain tumor is approximately 63%. Brain tumors in children differ from those in adults in several key ways. Tumors are more likely to be infratentorial in location (see Table 1 for types of tumors based on location). Brain tumors in children are much more varied in terms of histopathologic type and grade resulting in more diverse treatment regimens and outcome. Central nervous system (CNS) dissemination is common. Treatments for tumors in children must be significantly modified according to age to minimize the long-term impact these therapies can have on the developing nervous system.
General Principles The treatment of brain tumors in children relies on a combination of surgery, chemotherapy, and radiation therapy. For most brain tumors, surgical resection is the mainstay of therapy. Surgery alone can be curative for selected tumor types when gross total resection (GTR) is achieved. Surgery enables histologic diagnosis and symptomatic control. Surgical debulking of a tumor may improve efficacy of chemotherapy or radiation therapy. Improvements in surgical techniques and technology including intraoperative neuroimaging, frameless Johnson: Current Therapy in Neurologic Disease (7/E)
stereotaxy, and endoscopy have improved extent of resection and reduced surgical morbidity though infection, hemorrhage, and neurologic dysfunction remain significant. In many instances, surgical resection is limited by anatomy or extent of disease. Surgery cannot be used to eliminate or treat invasive disease that may have expanded beyond the visible borders of a tumor or in the setting of disseminated disease. Radiation therapy can be used to treat macroscopic tumor and/or local or disseminated microscopic tumor. It frequently follows attempted surgical resection of the primary tumor. The use of conformal field radiation allows the delivery of higher doses of radiation to the target area while limiting exposure of adjacent structures and other organs. Despite improvements, the side effects of radiation therapy can be severe, particularly in the youngest of children. Chemotherapy can also be useful in the treatment of some brain tumors. It is used almost always in conjunction with surgery, radiation, or both. Chemotherapy can be useful in treating primary and disseminated disease. It can be used to help delay radiation therapy or reduce the total radiation dosage needed and in some instances can be used prior to definitive surgery to facilitate surgical resection. Chemotherapeutic agents carry the risk of significant side effects including immunosuppression, mucositis, increased risk of secondary malignancy, cognitive changes, neuropathy, and seizures. New therapies and modes of delivery for brain tumors are being explored, including gene therapies, other molecular techniques, and localized administration of radioactive, chemotherapeutic, or biologic agents. Corticosteroids are useful in decreasing peritumoral edema and can quickly and effectively reduce symptoms related to swelling. We typically use dexamethasone 1 to 2 mg every 4 to 6 hours or a total daily dose of 1 to 1.5 mg/kg to a maximum of 32 mg/day. The use of corticosteroids should be considered in any patient with symptomatic edema and also may be used in many patients for several days preceding planned surgical resection. Common side effects of corticosteroids include gastrointestinal bleeding (generally requiring the use of an acid-reducing agent), hypertension, hyperglycemia, and behavioral changes. In addition, steroids can have the unintended effect of decreasing the permeability of the blood-brain barrier, theoretically reducing the efficacy of chemotherapy. 255
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TABLE 1 Differential Diagnosis by Tumor Location Location
Tumor Type
Hemispheric
Astrocytoma PXA PNET Ependymoma Ganglioglioma Oligodendroglioma DNT DIG AT/RT Meningioma Craniopharyngioma Pituitary adenoma Germinoma Astrocytoma NGGCTs Pineocytoma Pineoblastoma Germinoma NGGCTs AT/RT Pineal cyst Choroid plexus papilloma Choroid plexus carcinoma SEGA Astrocytoma Meningioma PNET Colloid cyst Ependymoma Oligodendroglioma Pilocytic astrocytoma Medulloblastoma Ependymoma Diffuse pontine glioma Vestibular schwannoma AT/RT
Sellar/suprasellar
Pineal region
Intraventricular/periventricular
Infratentorial (brainstem, cerebellum, and cerebellopontine angle)
PXA, Pleomorphic xanthoastrocytoma; PNET, primitive neuroectodermal tumor; DNT, dysembryoplastic neuroepithelial tumor; DIG, desmoplastic infantile ganglioglioma; AT/RT, atypical teratoid/rhabdoid tumor; NGGCTs, nongerminomatous germ cell tumors; SEGA, subependymal giant cell astrocytoma.
Seizures are a common complication of brain tumors in children. Seizures associated with tumors are most likely to be partial in onset, with or without secondary generalization. Despite the high incidence of seizures in patients with brain tumors, particularly supratentorial tumors, the benefit of the use of anticonvulsants for the prevention of a first seizure is uncertain. Some studies in adults have shown some benefit of short-term perioperative use of antiepileptic drugs, whereas others have not. In a child with a brain tumor and seizures, several factors must be taken into account in choosing the appropriate anticonvulsant, including the age of the patient, the type of seizure, the rapidity with which seizure control must be obtained, the route of administration, and potential interactions with chemotherapeutic
agents and other medications. Some of the newer anticonvulsants can provide excellent seizure control with fewer drug interactions. In particular, for long-term seizure control we frequently use levetiracetam at a starting dose of 10 mg/kg/day divided twice-daily, increasing by about 10 mg/kg per week to a goal of 40 mg/kg/day. Levetiracetam offers several advantages including excellent tolerability, no drug-drug interactions, and a broad spectrum of seizure control. For acute seizure control, drugs that allow rapid loading such as fosphenytoin, valproic acid, and phenobarbital may be necessary. The duration of anticonvulsant therapy must be individually tailored to the patient’s circumstances. We generally continue antiepileptic therapy in patients with known seizures for at least a 2-year seizure-free interval after surgical resection, though there are no specific data to suggest the most efficacious duration of therapy. Tumors are frequently associated with signs and symptoms of raised intracranial pressure. This occurs as a result of direct mass effect, peritumoral edema, or ventricular obstruction and hydrocephalus. For a discussion on the management of increased intracranial pressure, see Brain Metastases chapter. Therapies for specific tumors vary from institution to institution and trial to trial. Most children in the United States being treated for cancer are treated on cooperative group, multi-institutional, or single-institution studies. As such, treatment regimens are constantly changing, especially with regard to radiation therapy or chemotherapy dosing and/or specific therapeutic agents used.
Specific Therapies PILOCYTIC ASTROCYTOMAS/LOW-GRADE FIBRILLARY ASTROCYTOMAS Astrocytomas make up approximately one third of brain tumors in childhood. Unlike adults, low-grade astrocytomas, including pilocytic and fibrillary astrocytomas (World Health Organization [WHO] grades 1 and 2), predominate. Pilocytic astrocytomas make up about 10% of supratentorial astrocytomas and 85% of cerebellar astrocytomas. Pilocytic astrocytomas can occur throughout the neuraxis but have particular predilection for the cerebellum, cerebral hemispheres, thalamus and basal ganglia, the optic pathway (including the chiasm and hypothalamic region), and brainstem (dorsal exophytic brainstem glioma). Tumors with features of a low-grade astrocytoma on neuroimaging may potentially be followed expectantly on serial scans without resorting to surgical intervention, particularly if resection would carry a high risk of morbidity because of the tumor’s location. Magnetic resonance (MR) spectroscopy sometimes can be helpful in distinguishing between low- and high-grade neoplastic processes. For low-grade astrocytomas that show progression on serial imaging or that cause symptoms that cannot be effectively managed medically, surgery is the mainstay of therapy. For low-grade astrocytomas in locations conducive to GTR, outcomes are excellent with greater than 90% long-term progression-free survival. Johnson: Current Therapy in Neurologic Disease (7/E)
Childhood Brain Tumors
ANAPLASTIC ASTROCYTOMAS/ GLIOBLASTOMA MULTIFORME High-grade astrocytomas (WHO grades 3 and 4) are less common in children. Treatments to date have been disappointing in providing cure or significant survival benefit
to most of these children. Because of the infiltrative nature of the tumors, GTR is uncommon. Maximal surgical resection does provide some survival benefit, particularly for patients with anaplastic astrocytomas. Adjunctive therapy with radiation therapy and/ or chemotherapy may provide some additional modest improvement. Other treatment modalities are being explored, including interstitial brachytherapy with radioisotope seeds implanted into the tumor bed, highdose chemotherapy with autologous stem cell rescue, radiosensitizers, localized administration of chemotherapeutic agents in implanted polymers, and various gene and molecular therapies. BRAINSTEM GLIOMAS Brainstem tumors are relatively common in children, making up 10% to 25% of all childhood brain tumors. There are distinct subtypes of brainstem tumors with widely divergent natural histories, prognoses, and treatments. They are characterized by their location (medullary, pontine, midbrain, tectal), whether they are diffuse or focal, and whether they are intrinsic or exophytic. The most common brainstem tumor is the diffuse intrinsic pontine glioma. These tumors typically present with a fairly brief clinical history, with weakness, gait problems, and cranial nerve findings. They most commonly occur in children aged 6 to 10 years. Histologically, these tumors are fibrillary astrocytomas. Diffuse pontine gliomas respond poorly to treatment and survival is usually less than 18 months. Biopsy is not necessary if the clinical course and neuroimaging are consistent with a diffuse pontine glioma. Treatment is palliative with focal radiation therapy with or without chemotherapy.
FIGURE 1. Treatment algorithm for astrocytomas. WHO, World Health Organization; GBM, glioblastoma multiforme; XRT, radiation therapy.
Astrocytomas
Pilocytic astrocytoma (WHO 1)
Fibrillary astrocytoma (WHO 2)
Anaplastic astrocytoma GBM (WHO 3–4) Best resection Chemoradiotherapy + adjuvant chemotherapy
Surgical resection if feasible
Consider observation with interval scans
Surgical resection
Observation with interval scans
If progression
Observation with interval scans
If progression consider chemotherapy vs. XRT
Johnson: Current Therapy in Neurologic Disease (7/E)
Neoplastic Disease
Subtotal resection can be useful in reducing symptoms and prolonging survival, but the incidence of progression is variable. Chemotherapy is commonly used in instances of recurrence, followed by radiation therapy if necessary. For tumors in locations that make resection impossible without significant morbidity, such as the optic pathways, thalamus, or hypothalamus, radiation therapy or chemotherapy may be used as the primary mode of treatment. Stereotactic radiosurgery may also prove to be an effective treatment for some unresectable tumors or tumor recurrences (Figure 1). Optic pathway gliomas are low-grade astrocytomas originating within the optic nerves, chiasm, or optic radiations. These tumors have a variable natural history ranging from no progression to aggressive progression or occasionally regression. Patients with optic pathway glioma and neurofibromatosis (NF)-1 tend to have a more benign course. Generally, conservative management with serial neuroimaging and ophthalmologic examination is preferred. However, surgery is considered in instances of significant proptosis or visual loss and particularly in unilateral tumors located anterior to the optic chiasm. Chemotherapy has been shown to be effective and is commonly used in symptomatic patients younger than 5 years of age, in whom radiation therapy would carry a high risk of associated morbidities. Radiation therapy is more commonly used in older children who have had a partial resection or progression after surgery and/or chemotherapy.
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If progression consider chemotherapy vs. XRT
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Dorsally exophytic and focal brainstem tumors tend to be pilocytic astrocytomas and to respond well to surgical resection when technically feasible. Adjunctive chemotherapy or radiation therapy is generally reserved for recurrent or progressive disease.
adjuvant chemotherapy. Chemotherapeutic regimens have included standard agents such as cisplatin, etoposide, vincristine, and cyclophosphamide (or other oxazaphosphorines) in various combinations. Salvage therapy is generally palliative in nature.
EPENDYMOMAS
MEDULLOBLASTOMA
Ependymomas make up about 10% of childhood brain tumors. About two thirds of ependymomas are infratentorial. Ependymomas have a propensity for seeding the neuraxis, with reports of metastatic rates ranging from 5% to 20%. Evaluation should include MR imaging of the entire neuraxis and cerebrospinal fluid (CSF) cytopathology. Infratentorial ependymomas are typically located in association with the ventricular system, whereas supratentorial ependymomas tend to be located within the parenchyma. The peak incidence in children is around 4 to 5 years of age with a moderate male predominance. Maximal surgical resection is critical to the outcome for patients with ependymoma. Survival rates for patients after GTR range from 50% to 70% and less than 40% after subtotal resection. For supratentorial tumors with nonanaplastic pathology that are resectable with a wide margin and with no evidence of metastatic disease, adjuvant therapy may not be necessary (Figure 2). Adjuvant radiation therapy is used for all infratentorial tumors, for subtotally resected supratentorial tumors, for those with anaplastic histology, or in the setting of neuraxis dissemination. In young children where the morbidity from radiation therapy is high, radiation dose may be modified or even be deferred with the use of
Medulloblastomas make up about 20% of all CNS tumors in children. The peak incidence is in children 5 to 9 years of age, with 70% diagnosed prior to the age of 20. Three fourths of medulloblastomas arise within the midline of the cerebellum; the remainder arise in the cerebellar hemispheres. Patients typically present with signs of raised intracranial pressure, ataxia, and cranial nerve deficits. Medulloblastomas have a propensity for seeding the CNS, which impacts prognosis and treatment, so complete CNS imaging with contrast-enhanced MR scanning should be part of the initial evaluation. Cytologic examination of the CSF should be performed preoperatively or 10 to 21 days following surgery. Treatment consists of surgical resection, chemotherapy, and local and craniospinal radiation (Figure 3). The goal of surgery is maximal resection without causing severe neurologic sequelae. GTR is associated with better outcomes. For treatment stratification, patients are divided into standard-risk or high-risk patients based on the extent of resection and presence or absence of neuraxis dissemination. Increasingly, a variety of other risk factors have been identified including histologic subtypes (e.g., large cell, anaplastic variants) and molecular markers (e.g., c-Myc or Trk-C expression). The extent
Ependymoma
Supratentorial GTR
Infratentorial M+ disease
Infratentorial M0 disease
Nonanaplastic histology
Anaplastic histology
GTR
STR
Observation
Focal irradiation
Focal XRT to region of tumor only
Neoadjuvant chemotherapy
FIGURE 2. Treatment algorithm for ependymoma. GTR, Gross total resection; STR, subtotal resection; M0, localized disease; M+, neuraxis dissemination or metastases; CSI, craniospinal irradiation; XRT, radiation therapy.
Consider CSI Adjuvant chemotherapy
Second look surgery for attempted GTR
Focal XRT to region of tumor only
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Childhood Brain Tumors
Medulloblastoma
Standard risk: GTR(40 years), the usefulness of additional testing depends on the type of dystonia. Aside from brain MR imaging, extensive testing is rarely revealing for the primary focal dystonias, such as blepharospasm, cervical dystonia, or writer’s cramp. Additional testing is also of limited value when the clinical evaluation suggests that dystonia is part of a neurodegenerative syndrome such as corticobasal degeneration or progressive supranuclear palsy. Virtually all inherited developmental disorders may rarely present in adulthood. However, the yield for testing for most of these is very low and generally not necessary, unless the clinical features or family history point in a specific direction. Additional tests are therefore warranted only when the clinical evaluation suggests the dystonia might be related to some other identifiable process. For younger patients (
